Medicinal Chemistry Conference (MedChem-2017)
Book of Abstracts
27-28th November 2017
Venue: IC & SR Main Auditorium
Organized by
Department of Chemistry Indian Institute of Technology Madras Chennai – 600036
Message from the Conveners
On behalf of the organizing committee and the Department of Chemistry IIT Madras, it is our pleasure to warmly welcome you to MedChem-2017. This is the fifth conference in the series that started in 2009 as biannual event and is part of our activities related to IITM-AztraZeneca Endowment Program for promoting education and research in the area of Medicinal Chemistry. The first conference on Current Trends in Medicinal Chemistry (then) was held in 2009. Then on, each conference had focus on specific therapeutic areas, like, Infection, Cancer and Diabetics.
This year, MedChem-2017 is being organized with a focus on “Emerging Medicinal Chemistry Approaches against Neuropsychiatric and Neurodegenerative Diseases”. Considering the growing threat from Neurodegenerative Diseases that our population is exposed to, concerted drug development efforts through collaborative research need to be strengthened. An event like this would be an ideal platform to discuss the strategies ahead.
We are fortunate to have fourteen eminent scientists actively working on various aspects related to the theme of the conference, which include diagnosis, structure-based drug design, as well as pharmacokinetic- and pharmacodynamics, as speakers at this conference. There will be a poster session on the first day, which primarily brings research results in Neurodegenerative Diseases and related areas as well as those from the general area of medicinal chemistry. We are sure that the lectures and poster sessions will be enlightening and this event will add two memorable days to our research life.
Dr. Anbarasan P. Dr. Md. Mahiuddin Baidya
Patron Chairperson Conveners
Prof. Bhaskar Ramamurthy Prof. Indrapal Singh Aidhen Dr. Anbarasan P. Director, IIT Madras Head, Department of Dr. Md. Mahiuddin Baidya Chemistry, IIT Madras
Treasurer
Dr. M. Jeganmohan
Organizing Committee
Dr. Arnab Rit
Dr. Beeraiah Baire
Dr. Debashis Chakraborty
Dr. Kartik Chandra Mondal
Dr. Kothandaraman Ramanujam
Dr. Sundarghopal Ghosh
Dr. Venkatakrishnan P.
Scientific Advisory Committee
Dr. Krishnamoorthy Srinivas, Chairman-Emeritus, Institute of Neurological Sciences, VHS, Chennai.
Dr. Ram Vishwakarma, Director, IIIM, Jammu.
Prof Javed Iqbal, Chairman, Cosmic Therapeutics, Hyderabad.
Dr. Ahmed Kamal, Director, NIPER Hyderabad.
Dr. Anders Johansson, AstraZeneca Gothenburg, Sweden.
Dr. B. Gopalan, Orchid Pharma, Chennai.
Prof. K. K. Balasubramanian, Emeritus Professor, IIT Madras.
Prof. D. Karunagaran, Dept. of Biotechnology, IIT Madras.
Prof. Amal Kanti Bera, Dept. of Biotechnology, IIT Madras.
Prof. S. Sankararaman, Dept. of Chemistry, IIT Madras.
Prof. Indrapal Singh Aidhen, Dept. of Chemistry, IIT Madras.
Dr. K. M. Muraleedharan, Dept. of Chemistry, IIT Madras.
Programme
MedChem 2017: Programme schedule
Monday, November 27, 2017 08:00 – 09:00 Registration
09:00 – 09:35 Inauguration
SESSION I
Chairperson: Prof. Indrapal Singh Aidhen
09:35 – 10:20 Plenary Lecture - Dr. Roland Burli, Medicinal Chemistry Neuroscience IMED Astrazeneca, Cambridge
10:20 – 10:35 Tea break
SESSION II
Chairperson: Prof. Mukesh Doble
10:35 – 11:05 Invited Lecture - Dr. E. S. Krishnamoorthy, Neurokrish Consulting Pvt. Ltd
11:05 – 11:35 Invited Lecture - Dr. P. Srihari, CSIR-IICT, Hyderabad
11:35 – 12:05 Invited Lecture - Dr. K. P. Mohanakumar, IUCBMR, Kottayam
12:05 – 12:35 Invited Lecture - Dr. Prem N. Yadav, CSIR-CDRI, Lucknow
12:35 – 14:00 Lunch
SESSION III
Chairperson: Prof. G. Sekar
14:00 –14:30 Invited Lecture - Dr. Rishikesh V. Behere, KEM Hospital Research Center, Pune
14:30 –15:00 Invited Lecture - Dr. D. Srinivasa Reddy, CSIR-NCL, Pune
15:00 – 16:15 Tea break and Poster Presentation
SESSION III Chairperson: Prof. G. Sekar
16:15 – 16:45 Invited Lecture - Prof. Vidita Vaidya, TIFR, Mumbai
16:45 – 17:15 Invited Lecture - Prof. Pravat K. Mandal, NBRC, Manesar
17:15 – 17:45 Concluding Remarks for the Day
19:30 – 21:00 Dinner
Tuesday, November 28, 2017
SESSION I
Chairperson: Prof. S. Sankararaman
09:00 – 9:30 Invited Lecture - Prof. Akshay Anand, PIMER, Chandigarh
09:30 – 10:00 Invited Lecture - Prof. Sandeep Verma, Department of Chemistry, IIT Kanpur
10:00 – 10:30 Invited Lecture - Prof. Nihar Ranjan Jana, NBRC, Manesar
10:30 – 10:45 Tea break
SESSION II
Chairperson: Prof. K. M. Muraleedharan
10:45 – 11:15 Invited Lecture - Prof. Amal Kanti Bera, IIT Madras, Chennai
11:15 – 11:45 Invited Lecture - Prof. Mange Ram Yadav, M.S. University of Baroda, Vadodara
11:45 – 12:15 Concluding Remarks and Valedictory Function
12:15 – 14:00 Lunch
Plenary Lecture (PL)
PL 1 β-Secretase Inhibitors as a Therapy for Alzheimer’s Disease
Roland Bürli AstraZeneca, Cambridge United Kingdom E-mail: [email protected]
Alzheimer’s disease (AD) affects close to 50 million patients and current treatments lead at best to minor improvements of symptoms. Therapeutic approaches acting on the underlying mechanisms of the pathology have the potential to slow down disease progression, thus positively impacting the patient’s quality of life. The AD pathology is characterized by accumulation of amyloid plaques and neurofibrillary tangles which ultimately are thought to be the cause of neuronal loss. The formation of Aβ, plaque-forming peptides, initiates with cleavage of the amyloid-β protein precursor (AβPP) by β-secretase 1 (BACE1). This finding and further genetic evidence has led to a widely recognized hypothesis that inhibition of BACE1 may lead to slowing AD disease progression and has spurred significant efforts in the Industry to develop brain-permeable BACE1 inhibitors.
The active site of BACE1 presents a relatively open and hydrophilic pocket and as a result, it has been challenging to combine the properties required for good brain permeability with high affinity for BACE1. At AstraZeneca, a large effort has culminated in the identification of Ianabecestat (AZD3293), a BACE inhibitor with good brain permeability and potency, which is now being investigated in Phase III clinical trials in collaboration with Eli Lilly. The properties of Ianabecestat and key parameters leading to its discovery will be discussed. Notably, there are two isoforms of β-secretase, namely BACE1 and BACE2. Whereas BACE1 has been extensively investigated in the context of AD research, until a few years ago less was known about the biological role of BACE2. It has been shown that BACE2 plays an important part in processing the pigment cell-specific melanocyte protein PMEL and ablation of BACE2 therefore can result in partial hypopigmentation in preclinical species. The implications of this finding are being explored in clinical trials. In an initiative to reduce potential off-target effects, we analyzed the internal crystal structures and biological data of both forms of BACE to form a structural hypothesis to identify BACE1-selective inhibitors.
Invited Lecture (IL)
IL 1
Epilepsy : From Symptoms to Substrate
Prof. (Dr.) Ennapadam S Krishnamoorthy1*; Vivek Misra2 1Founder; 2Research Associate, Neurokrish – the neuropsychiatry centre E-mail: [email protected]
Epilepsy is the condition with recurrent seizures, relatively common neurological disorder affecting 50 million people worldwide. A multitude of etiologies cause epilepsy, including tumors, developmental abnormalities, febrile illness, trauma, or infection. However, in 2/3 of the cases, the cause is unknown. Traditionally, scalp electroencephalography (SEEG) and often invasive (subdural grid or depth electrode) EEG are used to identify the epileptogenic regions of the brain, but increasingly magnetic resonance imaging (MRI), positron emission tomography (PET), ictal single photon emission computed tomography (SPECT), magnetoencephalography (MEG) and more recently, Magnetic Resonance Spectroscopy (MRS) been used as standard Epilepsy imaging protocol
Studies demonstrated that there may be a differential role for the amygdala, hippocampus and possibly other temporal structures, in the development and/or the expression of psychopathology. This finding highlights an interesting trend with regard to affective illness in MRI volumetry studies—namely, preservation or even increase in amygdala volumes with the non- schizophreniform psychosis, particularly affective psychosis. This trend is particularly interesting given that hippocampal sclerosis has been reported consistently in unipolar major depression, leading to experts terming it the region of interest in imaging studies.
Magnetic resonance spectroscopy (MRS), also known as nuclear magnetic resonance (NMR) spectroscopy, is a non-invasive, ionizing-radiation-free analytical technique that has been used to study metabolic changes in patients with epilepsy to screen for metabolic derangements such as inborn errors of metabolism.
Focusing upon Hippocampus / amygdala complex, decreases in N-acetyl aspartate (NAA) as seen by proton MR spectroscopy are found in hippocampal sclerosis, and elevated levels of lipids/lactate have been observed in the patients with acute seizures. Such information plays a crucial role in management as lipids/lactate may be a sensitive marker for acute temporal lobe seizures. Further, Proton MR spectroscopy has been shown to be useful in the preoperative evaluation of patients with temporal lobe seizures. Specifically, proton MR spectroscopy may help to identify the epileptogenic hippocampi by showing low levels of N-acetyl aspartate (NAA). During the triage phase of pre-surgical imaging workup of the patient with epilepsy, MRS is indicated to characterize masses that may be equivocal on conventional MR imaging for dysplasia versus neoplasia and may serve a role for confirmation of EEG- determined lateralization in cases of TLE when the conventional MR image is negative for a lesion.
In psychiatry, MRS has been used to study depression, Alzheimer’s Diseases, schizophrenia, epilepsy resulting in metabolic changes while giving us the advantage of being non-invasive in nature.
We conclude that MRS used in conjunction with MR volumetric and functional MRI studies may have a useful role to play in delineating more clearly the biological basis of epilepsy, behavioural disorders and the interface thereof. A better understanding of the neuro-chemical basis will also enhance possibilities with respect to treatment.
IL 2
Total Synthesis and Diversity Oriented Synthesis of small molecules for Neurotherapeutic properties
P. Srihari CSIR-Indian Institute of Chemical Technology, Hyderabad-500007 E-mail: [email protected]
Taking care of neuorological and psychiatric disorders that affect mood or emotion and cognitive functions is globally an important challenge. The neural circuitries function properly when there is even support of neurotrophins; the level of whose has to be sustained, stimulated and augmented during the advanced phase of individuals. In this regard, small molecule chemical entities that can cross the blood-brain barrier and repair and /or regenerate neurons is an attractive area of focus. In the present context, the total synthesis of diacetylene containing molecules petrosiols A & E, terpenoid molecule paecilomycine A with neuronal activities and our approach for the diversified synthesis of analogues for paecilomycines with novel spirocyclic scaffold displaying potent neurotrophic, neuroprotection and neurogenic activities will be presented.
