DOCSLIB.ORG

Organic Chemistry Frontiers

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Organic Chemistry Frontiers ORGANIC CHEMISTRY FRONTIERS View Article Online REVIEW View Journal | View Issue Stereoselective synthesis and applications of spirocyclic oxindoles Cite this: Org. Chem. Front., 2021, 8, 1026 Alexander J. Boddy and James A. Bull * The development of novel synthetic strategies to form new chemical entities in a stereoselective manner is an ongoing significant objective in organic and medicinal chemistry. This review analyses the develop- Received 11th September 2020, ment of new stereoselective approaches to spirocyclic oxindoles with spiro-3- to 8-membered rings. It Accepted 5th January 2021 highlights the importance of these structures for applications in medicinal chemistry, as intermediates or DOI: 10.1039/d0qo01085e final products in total synthesis and as model compounds for the development of enantioselective cata- rsc.li/frontiers-organic lytic methodologies. the substituents of the rings.2 Spirocyclic compounds can Creative Commons Attribution 3.0 Unported Licence. Introduction improve certain physicochemical properties such as lipophili- The application of spirocyclic structures in drug discovery has city, aqueous solubility and metabolic stability, in comparison seen a dramatic increase in attention in recent years, alongside to the respective monocyclic structure.3 Furthermore, they major developments in their synthetic chemistry.1 Defined as a access relatively underexplored chemical space and novel intel- bicycle connected by a single fully-substituted carbon atom, lectual property (IP) space. Saturated spirocycles provide a which is not connected by an adjacent atom, spirocycles are dense, rigid scaffold, with the potential to append more substi- inherently highly 3-dimensional structures. The shared tetra- tuents, and so occupy an increased number of defined vectors hedral sp3-carbon atom positions the planes of the 2 rings compared to flat aromatic compounds.4 All of these factors have This article is licensed under a orthogonally, despite the torsional strain this may impose on contributed to a greater uptake in medicinal chemistry and have demanded significant advances in organic synthesis to provide spirocycles in a controlled and stereoselective manner.5 Department of Chemistry, Imperial College London, Molecular Sciences Research This review