References:
1) For our contributions in the synthesis of diacetylenic hydroxyl natural products, see a) Yadav, J. S.; Kumaraswamy, B.; Sathish Reddy, A.; Srihari, P. Janakiram, R. V; Shasi V. Kalivendi, J. Org. Chem. 2011, 76, 2568. B) Sathish Reddy, A.; Srihari, P. Tetrahedron Lett. 2013, 54, 6370; Gangadhar, P.; Sathish Reddy, A; Srihari, P. Tetrahedron 2016, 72, 5807. C) Gangadhar, P.; Rajesh, P.; Srihari, P, ChemistrySelect 2017, 2, 4106. 2) For synthesis of paecilomycine A and analogues, see a) Mehta, G.; Ramesh, S.; Srihari, P. Tetrahedron Lett. 2012, 53, 829. b) Mehta, G.; Ramesh, S.; Srihari, P. Tetrahedron Lett. 2011, 52, 1663. 3) For paeciloymcine analogues see a) Mehta, G.; Ramesh, S.; Srihari, P.; Gajendra Reddy, R.; Sumana, C. Org. Biomol. Chem. 2012, 10, 6830. B) Sumana, C.; Swati, M.; Gajendra Reddy R.; Das, T.; Priya, J.; Scherazad, K.; Wenson, D. R.; Anumita, S.; Ramesh, S.; Srihari, P.; Steven G.; Mehta, G.; Arvind, K. Scientific Reports 2015, 14134. C) Joshi, P. C.; Ramesh, S.; Bhattacharya, D.; Raghunath Reddy, B.; Veeraval, L.; Das,T.; Swati, M.; Wahul, A. B.; Shailaja, K.; Srihari, P.; Mehta, G.; Arvind Kumar, Sumana, C., Scientific Reports, 2017, Art no.1492. IL 3
Discovering an herbal molecule for the treatment of Parkinson's disease
Mohanakumar K P
Inter University Centre for Biomedical Research & Super Specialty Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board PO, Kottayam - 686009, Kerala State, India. E-mail: [email protected]; [email protected]
Astute prescriptions are inscribed in Indian traditional medicine treatise for the treatment of Parkinson’s disease (PD). There is indisputable acceptance for such therapeutic procedures from the general population, from the wealthy or the commoner, the educated and the illiterate alike. However, presence of undesirable molecules that are contraindicated for the disease in such medication is a major worry for the clinicians and regulatory bodies. We have deciphered the bad and the good molecules of traditionally used herbs in Parkinson’s disease, and would deliberate on the mechanisms of action of two molecules found in the traditional medicine, and their influence on PD. A prospective clinical trial on the effectiveness of Ayurvedic medication in a population of PD patients revealed significant benefits, which have been attributed to L- DOPA present in the herbs1. Later studies revealed better benefits with one of the herbs alone, compared to pure L-DOPA in a clinical trial conducted in the UK2, or Italy3 and in several studies conducted on animal models of PD in independent laboratories world over4-6. We have adapted strategies to segregate molecules from the herb, and then carefully removed L-DOPA contained therein, and tested each of these sub-fractions for anti-PD activity in 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine, rotenone and 6-hydroxydopamine-induced animal models of PD, and transgenic mitochondrial cybrids. We report here two classes of molecules contained in the herb, one of which possessed severe pro-parkinsonian (phenolic amine derivatives) and the other having excellent anti-parkinsonian potential (substituted tetrahydroisoquinoline derivatives). The former has been shown to cause severe dopamine depletion in the striatum of rodents, when administered acutely or chronically. It also caused significant behavioural aberrations, leading to anxiety and depression7. The latter class of molecules administered in PD animal model8, caused reversal of behavioural dysfunctions and significant attenuation of striatal dopamine loss. These effects were comparable or better than the effects of the anti-PD drugs, selegiline or L-DOPA. The mechanism of action of the molecule has been found to be novel, at the postsynaptic dopamine receptor signalling, α-synuclein oligomerization, tyrosine hydroxylase transcription and at dopaminergic neurons9,10. The molecule helped in maintaining mitochondrial electron transport chain complex activity and stabilized cellular respiration, and mitochondrial fusion-fission machinery with specific effect on the dynamin related protein-110. In an animal model of Huntington's disease, it was found ineffective. Whereas in a sporadic Alzheimer's disease model and in neurolathyrism in rats, the molecule rendered significant beneficial effects. It is probable that the patients could be benefitted from the synergistic actions of several molecules present in a traditional preparation. However, the data in our hands suggest complicated mechanisms of actions of Ayurvedic medication. There is surely hope for identifying, synthesizing and optimizing the activity of anti-Parkinsonian molecules present in traditional Ayurvedic herbs.
References:
1) Nagashayana N, Sankarankutty P, Nampoothiri MRV, Mohan PK and Mohanakumar KP. J Neurol Sci, 176, 124-7, 2000. 2) Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ. J Neurol Neurosurg Psychiatry 75, 1672-7, 2004. 3) Cilia R, Laguna J, Cassani E, Cereda E, Pozzi NG, Isaias IU, Contin M, Barichella M, Pezzoli G. Neurology;89;432-438, 2017. 4) Manyam BV, Dhanasekaran M, Hare TA. Phytother Res 18, 706-12, 2004. 5) Kasture S, Pontis S, Pinna A, Schintu N, Spina L, Longoni R, Simola N, Ballero M, Morelli M. Neurotox Res 15, 111-22, 2009. 6) Lieu CA, Kunselman AR, Manyam BV, Venkiteswaran K, Subramanian T. Parkinsonism Relat Disord 16, 458-65, 2010. 7) Sengupta T and Mohanakumar KP, Neurochem Int 57, 637-46, 2010. 8) Sengupta T, Vinayagam J, Nagashayana N, Gowda B, Jaisankar P and Mohanakumar KP, Neurochem Res 36, 177-86, 2011. 9) Sengupta T, Vinayagam J, Singh R, Jaisankar P, Mohanakumar KP. Adv Neurobiol 12:415-96, 2016. 10) Singh R. Molecular basis of neuroprotection against parkinsonism by identified Ayurvedic molecules. PhD Thesis (Biochemistry, Science Faculty) submitted to University of Calcutta, July 2016.
IL 4
Targeting Kappa Opioid receptor for treatment resistant depression (TRD)
Prem N. Yadav
CSIR-Central Drug Reseasrch Institute, Lucknow-226031 E-mail: [email protected]
Decades if scientific evidence shows significant role of opioid dysregulation in various psychiatric conditions, and the therapeutic potential of opioid modulation. Psychotomimetic and prodepressive effect by kappa opioid receptor activation in rodents and human has also been shown.. Our recent works reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine and citalopram. Additionally, sustained KOR activity increased NR2B-NMDA stimulation in selective brain regions only. Surprisingly, this KOR mediated NMDA stimulation and associated depressive behaviour is reversed by NR2B selective antagonist, but not by SSRIs. These observations clearly revealed a cross talk between KOR and NMDA, which is involved in treatment resistant depression. Considering our own observations and other labs around world, it is increasingly clear that antagonism of KOR is a valid therapeutic strategy for depressive disorders.
IL 5
Understanding One Carbon Metabolism and epigenetic influences on brain growth: A new hope for a new
generation
Rishikesh V. Behere Wellcome DBT India Alliance Intermediate Fellow & Associate Consultant Psychiatry, KEM Hospital Research Center, Pune E-mail: [email protected]
Growth and development of brain structure and function is a process that starts from the womb and is said to continue till adolescence. Recent evidences suggest that even into adulthood neurons are amenable to modulation by process of plasticity. Early brain growth and development determines risk for neurodevelopmental disorders and the intellectual capacity ultimately achieved by an individual. This directly translates into how productive the individual will be and contribute to society. Brain growth and development is multifactorial which includes genetic composition and environmental influences. However, genetics alone has proved inadequate in providing us answers to this enigmatic puzzle. Epigenomics provides us a framework to understand how environment modulates gene expression. The immediate cellular environment is influenced by micronutrients obtained from the food we eat. Micronutrients which are part of the one carbon metabolism pathway (Vitamin B12, folate, homocysteine, methionine, pyridoxine) play a direct role in critical cellular pathways (DNA methylation, Purine & Pyrimidine synthesis) influencing epigenetics. As compared to the unmodifiable genetic factors, cellular environmental influences may be modifiable by nutritional intervention and offer a new hope for improving neurodevelopmental outcomes in future generations. This talk will introduce the concept of fetal programming, review the role of epigenetics in brain development and provide an overview to ongoing work on these concepts from the Pune Maternal Nutrition Study (PMNS).
IL 6
Natural Product Analogues and Silicon Incorporation towards Potential Agents for Treating CNS Disorders
D. Srinivasa Reddy CSIR-National Chemical Laboratory, Organic Chemistry Division, Dr. Homi Bhabha Road, Pune E-mail: [email protected]
Our research group at CSIR-NCL works on total synthesis of biologically active natural products and medicinal chemistry with an ultimate aim of discovering drugs. In my presentation, some of the recent achievements of our group will be discussed; in particular, projects which have potential for taking forward for the development of agents for treating Central Nervous System (CNS) disorders. Recently, we have accomplished the first total synthesis of natural products such as botryosphaeridione, pleodendione, nitrosporesines and their analogues. In collaboration with Dr. Anirban Basu’s group at National Brain Research Centre, all the synthesized compounds were screened in neural anti- inflammatory assays using LPS induced microglia cells (N9) and identified a few compounds as potential lead compounds for further profiling. In addition, I will be discussing on “Silicon-incorporation approach” in medicinal chemistry which we are pursuing in our group. In particular, significant progress has been made using a new concept called “Silicon-switch approach”. This particular approach is expected to be more beneficial in the area of CNS drug discovery, where we could enhance brian:plasma (B/P)ratio significantly through silicon incorporation (for example, linezolid scaffold).
References: 1) Kishor L. Handore, Prakash D. Jadhav, Bibhabasu Hazra, Anirban Basu And D. Srinivasa Reddy, ACS Med. Chem. Lett., 2015, 6, 1117 2) Satish Chandra Philkhana, Abhishek Kumar Verma, Gorakhnath R. Jachak, Bibhabasu Hazra, Anirban Basu And D. Srinivasa Reddy, Eur. J. Med. Chem., 2017, 135, 89 3) D. Srinivasa Reddy, B. Seetharamsingh and Remya Ramesh, WO 2013/054275 A1; US20140296133; 4) B. Seetharamsingh, Remya Ramesh, Santoshkumar S. Dange, Pankaj V. Khairnar, Smita Singhal, Dilip Upadhyay, Sridhar Veeraraghavan, Srikant Viswanadha, Swaroop Vakkalanka and D. Srinivasa Reddy, ACS Med. Chem. Lett., 2015, 6, 1105 5) Remya Ramesh and D. Srinivasa Reddy, J. Med. Chem. 2017, in press, DOI: 10.1021/acs.jmedchem.7b00718 IL 7
Fast-Acting Antidepressants - Strategies to accelerate effects on neuronal plasticity
Vidita Vaidya Department of Biological Science, Tata Institute of Fundamental Research, Mumbai E-mail: [email protected]
Depression is thought to involve an inability to mount adaptive structural changes in key neuronal networks. Animal models of depression exhibit a decline in hippocampal neurogenesis and show reduced trophic factor expression. In contrast, chronic antidepressant treatments increase adult hippocampal neurogenesis and trophic factor expression, changes required for specific behavioral effects of antidepressants. However, these adaptive changes arise only in response to sustained antidepressant administration and are slow in their onset, which is thought to contribute to the delay in the therapeutic effects of existing antidepressants. We have identified an important role for norepinephrine and thyroid hormone in the regulation of adult hippocampal neurogenesis.
Despite the strongly pro-proliferative effects of norepinephrine, alpha2-adrenergic receptors robustly downregulate progenitor turnover. We have shown that by using a targeted strategy of blocking effects on the alpha2-adrenoceptor at the same time as elevating norepinephrine levels through the use of a classical antidepressant, it was possible to substantially speed up the neurogenic and trophic effects of antidepressants. Further, we find that speeding up the neurogenic and neurotrophic changes was accompanied by a hastening of the behavioral effects of antidepressant treatments, which were now observed within a week of treatment rather than the 3 weeks normally required in animal models. In my talk I will discuss the specific effects of norepinephrine and thyroid hormone on structural plasticity in the hippocampus and elaborate upon the possible implications to fast-acting antidepressant treatments.
IL 8
A Novel Diagnostics approach for Early Detection of Alzheimer’s Disease from Brain Anti-oxidant level with high sensitivity and specificity
Pravat K Mandal Neuroimaging and Neurospectroscopy Laboratory, National Brain Research Center, India & Honorary Professorial Fellow, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia E-mail: [email protected]
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. Although the disease was discovered more than 100 years ago and pathology is well known, the causal process is still not clear. It is proven that age is a prime risk factor for AD. Amyloid theory dominated more than a decade for the cause of the disease, however autopsy studies on the brains of many elderly people with cognitive function intact till death, showed higher amyloid beta peptide load. The major hypothesis countering the Amyloid theory is that oxidative stress increment and subsequent depletion of antioxidant brain glutathione (GSH) is one of the possible causes of the AD. This talk provides compelling in vivo evidence that estimation of GSH levels in specific brain regions with magnetic resonance spectroscopy constitutes a clinically relevant biomarker for MCI and AD.
IL 9
Behavioral Neuroscience as means to screening novel biotherapeutics, herbal extracts and synthetic analogs
Akshay Anand Neuroscience Research Lab, Department of Neurology, PGIMER, Chandigarh, INDIA E-mail: [email protected]
Several animal models have been used to examine the effects of herbs, synthetic analogs and validating therapies. With emergence of stem cell related research investigations, the need for reproducible model systems has arisen. Animal models in Neuroscience are useful behavioral tools for screening novel therapeutics. The data from several such studies will be presented which will provide perspective in drug discovery and comparative biotherapeutics. This will include the establishment of Scopolamine model of amnesia, Abeta induced animal model of Alzheimer’s Disease, PPA model of retinal injury, laser injury model of retinal injury and NMDA induced RGC depletion model followed by their respective validation using modern histopathological and imaging technologies. The data from standardization of lineage negative BMSCs and those derived from Umbilical cord blood would be discussed and variations in routes, doses and types of stem cells in the perspective of their screening and discovery will be brought out by sharing our experience from a Quality Assurance compliant laboratory. Additionally Morris Water Maze and Active Avoidance will be described with the help of videos and the data generated from our lab while working with Indian herb, *Bacopa Monniera*, will be presented to highlight the importance of behavioral Neuroscience for drug discovery and translation in Neuroscience.
IL 10
Biocompatible Delivery Vehicles with Photoactive and Redox Triggers
Sandeep Verma Department of Chemistry & Department of Biological Sciences and Bioengineering, IIT Kanpur E-mail: [email protected]
Soft nanoscale structures present exciting prospect in drug delivery, tissue engineering, and biosensing. It is possible to engineer biocompatibility and stimuli-responsive character, for example pH, ionic strength, temperature, light, and redox environment, in such structures to allow for active molecule encapsulation, followed by targeted delivery. In this talk, I will present two recent approaches for such systems: one involving a photoactivatable dopamine-conjugated platinum anticancer complex incorporated in guanine tetrad-borate hydrogels1 and the other one consisting of a self-assembling peptide conjugate, carrying a nitric oxide release handle2.
References
1) Venkatesh, V.; Mishra, N. K.; Romero-Canelón, I; Vernooij, R. R.; Shi, H.; Coverdale, J. C. C.; Habtemariam, A.; Verma, S.; Sadler, P. J. J. Am. Chem. Soc., 2017, 139, 5656–5659 2) Pal, H. P.; Mohapatra, S.; Gupta, V.; Ghoshb, S.; Verma, S. Chem. Sci., 2017, 8, 6171-6175
IL 11
Toxic Protein Aggregation in Neurodegenerative Diseases
Nihar Ranjan Jana
National Brain Research Centre, Manesar, Gurgaon-122 051 E-mail: [email protected]
One of the common pathological hallmark of most age-related neurodegenerative disorders including Huntington’s disease (HD) and Alzheimer’s disease (AD) is the accumulation of mutant disease proteins as inclusion bodies. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular protein quality control system. Furthermore, the cellular ability to maintain protein homeostasis declines with age. In HD, AD and other neurodegenerative diseases, distinct proteostasis nodes such as molecular chaperones, ubiquitin proteasome system (UPS) and autophagy are found to be severely affected. Therefore the mechanism that restores protein homeostasis either by upregulating the function of chaperones or enhancing the clearance of mutant disease proteins are capable to delay the progression of the disease in various animal models. In my laboratory, we are using HD and AD as a model system to understand the mechanistic basis of impaired protein homeostasis and how that can be restored. In my talk, I will focus on dysfunction of quality control system in AD and HD and how its restoration ameliorates the progression of the diseases.
IL 12
Estrogen, Stroke and Acid-Sensing Ion Channels
Amal Kanti Bera
Department of Biotechnology, Indian Institute of Technology Madras, Chennai- 600036 E-mail: [email protected]
Acid-sensing ion channels (ASICs) are neuronal ion channels that respond to low pH in the extracellular region. Activation of ASICs during cerebral ischemia has been implicated in stroke-induced brain damage. We found that estrogen modulates the expression of ASICs in rat brain. ASIC1a exacerbates ischemic cell damage while ASIC2a subtype is neuroprotective. The increase of ASIC2a expression possibly increases the population of ASIC1a and 2a containing heteromeric channels which have much lower activation pH than homomeric ASIC1a. Thus, shifting of pH50 to lower values renders the channel ineffective at the moderate drop of extracellular pH during ischemia. We detected an up-regulation of ASIC2a levels in female mice with intact ovaries following an experimental stroke, whereas the levels of ASIC1a went down. This pattern, however, was not seen in male and ovariectomised mice. Estrogen supplementation in ovariectomised mice reinstated the ASIC2a levels and decreased ASIC1a. This substantiates our hypothesis that estrogen exhibits neuroprotective properties by regulating ASICs. There is no ASIC-specific blocker available for therapeutic use. Quercetin, a plant flavonoid blocks ASICs. Computational analysis revealed that quercetin binds to the channel in a cavity at the central vestibule, lined by several negatively charged residues like glutamate and aspartate, which was verified experimentally. Thus, quercetin and its derivatives may be useful for targeting ASICs.
IL 13
Design and Evaluation of Multitarget-directed Ligands as Anti-Alzheimer’s Agents
Mange Ram Yadav
Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara -390 001, Gujarat E-mail: [email protected]
Alzheimer’s disease among various neurodegenerative diseases is posing a serious challenge to the growing population of old-age people throughout the continent. Currently, very limited therapeutic options are available therefore, design and development of new effective drugs to control/manage the disease is urgently needed. The etiology of the disease remains unknown and many hypotheses are put forward pointing the causative factors responsible for the initiation of the disease. Discovering multitarget-directed ligands is considered as a promising drug discovery approach for this complex multi-factorial disease. Three series of compounds, 10-substituted isoalloxazines, 3-substituted 5,6-diaryl-1,2,4-triazines and benzylpiperidine-linked diarylthiazoles were designed and synthesized as potential anti-Alzheimer’s agents. The synthesized derivatives were evaluated for their anti-cholinesterase and anti- butyrylcholinesterase activity in vitro, anti-Tauβ aggregatory property and anti-oxidant activity by various in vivo/in vitro models. Brain ACh and BuCh were also estimated. PAMPA-BBB assay indicated their significant permeability into the CNS. Some compounds from the series offered promising results and also protected the neurons from further degeneration as assessed by flow cytometry, Western blot analysis and behavioral studies. 3,5-Difluorobenzylpiperidine derivative of 4,5-bisarylthiazol-2-ylamine offered the best results among all of the synthesized compounds of the series.
Poster Presentation (PP)
PP 1
Mn3O4 Nanozyme with Cytoprotective role in Parkinson’s Disease Model: Effect of Size and Morphology on Multi-Enzyme Activity
Namrata Singh,a,b,c Mohammed A. Savanur,b Shubhi Srivastava,b Patrick D’Silva,b Govindasamy Mugesh*a aDepartment of Inorganic and Physical Chemistry, bDepartment of Biochemistry, cCenter for Nanoscience and Engineering, Indian Institute of Science, Bangalore-560012; E-mail: [email protected]
Reactive oxygen species (ROS) generated as a consequence of normal physiological processes serve a crucial role in various cellular signalling pathways. In a healthy cell, excess ROS is neutralized by antioxidant defence machinery that includes enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidases (GPx).1 However, any aberrations leading to inefficient cellular antioxidant mechanisms results in oxidative stress that has been implicated in progression of several pathophysiological conditions such as neurodegeneration, cancer, diabetes, atherosclerosis, kidney disorders, aging etc.2 Thus, there is a requirement of artificial antioxidant enzymes which can provide protection against harmful consequences of oxidative damage by maintaining redox balance of cell. In this study, we report that Mn3O4 nanoparticles possess remarkable antioxidant activity by functionally mimicking three major cellular antioxidant enzymes i.e. SOD, CAT and GPx.3 The multi-enzyme activity of Mn3O4 is morphology and as well as size dependent. These nanoparticles compliment the cellular antioxidant machinery by restoring the ROS balance and preventing oxidative stress induced damage of biomolecules. The nanozymes perform similar function in a cellular model of Parkinson’s disease, indicating that the multienzyme mimic Mn3O4 nanoparticles can provide therapeutic potential to prevent ROS mediated neurological conditions.
Figure 1. Scheme showing the triple enzyme activity of Mn3O4 nanoflowers and its role in cytoprotection.
References:
1) H. Sies, Oxidative stress: oxidants and antioxidants, Academic Press, 1991. 2) a) T. Finkel, N. J. Holbrook, Nature, 2000, 408, 239-247. b) L. Lyras, N. J. Cairns, A. Jenner, P. Jenner, B. Halliwell, J. Neurochem 1997, 68, 2061-2069. 3) N. Singh, M. A. Savanur, S. Srivastava, P. D’Silva, G. Mugesh, Angew. Chem. Int. Ed., 2017, DOI: 10.1002/anie.201708573.
PP 2 Synthesis, Characterization, Docking Study and Anti-microbial Evaluation of some Novel substituted 1,2,4-Triazole Derivatives
K.Madhivadhania, K. Abdul Gafoorb and Dr. K. Girijaa ⃰ Department of Pharmaceutical Chemistry, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Government of Puducherry Institution), Indira Nagar, Gorimedu, Puducherry-06. E-mail: [email protected]
A series of Mannich base substituted 1,2,4-triazoles were synthesized by condensation of 1,5- diphenyl-1,2-dihydro-3H- 1,2,4-triazole-3-thione with different primary amines. The structure of the synthesized compounds were characterized by FT-IR, IR, 1H-NMR, 13C-NMR and Mass spectral analysis. The synthesized compounds were docked against the target enzyme Cytochrome P 121 and 14-alpha demethylase to investigate the interaction between the synthesized compounds and the amino acid residue of the target enzymes. Based on docking score the compounds AT2, AT6 and AT8 were screened for their Anti-bacterial activity against Staphylococcus aureus, Vibrio haemolyticus and anti-fungal activity against Candida albicans. The tested compounds showed a significant anti-bacterial and anti-fungal activity compared to the standard drug Ampicillin and Flucanazole respectively.
References: 1. Balakrishna kalluraya and Jadhav Sudhakar, Indian journal of Chemistry, 2010 vol I(4) 2010: 281-286. 2. Jaiprakash N.Sangshetti, Deepak K. Lokwani, Aniket P.Sarkate, Devanand B. Shinde, Chemical Biology and Drug Design, 2011:800-809 3. Ionut Lediti, Vasile Bercean, Anda Alexa, Codruta Soica, Lenuta-Maria Suta, Cristina Dehelean, Cristina Trandafirescu, Delia Muntean, Monica Licker and Adriana Fulias, Journal of Chemistry, 2015,
PP 3
Study of antioxidant and analgesic activities of pyrazoline pyrazoles
P.K.P. Gaitry Chopraa* and B.D. Sarafb aDepartment of Applied Chemistry, Datta Meghe Institute of Engineering, Technology and Research, Wardha, India - 442001 bDepartment of Chemistry, Institute of Science, Civil lines, RT Road, Nagpur, India - 440001 E-mail: [email protected]
The incorporation of heterocyclic rings into prospective pharmaceutical candidates is a major tactic to gain activity and safety advantages. Pyrazole and its derivatives, a class of well-known nitrogen containing heterocyclic compounds, occupy an important position in medicinal chemistry with having a wide range of bioactivities.
The present work deals with the synthesis of 5-(2-hydroxyphenyl)-3-methyl-4-(1-acetyl- 5-aryl-Δ2-pyrazolin-3-yl)-pyrazoles [2 (a-f)] and 1-phenyl-5-(2-hydroxyphenyl)-3-methyl-4-(1- phenyl-5-aryl-Δ2-pyrazolin-3-yl)-pyrazoles [3 (a-f)] by the action of hydrazine hydrate and phenylhydrazine respectively on 3-cinnamoyl-2-methylchromones [1 (a-f)]. The structures of synthesized compounds were established on the basis of their physical and spectral data. The synthesised compounds were screened for their antibacterial activity against four bacteria viz. S. sciuri, S. aureus, S. typhi and E. coli and their antioxidant potential was evaluated by using 1, 1- diphenyl-2-picrylhydrazyl (DPPH) scavenging assay. These compounds were also tested for their analgesic activity by tail flick method. All the compounds were found to possess antibacterial and analgesic activities and were antioxidant in nature.
PP 4 Design, synthesis, in vitro evaluation and docking studies of novel 1,3-disubstituted pyrazole-2,4-disubstituted thiazole hybrids embedding benzothiazole and coumarin moieties as antibacterial, anticandidal and anti-biofilm agents Ramesh Gondrua, K Sirishab, Sneha Rajc, Shravan Kumar Gundad, C Ganesh Kumarb,*, Mukesh Pasupuletic,*, Rajitha Bavantulaa,*
aDepartment of Chemistry, National Institute of Technology, Warangal-506004, Telangana State, India bMedicinal Chemistry and Biotechnology Division, CSIR–Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500 007, Telangana, India. cDivision of Microbiology, CSIR−Central Drug Research Institute, Sector 10, Jankipuram extension, Sitapur Road, Lucknow-226031, Uttar Pradesh, India. dBioinformatics Division, PGRRCDE, Osmania University, Hyderabad–500007, Telangana, India.
In the present study, a series of novel 1,3-disubstituted 1,2-pyrazole-2,4-disubstituted 1,3- thiazole hybrids constituting benzothiazole and coumarin moieties 4a-l were designed and achieved via one pot three component condensation reaction. All the synthesized compounds were ascertained by analytical and spectroscopic methods (IR, MS, 1H and 13C NMR), and elemental analyses (CHN). The synthesized compounds were later assessed for their in vitro antimicrobial and MBC/MFC activities against both Gram-positive and Gram-negative pathogenic bacterial and fungal strains. Among the tested series, compounds 4b, 4g, 4k and 4l exhibited promising inhibitory activity against the tested bacterial strains with MIC/MBC spectrum of 1.9/7.8 µg/mL to 3.9/7.8 µg/mL and the compounds 4b, 4c, 4j, 4k against various Candida strains with MIC/MFC values of 3.9/7.8 µg/mL. Anti-biofilm and toxicity profile of the compounds were also tested. The biofilm inhibition results revealed that the compound 4j against
S. aureus MTCC 96 exhibited promising activity with IC50 value of 11.8 µM, while 4k against S. aureus MLS16 MTCC 2940, K. planticola MTCC 530 and C. albicans MTCC 3017 exhibited promising activity with IC50 values of 12, 14 and 16 µM, respectively. Molecular docking studies were performed to explore the binding interaction between synthesized hybrids and dehydrosqualene synthase protein. Present study has emphasized a novel and potent class of antibacterial (S. aureus) inhibitors with potential biological activities.
References:
1) M. Zasloff, organisms, 2002, 415, 389–395. 2) U. Theuretzbacher, Int. J. Antimicrob. Agents. 2012, 39, 295–299. 3) M. Ahn, P. Gunasekaran, G. Rajasekaran, E.Y. Kim, S.-J. Lee, G. Bang, K. Cho, J. Hyun, H. Lee, Y.H. Jeon, N. Kim, E.K. Ryu, S.Y. Shin, J. K. Bang, Eur. J. Med. Chem. 2017, 125, 551–564. 4) C. Mallikarjunaswamy, D. G. Bhadregowda, L. Mallesha, J. Saudi Chem. Soc. 2016, 20, S606–S614. PP 5 Synthesis, Characterization, Molecular Docking and In vitro Cytotoxic Evaluation of 4-Anilino Quinazolines
K. Hemalatha, K.Girija
Department of Pharmaceutical Chemistry, College of Pharmacy, Mother Theresa Post Graduate and Research Institute of Health Sciences, (A Government of Puducherry Institution), Indira Nagar, Gorimedu, Puducherry-605 006. E-mail: [email protected]
A series of novel 4-anilino quinazoline derivatives were designed and synthesized from anthranilic acid via 2-phenyl benzoxazine-4-ones. The synthesized compounds were characterized using FT-IR, 1H-NMR, 13C-NMR and Mass spectral analysis. The structures of the synthesized compounds were optimized with Auto Dock 4.2 to investigate the interaction between the compounds and the amino acid residues of target protein Epidermal Growth Factor Receptor-Tyrosine Kinase. The free energies of binding and inhibition constants (Ki) of the docked ligands were calculated by the Lamarckian Genetic Algorithm (LGA). Molecular descriptor properties and toxicity profile were predicted by software. Further, all the compounds were subjected to in vitro cytotoxic activity against Dalton Lymphocyte Ascities cells. The docking results showed that the compounds SGQ4, DMUQ5, 6AUQ6 and PTQ8 produced significant docking affinity for the protein Tyrosine Kinase with the binding energy of -7.46, -7.31, -6.85 and -6.74 Kcal/mol respectively compared to the standard Erlotinib (Binding energy: -3.84 Kcal/mol). The cytotoxicity results also showed that the above studied compounds exhibited significant cytotoxic activity (70-75% cell death of DLA cells). All the designed molecules passed Lipinski rule of five successfully and they were found to be safe.
R
HN
N
N
4-Anilino quinazoline derivative References:
1. Chen YF, Fu LW. Mechanisms of acquired resistance to tyrosine kinase inhibitors. Acta Pharm Sin B. 2011; 1, 197−207. 2. Bhavin Marvania, Pei-Chih Lee, Ravi Chaniyara, Huajin Dong, Sharda Suman, Rajesh Kakadiya, Ting- Chao Chou, Te-Chang Lee, Anamik Shah, Tsann-Long Su: Design, Synthesis and Anti-tumor evaluation of phenyl N-mustard-quinazoline conjugates; Bioorganic & Medicinal Chemistry 2011: 19, 1987-1998. 3. Karabi Datta, Maitrayee Choudhuri, Subhas Guha, Jaydip Biswas; Breast Cancer Scenario in a Regional Cancer Centre in Eastern India over Eight Years - Still a Major Public Health Problem. Asian Pacific Journal of Cancer Prevention. 2012; 13, 809-813. PP 6
Synthesis and molecular docking studies to evaluate the anti-alzheimer effect of furanylspirooxindolopyrroloizidines
Venkata Bharat Nishtala, Basavoju Srinivas* Department of Chemistry, National institute of Technology Warangal, Warangal-506 004, Telangana state, India E-mail: [email protected]
Efficient synthesis of novel furanyl spirooxindolopyrrolizidines derivatives was expediently accomplished with regio-selectivity via one-pot, multicomponent 1,3-dipolar cycloaddition using ultrasonication. Chalcones derived from both heteroaryl methyl ketones and furfural, were used as dipolarophiles in these reactions. The synthesized compounds were analyzed by 1H and 13C NMR, mass spectrometry, elemental (CHN) analysis and Single-crystal X-ray diffraction studies. A molecular docking study was carried out to evaluate the in silico Anti-Alzheimer’s activity of the synthesized compounds by using AutoDock Tools (ADT) version 1.5.6 and AutoDock version 4.2.5.1 docking program against Alzheimer's disease amyloid A4 PRO (protein):1AAP (PDB ID). Among all the synthesized compounds, the compound 4e exhibit good anti- alzheimer’s activity having binding energy -6.3 kcal/mol. when compared with donepezil (binding energy -6.4kcal/mol), which was taken as standard, the compounds 4e (-6.3kcal/mol), 4h (-6.2 kcal/mol), 4i (-6.2kcal/mol) and 4j (-6.1kcal/mol) shows good anti-alzheimer’s activity.
References:
1) V. B. Nishtala, J. B. Nanubolu and S. Basavoju, Res Chem Intermed., 2017, 43, 1365-1381. 2) http://autodock.scripps.edu/resources/references.
PP 7
Molecular docking approach to evaluate the anti-alzheimer activity of Pyridinyl-4-aminophenylmethane sulphonamide and its derivatives on alzheimer’s disease amyloid A4 protein: 1AAP
Allaka Bhargava Sai, Srinivas Basavoju* Department of Chemistry, National Institute of Technology Warangal, Warangal -506 004, Telangana, India. E-mail: [email protected]
A molecular docking study was carried out to evaluate insilico anti-alzheimer activity of pyridinyl-4-aminophenylmethanesulphonamides using AutoDock Tools (ADT) version 1.5.6 and AutoDock version 4.2.5.1 docking program against Alzheimer's disease amyloid A4 PRO (protein): 1AAP (PDB ID). The binding affinities of pre-existing drug donepezil and pyridinyl-4 aminophenylmethanesulphonamide derivatives were screened against alzheimer’s disease amyloid A4 protein: 1AAP (PDB ID). When compared with standard drug donepezil (binding energy -6.4kcal/mol), the compound 1f shows relatively good anti-alzheimer’s activity. The results indicate that the compounds 1b, 1f (ligand binding energy–5.9kcal/mol and –6.1 kcal/mol) show good anti-alzheimer activity than the other derivatives.
References: 1) http://autodock.scripps.edu/resources/references. 2) T. R. Hynes, M. Randal, L.A. Kennedy, C. Eigenbrot and A. A. Kossiakoff, Biochemistry, 1990, 29, 10018-10022
PP 8
Synthesis of some quinoline-based pyrazoline derivatives and their evaluation as Potential antimicrobial agents Dr. S. Muniraj,* G. Suresh Department of Chemistry, Ramakrishna Mission Vivekananda College, Mylapore, Chennai, 600 004; E-mail: [email protected]
Nitrogen containing Heterocyclic compound has many biological application in medicinal field to treat anti-inflammatory, antimalaria, HIV and anticancer, particularly quinoline and their derivatives1-2. New quinoline -based pyrazoline compounds (4a-i) have been synthesized in good yields by a two-step procedure3. In the first step of quinoline chalcone synthesis from quinoline aldehyde with acetophenone in the occurrence of NaOMe/MeOH, followed by substituted hydrazine hydrate with quinoline chalcone condensed in the presence of EtOH / CH3COOH to obtain novel quinoline pyrazoline derivatives. All the synthesized compounds were evaluated for both chemical characterization and biological activity. Chemical characterization has been achieved by IR, NMR and Mass. To evaluate biological studies antimicrobial and antifungal activity has been performed. The synthesized compounds tested against bacterial and fungal culture Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Rhizopus, Aspergillus niger and Candida respectively. Molecular docking studies for the final compounds and standard drugs were performed using the auto dock program.
Scheme: Synthesis of some quinoline-based pyrazoline derivatives (4a-j)
References: 1. A. Marella, O. P. Tanwar, R. Saha, M. R. Ali, S. Srivastava, M. Akhter, M. Shaquiquzzaman, M. MumtazAlam, Saudi Pharmaceutical Journal, 2013, 21, 1, 1-12. 2. O. Afzala, S. Kumar, Md RafiHaider, Md RahmatAli, R, Kumar, M. Jaggi, Sandhy, Bawa, Eur. J. Med. Chem, 2015, 97, 5, 871-910. 3. P. M. Sivakumar, G. Suresh, V. Prabhawathi and M. Doble, Chem. Biol. Drug. Des, 2010, 76, 407-411. Acknowledgement: This work was supported by the University Grant Commissions (UGC), Hyderabad-500001, under the project grants no. F MRP-5615/15(SERO/UGC), Link no: 5615, Comcode: TNMD013, January 2015.
PP 9 Identification of Tautomers of Curcumin, Preferential Stabilization of Enol by Pipeine, and Isomers of Curcumin∩Cyclodextrin Complexes: New Insights from Ion Mobility Mass Spectrometry
Abhijit Nag†, Papri Chakraborty†, Ganapati Natarajan†, Ananya Baksi†, Sathish Kumar Mudedla‡, Venkatesan Subramanian‡ and Thalappil Pradeep*,† †DST Unit of Nanoscience and Thematic Unit of Excellence, Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, India ‡Chemical Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, India E-mail: [email protected] A detailed examination of collision cross sections (CCSs) coupled with computational methods has revealed new insights into some of the key questions centered around curcumin, one of the most intensively studied natural therapeutic agents.1-2 In this study, we have distinguished the structures and conformers of the well-known enol and the far more elusive keto form of curcumin by using ion mobility mass spectrometry (IM MS).1-2 The values of the theoretically predicted isomers were compared with the experimental CCS values to confirm their structures. We have identified a folded structure for the keto form and the degree of folding was estimated. Using IM MS, we have also shown that ESI MS reflects the solution phase structures and their relative populations. The ratio of populations depended on multiple factors which were examined. Piperine, a naturally occurring heterocyclic compound, is known to increase the bioavailability of curcumin. However, it is still not clearly understood that which tautomeric form of curcumin is better stabilized by it. We have identified preferential stabilization of the enol form in presence of piperine using IM MS. Cyclodextrins (CDs) are used as well-known carriers in the pharmaceutical industry for increasing the stability, solubility, bioavailability, and tolerability of curcumin. However, the crystal structures of supramolecular complexes of curcumin∩CD are unknown. We have determined the structures of different isomers of curcumin∩CD (α- and β-CD) complexes by comparing the CCSs of theoretically predicted structures with the experimentally obtained CCSs, which will further help in understanding the specific role of the structures involved in different biological activities.
keto∩β-CD dimer enol∩β-CD dimer
piperine keto enol
CCS 211.0 Å2 2 4 6 8 10 12 Drift time (ms) keto CCS 196.0 Å2 enol 0 2 4 6 8 10 12 Drift time (ms) Figure 1. Drift time profile of curcumin (m/z = 367) showing the two isomeric species with drift times of 4.92 and 5.72 ms, with CCS values, 196.0 Å2 and 211.0 Å2, respectively. Shift of the keto enol equilibrium towards the enol form with increase in piperine concentration in the solution. Top of the Figure 1 the structure of enol and keto docked β-cyclodextrin dimer, respectively, evaluated from ion mobility mass spectrometry.
References: 1. Wanninger, S.; Lorenz, V.; Subhan, A.; Edelmann, F. T., Metal complexes of curcumin - synthetic strategies, structures and medicinal applications. Chemical Society Reviews 2015, 44 (15), 4986-5002. 2. Argyropoulou, A.; Aligiannis, N.; Trougakos, I. P.; Skaltsounis, A.-L., Natural compounds with anti-ageing activity. Natural Product Reports 2013, 30 (11), 1412-1437. PP 10
Synthesis of some new substituted Thiazolyl Aminoethoxy Quinolines and their Antimicrobial Activity
Acharyulu V.N. Periyala* and A. Sattibabu Dept. of Chemistry, Aditya Engineering College (autonomous), Surampalem, Kakinada-533437, Andhra Pradesh, India E mail: [email protected]
The importance to discover new antibacterial agents was once again highlighted, due to the rapid development of bacterial resistance to the existing antibacterial agents. Heterocyclic compounds containing thiazole rings represent a significant group of organic compounds, which possess wide spectrum of biological activities. Many quinoline derivatives serve as basic pharmacophore for various biological activities i.e. antimalarial, anti-inflammatory etc.. So it is proposed to synthesize a new series of substituted thiazolyl aminoethoxy quinoline derivatives and studying their biological activity. To achieve this objective, the substituted 5-hydroxy quinolines were treated with 1,2-dibromoethane. The resulting bromoquinolines were reacted with various thiazoles to afford the target molecules. These compounds were screened for antimicrobial activity against Gram-positive organisms and Gram-negative organisms. Ciprofloxacin was used as internal standard to analyse the results. The methyl analogue was found to be equipotent to ciprofloxacin against E.Coli.
References:
1. Y . Lu J Med Chem. 2009, 52(6), 1701-11 2. Z. Jin, Nat. Prod. Rep. 2013, 30, 869–915. 3. K. M. Aitken, R. A. Aitken, Tetrahedron, 2008, 64, 4384-4386.
PP 11
A comparative binding study of benzimidazo quinoline derivatives with BSA protein-An experimental and theoretical approach
Malathi M*, Manikandan I, Subhapriya P Department of Chemistry, Bannari Amman Institute of Technology E-mail: [email protected]
In the present work BSA protein binding of benzimidazo qunoline derivatives were analyzed through UV-visible absorption and emission spectral studies. An aqueous ethanoic medium was used for the binding study. DFT calculation was used to get theoretical optimized structure. In order to explore the mode of protein binding, auto dock study is performed. From the optimized structure the molecular discriptor,HOMO and LUMO and other theoretic descriptors were compared.
Figure 1. Binding interaction of a quinoline benzimidazole with BSA protein.
References
1) M. Malathi and K. M. Muraleedharan, J Mol Struct 2015, 1099, 257-265.
PP 12
NaN3/NH4Cl promoted intramolecular aza-annulation: A general route for various N-containing hetrocyclic Scaffolds
Arabinda Mandal, Shubhankar Samanta and Susanta Kumar Manna Department of Chemistry, Bidhannagar College, Kolkata 700064, India E-mail: [email protected]
Pyrrole, isoquinoline and isoindolinones moiety are widely distributed in both natural and artificial molecules. Being inspired the importance, the synthesis of substituted pyrroles, isoquinolines and isoindolinones has attracted considerable attention and many synthetic efforts have been devoted so far to synthesise these classes of compounds. Among them, azide base cyclisation is enormously used for the C–N bond formation due to its ease of accessibility and evolution of environmentally benign N2 gas. Recently, we have reported a sodium azide promoted green synthesis of pyrrole and isoquinoline derivatives via aza-exo-trig and azaendo- dig cyclisation respectively. A significant application of this methodology was further demonstrated by the short synthesis of the core structure of marine alkaloid lamellarin Q, which was showed wide varieties of biological activities like strong cytotoxic activity against tumor cell lines, reversal of multidrug resistance, HIV-1 integrase inhibition and antibiotic activity. In continuation of heterocyclic synthesis, an interesting results was obtained when the carboxylic acid derivative was subjected to NaN3/NH4Cl treatment then isoindolinones moiety was produce. This protocol has remarkable biologically property such as anxiolytic, sedative, hypnotic, and muscle relaxant activity.
Scheme 1: NaN3/NH4Cl promoted intramolecular aza-annulation
References:
Jana, A.; Manna, S. K.; Mondal, S. K.; Mandal, A.; Manna, S. K.; Jana, A.; Senapati, B. K.; Jana, M.; Samanta, S. Tetrahedron Lett. 2016, 57, 3722–3726 PP 13
Synthesis, Biological Studies on Various Type of Pyrrole Fused Heterocyclic Compounds
Suresh Kumar Mondal, Subhankar Samanta*
Department of Chemistry, Bidhannagar College, Kolkata 700064, India; Department of Chemistry and Chemical Technology Vidyasagar University Midnapore 721102, West Bengal, India E-mail: [email protected]
Pyrrole fused heterocycles are the building block of various bioactive molecules and drugs. Here devising several convenient and efficient protocol for the synthesis of highly strained novel ring system like pyrrolo-pyrazolone, oxazocinone and rare pentacyclic compounds by intramolecular cyclisation. Pyrrole fused skeleton exists in the core structure of a number of clinically active compounds and natural products like antipyrine, edaravone, lamellarine, chiorizidine A, lukanol A&B etc. A series of highly condensed pyrrole fused compounds have been achieved by employing the easily available starting materials in a simple condition. The products were formed very rapidly with a good yield (up to 75%) and also it had a tolerance to wide scope of substrates. According to demand in the pharmaceutical industry the development of efficient route to these nitrogen-containing uncommon molecules is of paramount importance. In addition with the wide application of this type of compounds in human society, we have targeted synthesis of these new types of pyrrole fused compounds and explained the photophysical studies and biological activities such as citotoxicity and cell internalization in living cell like Chinese Hamster overy(CHO) and GL261 cell line.
Scheme: Various types of convenient protocol for synthesizing pyrrole fused heterocycles.
Reference:
1. (a) Tetrahedron Letters 2014, 55, 6411-6415; b) Org. Biomol. Chem. 2017, 15, 2411–2421; c) Chemistry select 2017, 29, 9312-9318. PP 14
Self-assembled rhodamine cored poly (aryl ether) dendron derivatives for metal ion sensing and in vitro bioimaging
Ramya Kannan,1,2 Neelakandan Vidhya Lakshmi,1 Vignesh Muthuvijayan2* and Edamana Prasad1*
1Department of chemistry, 2Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology, Madras E-mail: [email protected]
Micro/ nanostructures formed by small organic molecules are of growing interest in various fields, owing to its size tunable properties.1 Intracellular bio-imaging /fluorescence sensing with the small organic molecule is being explored extensively, where rhodamine-based chemosensors are one of the extensively studied systems for metal ion sensing due to its spirolactam ring opening mechanism. The major drawback of these organic molecules is the poor solubility in aqueous medium leading to precipitation. On the other hand, micro/nanostructured materials forming stable morphologies with a definite size are currently being explored for intracellular imaging.2 Dendrimers/ dendrons, a hyperbranched polymer is well known for their divergent synthetic structure and multifunctional periphery. These dendrons/dendrimers are known to self- assemble in certain solvents under suitable conditions. Poly (aryl ether) dendron, a class of dendrons have been extensively studied for its self-assembly and gelation.3 In this study, we intend to conjugate rhodamine moiety with poly (aryl ether) dendron system to form a self- assembled nanostructured material which can specifically sense a metal ion and also be taken up for intracellular bioimaging. Three different molecules with varying aryl functionalities conjugated with rhodamine have been synthesized and characterized for their self-assembly. The dendron systems could specifically bind to Hg2+ ion. The binding stoichiometry of the system toward Hg2+ was determined by various techniques, including UV−vis, fluorescence, and Job’s studies. The biocompatibility of the self-assembled systems and cell permeability with no or negligible cytotoxicity provides good opportunities for in vitro cell imaging studies.
References:
(1) Liu, H.; Xu, J.; Li, Y.; Li, Y. Acc. Chem. Res. 2010, 43 (12), 1496. (2) Behzadi, S.; Serpooshan, V.; Tao, W.; Hamaly, M. A.; Alkawareek, M. Y.; Dreaden, E. C.; Brown, D.; Alkilany, A. M.; Farokhzad, O. C.; Mahmoudi, M. Chem. Soc. Rev. 2017, 46 (14), 4218. (3) a) Rajamalli, P.; Sheet, P. S.; Prasad, E. Chem. Commun. (Camb). 2013, 49 (60), 6758. b) Vidhya Lakshmi, N.; Madhu Babu, T.; Prasad, E. Chem. Commun. 2016, 52 (3), 617. c) Kannan, R.; Muthuvijayan, V.; Prasad, E. New J. Chem. 2017, 41 (15), 7453.
PP 15
Interesting N-bearing heterocycles: Synthesis and interaction to ct-DNA
S. K. Manna, and S. Samanta* Department of Chemistry, Bidhannagar College, Kolkata-700064, India E-mail: [email protected]
Deoxyribonucleic acid (DNA), the carrier of genetic information, is the most fundamental building block of life. Interaction of small molecule with DNA always remains a fascinating field. Researchers have designed and synthesized such small molecule which could be an effective one to intercalate/cleave/bind to DNA. Heterocyclic molecules particularly, benzimidazoles, pyrrole fused heterocycles, pyrido pyrimidinium ions and their derivatives (Figure 1) always remain an enthralling field. Hence our focus was to design and developed an efficient, and domino protocol to the formation of important N-bearing heterocycles and to show their interesting bioactivity which could be a potential candidate for cancer diagnosis.
CH3CN Toluene
Jurkat- cell
Figure 1. Nitrogen containing fluorescent heterocyclic molecule.
Reference:
1) S. K. Manna, A. Mandal, S. K. Mondal, A. K. Adak, A. Jana, S. Das, S. Chattopadhyay, S. Roy, S. K. Ghorai, S. Samanta, and M. Hossain Org. Biomol. Chem., 2015, 13, 8037-8047. PP 16
Polyester Systems for Drug Delivery Applications: Design, Synthesis, and Characterization
Anjaneyulu K and Debashis Chakraborty * Department of Chemistry, Indian Institute of Technology Madras, Chennai-600 036, Tamil Nadu, India. E-mail: [email protected]
Polyesters, an important class of biodegradable polymers, have been widely used in drug delivery applications.1–3 Compared to passive targeting; targeted drug delivery method allows for the delivery of encapsulated drugs to the targeted site.2 This method reduce the risk of toxicity to normal cells and allowing for the accumulation of drug in sufficient concentrations to eliminate tumor cells. In this context, polyesters have significant importance for targeted drug delivery applications.2 This motivated us to synthesize fully alternative co-polyesters via ring-opening co- polymerization (ROCOP) method. In the present work, we are successfully synthesized polyesters for the first time through the anionic copolymerization of epoxides with phthalic anhydride, using triethylborane. Using an approach based on the activation of epoxides by Lewis acids and of phthalic anhydride by appropriate Lewis base, well defined alternating copolymers made of phthalic anhydride and epoxides were indeed obtained. Triethylborane was the Lewis acid chosen to activate the epoxides, and phosphazenium cations were selected as Lewis base to initiate the copolymerization. The advantages of such a copolymerization system are manifold: (i) no need for multistep catalyst/ligand synthesis as in previous works; (ii) no transition metal involved in the copolymer synthesis and therefore no toxicity; no coloration of the samples isolated; and (iii) no necessity for post-synthesis purification.
Scheme1. Polyester-polymers used as drug carriers in drug delivery applications
References: [1] O. Coulembier, P. Deg´ee, J. L. Hedrick , and P. Dubois, Prog. Polym. Sci., 2006, 31, 723–747. [2] V. Shantanu Lale, R. G. Aswathy, D. Athulya Aravind, Sakthi Kumar, and Veena Koul, Biomacromolecules, 2014, 15, 1737−1752. [3] (a) L. S. Yan, W. W. Wu, W. Zhao, R. G. Qi, D. M. Cui, Z. G. Xie, Y. B. Huang, T. Tong and X. B. Jing, Polym. Chem, 2012, 3, 2403–2412; (b) W. Zhao, Y. X. Wang, L. Liu, and D. M. Cui, Chem. Commun, 2012, 48, 4588–4590. PP 17
Synthetic, Biological Studies towards Isoindolinones and N-fused heterocycles
Shubhankar Samanta,* and Arabinda Mandal Department of Chemistry, Bidhannagar College, Kolkata 700064, India E-mail: [email protected]
Pyrrole, and isoindolinones moiety are widely distributed in both natural and artificial molecules. The isoindolinones structure has been attracted towards scientists for decades due to number of structures were explored over the years and promising drug conjugates such as thalidomide, lenalidomide isoindolinone based drug used by pregnant women against morning sickness and pomalidomide, Food and Drug Administration (FDA) as drugs against multiple myeloma.1 Further, Pyrrolo-pyridines are important structural constituents of numerous pharmaceuticals, natural products, and biologically active molecules (such as variolins B and A and N(3′)-methyl tetrahydrovariolin B).2 Because of their potential broad spectrum applications, the synthesis of substituted isoindolones, pyrroles, and pyrrolo-pyridine has attracted considerable attention and many synthetic efforts have been devoted so far to synthesise these classes of compounds. In this context, we wish to describe short synthetic route of diversely substituted N-fused hetrocycles via two component one-pot aza-annulation reactions from same scaffolds (Scheme 1). In recent communication, we synthesized library of fused pyrrolo-oxazocinone derivatives in good yields under mild reaction conditions which been successfully employed in bio-analytical imaging in two different cell lines i.e. on a healthy CHO cell line and a cancerous GL261 cell line.3 Hence, our next motivations will be photophysical and biological studies of these new synthesized compounds (Scheme 1).
Scheme 1: Synthetic route of N-fused hetrocycles via two component one-pot aza-annulation reactions
References:
1) a) A. Subbarayappa and P. U. Patoliya, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2009, 48, 545–552; b)R. J. Anderson and J. C. Morris, Tetrahedron Lett. 2001, 42, 8697-8699; c) S. K. Mondal, A. Mandal, S. K. Manna, Sk. A. Ali, M. Hossain, V. Venugopal, A. Jana, S. Samanta, Org. Biomol. Chem. 2017, 15, 2411–2421. PP 18
Detailed Mechanistic study of Beeraiah- Meyer- Schuster Rearrangement leads to a new class of butyrolactone based atropisomeric compounds
Debayan Roy, and Beeraiah Baire* Department of Chemistry, Indian Institute of Technology Madras, Chennai-600 036; E-mail: [email protected]
Previously in our laboratory, we have designed and explored the unconventional reactivity of propargylic alcohols in presence of acids (scheme 1A).1 When a Z-enoate group is attached to propargylic alcohols, they undergo a new type of Meyer-Schuster (M-S) rearrangement,2 by allowing the trapping of the M-S intermediate allenol (equivalent structure 2a) by nucleophiles. According to the proposed mechanism, this process involves the formation of a cyclic allene intermediate 2a. In order to support the proposed mechanism, we attempted to isolate this intermediate. These efforts lead to the generation of a novel class of non-biaryl atropisomeric compounds,3 based on the -arylbutyrolactones (scheme 1B). Systematic characterization of allene intermediate and further studies will be discussed in this presentation.
Scheme 1. A) Beeraiah-Meyer-Schuster Rearrangement; B) Isolation of allene intermediate and new class of non-biaryl atropsiometric compounds.
References
[1] (a) Tharra, P.; Baire, B. Chem. Commun. 2016, 52, 12147. (b) Tharra, P.; Baire, B. Chem. Eur. J. 2017, 23, 2014. [2] Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. B 1922, 55, 819. [3] (a) Feng, J.; Li, B.; He, Y.; Gu, Z. Angew. Chem. Int. Ed. 2016, 55, 2186. (b) Zhang, H. H.; Wang, C. S.; Li, C.; Mei, G. J.; Li, Y.; Shi, F. Angew. Chem. Int. Ed. 2017, 56, 116. (c) Raut, V. S.; Jean, M.; Vanthuyne, N.; Roussel, C.; Constantieux, T.; Bressy, C.; Bugaut, X.; Bonne, D.; Rodriguez, J. J. Am. Chem. Soc., 2017, 139, 2140. PP 19
Cyclic Amidines: Concise Synthesis of Antidepressive Drug Candidate GSK1360707
Kirana Devarahosahalli Veeranna, Kanak Kanti Das and Sundarababu Baskaran* Department of Chemistry, Indian Institute of Technology, Madras, Chennai-600036, India E-mail: [email protected]
Amidine, one of the most important class of pharmacophores, is present in various biomolecules, natural products, and biologically active and pharmaceutically important molecules.1 Moreover, amidine moiety exhibits divergent applications such as ligands, strong bases (PKa ranges from 5- 12) and prominent catalysts.2 Recent biological studies on synthetic amidine derivatives disclosed an antiresorptive, cardiovascular controller, nitric oxide synthase inhibitor and antagonist activities.3 Interestingly, various methods are reported for the construction of cyclic, acyclic and miscellaneous amidines. Practically, synthesis of amidines from amides, nitriles and thioamides are well known in the literature.3 Owing to their biological significance, development of new synthetic strategy for this class of compounds is much sought after. Presently, we have developed stepwise as well as one-pot multi-component methods for the synthesis of novel cyclic amidines using oxidative cyclization of carbanion as a key strategy (Scheme 1 and 2).4,5 The synthetic power of this methodology is exemplified in the concise synthesis of pharmaceutically important antidepressive drug candidate GSK1360707.5
Scheme 1. Silver(I)oxide catalyzed strategy towards the synthesis of cyclic amidines
Scheme 2. Concise synthesis of GSK1360707 from cyclic amidine
References: [1] J. V. Greenhill, P. Lue, Prog. Med. Chem. 1993, 30, 203. [2] J. Barker, M. Kilner, Coord. Chem. Rev. 1994, 133, 219. [3] C. Maccallini, M. Fantacuzzi, R. Amoroso, Mini-Rev. Med. Chem. 2013, 13, 1305. [4] B. Imhyuck, H. Hoon, C. Sukbok, J. Am. Chem. Soc. 2005, 127, 2039. [5] K. D. Veeranna, K. K. Das, S. Baskaran, Angew. Chem., Int. Ed. 2017, DOI: 10.1002/anie.201708138.
PP 20
Hetero Tetranuclear Transition Metal Coordination Complexes
Sai Manoj G N V T and Kartik Chandra Mondal* Department of Chemistry, IIT Madras, Chennai - 600 036 E-mail: [email protected]
III II A hetero-tetra nuclear complex having formula [(L-Me)4Y 2Zn 2 (o-vanillin) 2(MeOH)2] [L=(E)-2-((2-hydroxy-3-methoxybenzylidene)amino)-4-methylphenol][o-Vanillin= 2-Hydroxy- 3-methoxybenzaldehyde] was synthesized and characterized. In this complex the Yttrium metal is octa coordinated and possess distorted square anti prismatic geometry and Zinc is hexa coordinated and possess distorted octahedral geometry. Complex structure contains defect dicubane or butterfly topology with two ZnII ions in the body positions and each YIII ion in the wing positions. This complex is characterized by UV visible studies which show three absorbance bands at 309, 371 and 409 nm. This complex emits at 540 nm when it is excited at 371 and 409 nm. This class of complex has the potential to be utilized as tissue imaging by fluorescent imaging using soft light wave.
Figure 1. Single crystal XRD structure of complex [(L-Me)4Y2Zn2(o-vanillin)2(MeOH)2] and its characterization
References:
1) J.-C. G. Bünzli, J. Lumin. 2016, 170, 866-878. 2) A. J. Amoroso, I. A. Fallis, S. J. A. Pope, Coord. Chem. Rev. 2017, 340, 198-219.
PP 21
Molybdenum Based Metallomicellar Catalyst for Oxidation Reactions in Aqueous Medium P. Thiruvengetam, and D. K. Chand* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036. E-mail: [email protected]
Surfactant based metallomicellar systems are known as efficient catalyst for various organic transformations in aqueous medium.1 Oxomolybdenum complexes have been reported for several industrial processes such as sulfoxidation, olefin epoxidation and olefin metathesis. However, surfactant based oxomolybdenum metallomicellar complexes are less explored.2 A new surfactant based oxodiperoxo molybdenum complex CTA[MoO(O2)2L], Mo1 was developed and utilized for sulfoxidation reactions in our laboratory.3 In the present study, the catalytic activity of surfactant based oxomolybdenum complex, Mo1 has been inquired under eco-friendly condition towards oxidation of aromatic alcohols and olefins. The catalyst, Mo1 is found to be effective to prepare aromatic acids from corresponding benzylic alcohols using aqueous TBHP as green oxidant. This methodology is further extended for the oxidation of olefin derivatives to corresponding acids by increasing the amount of oxidizing agent.
Figure 1. Surfactant based Mo1 catalyzed oxidation reactions under aqueous condition.
References:
1) a) G. L. Sorella, G. Strukul, A. Scarso, Green Chem., 2015, 17, 644. b) S. C. A. Sousa, I. Cabrita, A. C. Fernandes, Coord. Chem. Rev.,2012, 41, 5641. 2) R. D. Chakravarthy, V. Ramkumar, D. K. Chand, Green Chem., 2015, 16, 2190. 3) R. D. Chakravarthy, Sulfoxidation reactions catalyzed by mononuclear oxomolybdenum complexes 2014, PhD thesis, IIT Madras.
PP 22
Quinone-Based Oxidative C-C Coupling of Arylamines
Sudesh Mallick, Sudhakar Maddala and Parthasarathy Venkatakrishnan* Department of Chemistry, Indian Institute of Technology, Madras, Chennai - 600036, Tamilnadu, INDIA. E-mail: [email protected]
While arylamine dimerization was popularly demonstrated using various metal-based oxidants,1 there are only scant reports based on simple organic oxidants.2 Our present work describes the synthesis of several arylamine dimers exploiting quinone-based chloranil/H+ (metal-free) as an organic reagent.3 The complete recyclability of the organic oxidant as well as the metal-free and halogen-free transformation are the key advantages of this synthesis. Using this new method, a variety of benzidines/naphthidines were synthesized from the corresponding arylamines in good to excellent yields. We have examined the steric as well as electronic preferences of oxidative dimerization, and a mechanism involving amine radical cation has been proposed.3 Further, the tetraphenylbenzidine derivative obtained via oxidative C–C coupling has been converted to blue- emissive hole-transporting material (HTM) via a simple chemical transformation. This study highlights the preparation of novel benzidines/naphthidines in a simple, economic and in an efficient manner.
------References:
1) a) M. Periasamy, K. N. Jayakumar, P. Bharathi, J. Org. Chem. 2000, 65, 3548-3550. b) M. Kirchgessner, K. Sreenath, K. R. Gopidas, J. Org. Chem. 2006, 71, 9849-9852. c) K. Sreenath, C. V. Suneesh, V. K. R. Kumar, K. R. Gopidas, J. Org. Chem. 2008, 73, 3245-3251. d) M. Bortoluzzi, F. Marchetti, G. Pampaloni, C. Pinzino, S. Zacchini, Inorg. Chem. 2016, 55, 887-893. 2) a) T. Saitoh, S. Yoshida, J. Ichikawa, J. J. Org. Chem. 2006, 71, 6414− 6419. b) L. Zhai, R. Shukla, R. Rathore, Org. Lett. 2009, 11, 3474-3477. 3) S. Maddala, S. Mallick, P. Venkatakrishnan, J. Org. Chem. 2017, 82, 8958-8972.
PP 23
Ruthenium-Catalyzed Remote C−H Sulfonylation of N-Aryl-2-aminopyridines with Aromatic Sulfonyl Chlorides
Balu Ramesh and Masilamani Jeganmohan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036 E-mail: [email protected]
The transition-metal-catalyzed direct functionalization of unactivated C−H bonds of organic molecules has received considerable attention in organic synthesis for the past two decades.1 Several methods are available in the literature for activating the C−H bond of organic molecules. Among them, the chelation-assisted C−H bond activation has gained tremendous attention due to the high selectivity.2 By employing this method, the ortho C−H bond of aromatics is successfully functionalized as well as extensively studied. Among various methods, ruthenium catalysed C−H bond functionalization of aromatics has gained tremendous attention.3 We reported an unusual ruthenium-catalyzed remote C−H sulfonylation at the C5 position of the pyridine group of N- aryl- 2-aminopyridines with aromatic sulfonyl chlorides via C−H bond activation. Synthesis of variety of sulfonylated N-aryl 2-aminopyridines, detailed mechanistic and DFT calculations will be discussed during this presentation.
References:
1) a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. b) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. 2) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. 3) Manikandan, R.; Madasamy, P.; Jeganmohan, M. ACS Catal. 2016, 6, 230.
PP 24
Organocatalyzed Cross-Aldol Reaction with Nitrosocarbonyl Intermediates toward Stereoselective Synthesistoward α-Hydroxy-β-amino Esters and Amides
Sumitava Mallik and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036 E-mail: [email protected]
A practical and flexible strategy toward α-hydroxy-β-amino esters and amides, which are important biological motifs, based on an organocatalytic cross-aldol reaction of in situ-generated nitrosocarbonyl intermediates followed by hydrogenation is presented. The protocol features operational simplicity, high yields, a wide substrate scope, and high regio- and diastereoselectivity profiles. The utility of this method was showcased through the synthesis of bestatin analogues and indole formation.
References:
(1) (a) Waldman, A.J.; Ng T. L.; Wang, P.; Balskus E. P. Chem. Rev. 2017, 117, 5784−5863. (b) Maji, B.; Yamamoto, H. Angew. Chem., Int. Ed. 2014, 53,14472. (c) Sandoval, D.; Samoshin, A. V.; Read de Alaniz, J. Org. Lett. 2015, 17, 4514. (d) Dana, S.; Ramakrishna, I.; Baidya, M.; Synthesis 2017, 49, 3281. (2) Mallik, S.;Bhajammanavar, V.; Ramakrishna, I.;Baidya, M. Org. Lett.2017, 19,3843. (3) Reddy, M. K.; Mallik, S.; Ramakrishna, I.; Baidya, M. Org. Lett.2017, 19, 1694. (4) Ramakrishna, I.; Bhajammanavar, V.; Mallik, S.; Baidya, M. Org. Lett.2017, 19, 516.
PP 25
Antibacterial Evaluations of Synthesized Diels-Alder Adducts
G. Vinoth Kumar,a* A. Rajendranb a Research and Development Centre, Bharathiar University, Coimbatore, 641 046 b Department of Chemistry, Sir Theagaraya College, Chennai, 600 021; E-mail: [email protected]
The Diels-Alder adducts obtained from the reactions participating isoprene, 2,3-dimethyl-1,3- butadiene, 1,3-cyclohexadiene with various dienophiles have excellent antibacterial activities at specific conditions. The antibacterial activities were analysed for two gram positive and two gram negative bacteria at various concentrations. The concentration at 100 micro litres provides excellent activity against microorganisms. Agar-Well diffusion method was used for culture of microorganisms. Syntheses of various compounds were performed by Biotage microwave reactor. Their structures were confirmed by spectram and the activities of these compounds will be discussed during presentation. Pseudomonas aeruginosa, E. Coli, Bacillus substilis, S. aureas were used as microorganisms.
PP 26
Design and Synthesis of Indole-Based IDO Inhibitors
Ankit Kumar Atri and Deepak B. Salunke* Department of Chemistry, Panjab University, Sector-14, Chandigarh 160 014 E-mail: [email protected]
IDO1 or Indoleamine 2, 3 - dioxygenase is an intracellular enzyme produced by macrophages and other immune regulatory cells in our body. It plays an important role in NAD synthesis as it catalyses the first and rate limiting step for the conversion of L-Tryptophan, an essential amino acid, into N-formyl L-Kynurenine and finally leading to Kynurenine. The depletion of tryptophan in tumor cells is identified as a critical micro-environmental factor involved in aiding immune escape through suppression of anti-tumor immunity. The over expression of IDO is correlated with poor prognosis for survival in patients with age related cataract, Alzheimer’s disease, HIV, ovarian and colorectal cancer etc. Thus, by creating peripheral tolerance to tumor antigens, IDO can undermine immune responses that thwart tumor cell survival in the context of an underlying inflammatory environment that facilitate tumor outgrowth. In preclinical studies, small molecule inhibitors of IDO strongly leverage the efficacy of a variety of classical chemotherapeutic agents, supporting the clinical development of IDO inhibitors as a therapeutic goal. To better understand the IDO active site and its catalytic mechanism, development of new more active analogs is required via systematic Structure Activity Relationship studies. Several IDO inhibitors have been identified in the past, like Brassinin, Norharman, Exiguamine A, 1-methyl-D-Tryptophan etc. Many of these IDO inhibitors have been found to contain an indole moiety in them, so our idea of research is to design and synthesize such indole based molecules that can act as IDO inhibitors. A brief literature survey and our current efforts towards the synthesis of new indole based heterocycles will be presented.
Reference:
1. Qian, S.; Zhang, M.; Chen, Q.; He, Y.; Wang, W.; Wang, Z. IDO as a drug target for cancer immunotherapy: recent developments in IDO inhibitors discovery. RSC Adv., 2016, 6, 7575-7581.
PP 27
A Fe(III)-catalyzed formal [3+2]annulation of indolyl-3-carbinols with alkynes. A Novel approach for the synthesis of cyclopenta[b]indoles
Soniya Gandhi and Beeraiah Baire* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600036; E-mail: [email protected]
Indoles are considered as privileged frameworks in the drug discovery. Among several indole derivatives, cyclopentannulated indoles have attracted great attention from organic chemists owing to their existence in several bioactive natural products and pharmaceutically important compounds such as MK-0524.1 Accordingly, a number of synthetic strategies have been developed for cyclopenta[b]indoles derivatives.2 Here in we developed a novel and efficient strategy for the synthesis of cyclopenta[b]indoles via FeCl3-catalyzed formal [3+2]annulation between indolyl-3-methanols and alkynes. This is the first report of its own kind, in terms of catalyst and starting material employed for this privileged structures. The discovery, development and mechanistic details of this process will be presented in the poster.
Scheme: (a) Our designed strategy for the synthesis of cyclopenta[b]indoles; (b) biologically active natural products with this framework
References:
1) a) I. Ngantchou, B. Nyasse, C. Denier, C. Blonski, V. Hannaert and B. Schneider, Bioorg. Med. Chem. Lett., 2010, 20, 3495. b) J. M. Richter, Y. Ishihara, T. Masuda, B. W.Whitefield, T. Llamas, A. Pohjakallio and P. S. Baran, J. Am. Chem. Soc., 2008, 130, 17938. 2) a) S. Dhiman and S. S. V. Ramasastry, Chem. Commun., 2015, 51, 557. b) P. Marino, Chem. Eur. J., 2017, 23, DOI: 10.1002/chem.201702124.
PP 28
Transition-Metal Catalyzed (Hetero)Arylation of Diazocompounds: Efficient Synthesis of Di(hetero)arylacetic acid derivatives
Jayanta Ghorai, and Pazhamalai Anbarasan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036 E-mail: [email protected]
In last few decades, transition metal catalysis has changed the power of organic chemistry by introducing a wide range of novel synthetic methods for C-C and C-heteroatom bond formations.1 On the other hand, diazocompounds have also emerged as a unique coupling partner in organic chemistry.2 Integration of these method would provide access to new structurally diverse frameworks. Thus, we herein describe the Rh(I) catalyzed coupling of arylboronic acids with diazocompounds to afford diarylacetate derivatives.3 The methodology has been used to synthesis 2-(3,4-dichlorophenyl)-2(4-methoxyphenyl)ethanol and its inhibition of the formation of prostaglandin E2, product of mPGES-1, was estimated.4 Additionally, Cp*Co(III) catalyzed arylation of diazocompound with indole through C2-selective C-H bond functionalization for the synthesis of aryl(heteroaryl)acetic acids will also be described.5
References:
[1] Roglans, A.; Pla-Quintana, A. and Moreno-Manas, M. Chem. Rev. 2006, 106, 4622 [2] Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R. and McKervey, M. A. Chem. Rev. 2015, 115, 9981 [3] Ghorai, J.; Anbarasan, P. J. Org. Chem. 2015, 80, 3455. [4] Devi, N. S.; Shanmugam, R.; Ghorai, J.; Ramanan, M.; Anbarasan, P. and Doble, M. Mol. Inf. 2017, 36, 1700073 [5] Ghorai, J.; Reddy, A. C. S.; Anbarasan, P. Chem. Eur. J. 2016, 22, 16042.
PP 29
Design and Synthesis of New Benzimidazoquinoxaline Derivatives as Modulators of Toll-Like Receptor 7/8
Neeru Goyal, Deepender Kaushik, Dr. Deepak B. Salunke* Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh, 160014; E-mail: [email protected]
Toll-Like receptor (TLR) 7 and 8 agonists are the potential vaccine adjuvants, since they directly activate antigen-presenting cells (APCs) and enhance Th1-driven immune response. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 as well as TLR8 on particular pharmacophore1,2. These include specific heterocyclic small molecules and occupy a small chemical space1,2. Based on the structural features, benzoimidazoquinoxaline scaffold was proposed to be TLR7/8 agonist and efforts were made to synthesize small set of compounds which were purified, characterized and are under biological evaluation for the possible TLR7/8 modulatory activity.
Figure 1. Basic scaffold of Benzoimidazoquinoxaline derivatives.
References:
1) Nikunj M. Shukla, Subbalakshmi S. Malladi, Cole A. Mutz, Rajalakshmi Balakrishna, and Sunil A. David, J. Med. Chem. 2010, 53, 4450–4465. 2) Euna Yoo, Deepak B. Salunke, Diptesh Sil, Xiaoqiang Guo, Alex C. D. Salyer, Alec R. Hermanson, Manoj Kumar, Subbalakshmi S. Malladi, Rajalakshmi Balakrishna, Ward H. Thompson, Hiromi Tanji, Umeharu Ohto, Toshiyuki Shimizu, and Sunil A. David, J. Med. Chem. 2014, 57, 7955−7970.
PP 30
Metal-Free Cross-Coupling of Anilines with Silyl Enol Ethers en route to αAmino Ketones and Extended Synthesis of Densely Functionalized Indoles
Vinod Bhajammanavar, Isai Ramakrishna and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036 E-mail: [email protected]; [email protected]
The -amino ketones constitute a very rapidly developing field of research as molecules containing this functionality are widely represented among pharmaceutically active compounds and complex natural products.1 The invention of practical synthetic strategies toward this high- value synthon has long been a challenge for organic chemists.2.3 Herein, we will discuss a practical protocols for the -amination of ketones using ready stock anilines and silyl enol ethers. This reaction proceeds via regioselective nitroso aldol cascade reaction4 involving C–N bond formation, and N–O bond cleavage in the presence of inexpensive and user-friendly Oxone as oxidant. This method was further extended to synthesis of densely functionalized indoles via vinylogous nitroso aldol cascade in a step economic way. The protocol is operationally simple, scalable, tolerates diverse functional groups and produces synthetically useful molecules in good to excellent yields.
References:
1. Bodnar, B. J.; Miller, M. J. Angew. Chem. Int. Ed. 2011, 50, 5630. 2. Maji, B.; Baidya, M.; Yamamoto, H. Chem. Sci. 2014, 5, 3941. 3. Sandoval, D.; Frazier, C. P.; Bugarin, A.; Read de Alaniz, J. J. Am. Chem. Soc. 2012, 134, 18948. 4. Ramakrishna, I.; Bhajammanavar, V; Mallik, S: Baidya, M. Org.Let. 2017, 19, 516.
PP 31
Synthesis of Toll-Like Receptor 7/8 Agonistic Imidazoquinolines
Simran Dhingra, Deepender Kaushik, Deepak B. Salunke* Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh, 160014; E mail: [email protected]
Toll-like receptors (TLRs) play an important role for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease, hepatitis C, herpes, keratosis, allergy, asthma and systemic lupus erythematosus (SLC). Several TLR7/8 agonists like Imiquimod (A), Resiquimod (B), 852A, ANA773 and many more are now undergoing preclinical and clinical evaluation.1 Among the most active TLR7/8 agonists, the synthetic analogue, 1-benzyl-2-butyl- 1H-imidazo[4,5-c]quinolin-4-amine (C) showed promising results in the primary screening2 but this interesting molecule is not much explored in the biological system because of the synthetic challenges in this molecule. The imidazoquinoline (C) is not commercially available and its promising total synthesis is not yet described in the literature. We focused our research on the complete optimization of the synthetic route of this imidazoquinoline and its analogues from commercially available starting material with good yield. The process is now optimized on small scale and the large scale synthesis is currently ongoing in our laboratory.
Figure 1. Structure of various Toll-Like receptor (TLR)-7/8 agonists.
References:
1) Elizabeth J. Hennesy, Andrew E. Parker and Luke A. J. O’Neill, Nature Review, 2010, 9, 293. 2) Nikunj M. Shukla, Subbalakshmi S. Malladi, Cole A. Mutz, Rajalakshmi Balakrishna, and Sunil A. David, J. Med. Chem. 2010, 53, 4450–4465.
PP 32
Photophysical Properties of Lanthanide Complexes of Non-Fluorinated β- Diktonates and Heterocyclic Amines
Wakeel Ahmed Dar and K. Iftikhar* Department of Chemistry, Jamia Millia Islamia, New Delhi 110 025, India
Non-fluorinated β-Diktonates like acac and heterocyclic amine –pyz are used to synthesize the lanthanide complexes of the variable coordination number (acac= acetylacetone, pyz=pyrazine), their photoluminescence in solid as well as in solution state is observed. The synthesized complexes were characterized by TGA/DTA, 1H NMR, UV/Vis and their photoluminescence is studied for modelling them in organic light emitting diode and their doping in polymers like PVA was also carried out, its photoluminescent properties was also obtainable and its photostability is also reported, making them favourable candidates for PLEDs.
Key Words: Lanthanides, Paramagnetic NMR, photoluminescence, absorption, energy level.
PP 33
Synthesis of 2-Acylbenzo[b]thiophenes via Cu-Catalyzed α-C-H Functionalization of 2-Halochalcones Using Xanthate as Sulfur Surrogate
S. Sangeethaa and G. Sekar * Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036; E-mail: [email protected]
Sulfur-containing compounds are extensively found in many pharmaceuticals and bioactive natural products.1 In particular, benzo[b]thiophene core containing acyl group in the 2-position are privileged scaffolds in medicinal chemistry.2 Importantly, use of odorless sulfur source from easily available starting material to construct in situ benzo[b]thiophene ring as well as selectively acyl group in the 2-position without using any external acyl source is highly desirable. As part of our ongoing research using xanthate as sulfur surrogate,3 recently we have developed an efficient, novel protocol for the synthesis of 2-acylbenzo[b]thiophenes from easily accessible 2- iodochalcones through α-C-H functionalization using Cu(OAc)2 catalyst and xanthate as sulfur surrogate (Scheme 1).4 This method is successfully applied to synthesize of diversely substituted 2-acylbenzo[b]thiophenes in good to excellent yields. Importantly, less reactive 2- bromochalcones also yielded the corresponding 2-acylbenzo[b]thiophenes in good yield. The reaction proceeds via in situ incorporation of sulfur followed by copper catalyzed cyclization to generate 2-acylbenzothiophenes without any external acyl source. The synthetic importance of the present methodology has been showed by synthesis of 1-(5-hydroxybenzothiophene-2- yl)ethanone in one step, which is a known pre-mRNA splicing modulator.
Scheme 1. Cu-Catalyzed synthesis of 2-acylbenzo[b]thiophenes using xanthate sulfur.
References:
1) a) Sulphur- Containing Drugs and Related Organic Compounds; Damani, L. A., Ed.; Wiley: New York, 1989. (b) Clayden, J.; MacLellan, P. Beilstein. J. Org. Chem. 2011, 7, 582. 2) a) Miralinaghi, P.; Schmitt, C.; Hartmann, R. W.; Frotscher, M.; Engel, M. ChemMedChem 2014, 9, 2294- 2308. (b) Romagnoli, R.; Baraldi, P. G.; Cara, C. L.; Hamel, E.; Basso, G.; Bortolozzi, R.; Viola, G. Eur. J. Med. Chem. 2010, 45, 5781-5791. 3) a) Prasad, D. J. C.; Sekar. G. Org. Lett. 2011, 13, 1008-1011. (b) Sangeetha, S.; Muthupandi, P.; Sekar, G. Org. Lett. 2015, 17, 6006-6009. 4) Sangeetha, S.; Sekar, G. Org. Lett. 2017, 19, 1670-1673. PP 34
Efficient Synthesis of Tryptamine Derivative from Indoles via Aminoethylation
Shanmugam Rajasekar, and Pazhamalai Anbarasan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036; E-mail: [email protected]
Substituted tryptamines are important structural motif found in many natural and biological active componds1. In particular, serotonin, 5-hydroxytryptamine is a neurotransmitter that is involved in the control of an organism’s state of mind and also influences the nervous system. Since the tryptamines are essential pharmacophore unit in various molecules, development of elegant synthesis of tryptamine derivatives is highly important. On the other hand, N-sulfonyl- 1,2,3-triazoles, potential surragate of diazo-imine,2 readily decomposes in the presence of rhodium(II) salt to give rhodium-bound imino carbene, which undergoes many synthetically useful transformations.3 In this context, we have developed a general and efficient one-pot aminoethylation of substituted indoles/pyrroles for the synthesis of various tryptamine derivatives employing alkynes and sulfonyl azides as readily accessible aminoethylating agent.4 Synthesized tryptamine derivative exhibiting pharmacophore activity towards multi-targeted inhibition of arachidionic acid cascade same will be presented.5
References:
1) a) Barceloux, D. G., in Medical Toxicology of drug abuse, Wiley, Hoboken, 2012, 193. b) Mitchell E. S.; Hoplight B. J.; Lear S. P.; Neumaier J. F. Neuropharmacology 2006, 50 412. c) Kochanowska-karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. 2) a) Anbarasan, P.; Yadagiri, D.; Rajasekar, S. Synthesis 2014, 46, 3004. b) Davies, H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 43, 5151. c) Guleveich, A. V.; Gevorgyan, V. Angew.Chem. Int. Ed. 2013, 52, 1371. 3) a) Horneff, P. T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972. b) Miura, T.; Tanaka, T.; Hiraga, K.; Stewart, S. G.; Murakami, M. J. Am. Chem. Soc. 2013, 135, 13652. c) Yadagiri, D.; Anbarasan, P. Org.Lett. 2014, 16, 2510. 4) Rajasekar, S.; Yadagiri, D.; Anbarasan, P. Chem Eur. J. 2015, 21, 17079. 5) Devi, N. S.; Rajasekar, S.; Ghorai. J.; Ramanan. M.; Anbarasan. P.; Doble, M. Mol. Inf. 2017, 36, 1700073. PP 35
New Drug Delivery Systems from Oxanorbornane-based Non-Ionic Amphiphiles
Soumya Saroj, U. Chandrashekhar Reddy and K. M. Muraleedharan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036; E-mail: [email protected]
Efficient and safe drug delivery has always been a challenge in the medical field. Multidrug therapy will be beneficial in many disease conditions like cancer, tuberculosis, malaria, HIV/AIDS, leishmaniasis etc where resistance issues can lead to poor treatment outcome on mono-therapy. 1, 2 Hence it is highly desirable to design novel drug carriers that can harbour multiple drugs. This however is a challenging task as it should not affect the drug efficacy and treatment goals. Unique structures of amphiphiles allow them to self-assemble differently in polar and nonpolar environment into lamellar, micellar, vesicular and fibrous structures3 Certain amino acid-modified chiral oxanorbornane-based amphiphiles synthesised in our lab, when taken in solvents like acetone, methanol were found to aggregate to vesicular structures. The drug loading & release profiles of these aggregates were then studied and these results will be discussed here4.
References:
1) Gorter, E.; Grendel, F. J Exp. Med. 1925, 41, 439 2) Hu. Aryal.; Zhang., Therap Delv, 2010. 1(2), 323 3) Mokhtari. R.B.; Homayouni.T.S.; Baluch.N.; Morgatskaya. E.; Kumar.S.; Das.B.; Yeger.H, Oncotarget, 2017, 8(23), 38022 4) (a) Janni.D.S.;Reddy.U.C.; Saroj.S.; Muraleedharan.K.M.; J.Mater.Chem.B. 2016; (b) Muraleedharan K.M.; U Chandrasekhar Reddy.; Soumya Saroj.; D. Sirisha Janni.; M. Ganeshan. Drug delivery applications of oxanorbornate-based amphiphiles. Patent 201641037950. 06 Nov 2017
PP 36
Partially Folded Conformations Through Α,Β 2,3-Hybrid Peptides
P. J. Gana, D. Balamurugan and Kannoth Manheri Muraleedharan * Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036; E-mail: [email protected]
Synthetic peptides comprising of building blocks like - and -amino acids are attractive candidates for targeting protein-protein interactions relevant in disease conditions like cancer.[1] Such systems fall under the category of foldamers, which are oligomers that can adopt well- defined conformation in solution. [2] While there have been significant efforts to understand the conformational preferences in this class of molecules, not much attention is given to systems which can exist in partially folded states, or undergo conformational transitions in a systematic manner. As part of our interest in this area, we are working on synthetic oligomers from -2,3- amino acids with different combination of chirality at - and -positions. This has resulted in a number of systems which can either exist in partially folded states or respond to polarity changes through specific torsional changes.[3] The design concepts and experimental results from our studies will be discussed during this presentation.
Strand Half-Helix Half-Strand
References:
1) C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem. Biol., 2007, 3, 252; b) M. Raj, B. N. Bullock and P. S. Arora, Bioorg. Med. Chem., 2013, 21, 4051. 2) D. Seebach and J. L. Matthews, Chem. Commun., 1997, 2015, 101, 3893-4012. (b) S. H. Gellman, Acc. Chem. Res., 1998, 31, 173. 3) (a) D. Balamurugan and K. M. Muraleedharan, Eur. J. Chem., 2015, 24, 5321; (b) D. Balamurugan and K. M. Muraleedharan. Chem. Eur. J., 2015, 21, 9332.
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Aryl-triazolyl amino acids based Pt (II) complexes and cationic peptides with potential anticancer properties
Bhartendu K Srivastava, Soumya saroj and K. M. Muraleedharan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036; E-mail: [email protected]
Design of oligomerizable building-blocks with inbuilt features for metal-complexation, conformation-control or supramolecular preferences can help in the development of new therapeutically important systems. Synthetic amino acids with inbuilt ‘bidentate ligand pocket’ are attractive building-blocks for the design of such therapeutically important chemical systems. Although their importance is well-recognized, a literature search revealed that only a limited number of ligands (eg. bipy) have been utilized for the design of such monomers.1 Introduction of new ligand combinations would indeed be valuable and is explored in the present work through amino acids having triazole-isoxazole (1) and aryl-triazolyl units (2)2. Apart from this, we have used aryl-triazolyl oligomers to prepare polycationic systems with good affinity towards DNA.3 The synthetic and characterization details these amino acids, peptides and their DNA interaction studies will be the subject of this presentation.
References:
1) a) Imperiali, B.; Fisher, S. L., J. Am. Chem. Soc. 1991, 113, 8527-8528G; b) Drienovska, I.; Rioz-Martinez, A.; Draksharapu, A.; Roelfes, G., Chem. Sci. 2015, 6, 770-776. 2) a) Srivastava, B. K.; Manheri, M. K., Chem. Commun. 2017, 53, 4485-4488; b) Srivastava, B. K.; Manheri, M. K., RSC Adv. 2016, 6, 29197-29201. 3) B K Srivastava, Soumya Saroj and K M Muraleedharan (manuscript under preparation).
PP 38
Design, synthesis and DNA binding abilities of polycationic peptide-Pt conjugates
Sateeshkumar K a, Kasipandi V a, Soumya Saroj a, Karunagaran D b, Muraleedharan K M a * a Department of Chemistry, b Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600 036; E-mail: [email protected]
Platinum-based chemotherapeutic agents are widely used for the treatment of various cancers such as testicular, ovarian, bladder, head & neck, lung and cervical cancers.1 Although effective, severe side effects and resistance development are the key issue that affect treatment success. The adverse side effects associated with Pt based chemotherapeutic agents arise due to their non- specific interaction with normal healthy cells.2 Several approaches are being followed currently to address these issues, such as attachment of a tumor targeting template to platinum warhead, pro-drug approach and use of nano delivery systems.3 Peptides are important class of targeting templates and extensively studied for tumor targeting of anti- cancer drugs.4 In this context, we present our approach for the synthesis of polycationic peptide platinum conjugates by using the diazides generated from amino acids serine and threonine. Design concepts, synthesis protocols, DNA binding abilities and results from preliminary biological studies will be discussed during this presentation.5
a b c b
Figure:1. Polycationic peptide platinum conjugate 1 (a), competitive EtBr displacement assay result of 1 (b), DNA conformational changes monitored by CD spectroscopy upon addition of 1. (c)
References:
1) Florea, A-M.; Busselberg. Cancers. 2011, 3, 1351. 2) Elizabeth, R.J.; Lippard, S. J. Chem. Rev. 1999, 99, 2467. 3) Johnstone, T. C.; Suntharalingam, K.; Lippard. S. J. Chem. Rev. 2016, 116, 3436. 4) Ndinguri, M.W.; Rajasree, S.; Robert, P.G.; Sita. A.; Robert. P.H. Bioconjugate Chem. 2009. 20, 1869. 5) Sateeshkumar, K.; Kasipandi, V.; Soumya, S.; Nalini, V.; Karunagaran, D,; Muraleedharan, K.M. manuscript submitted.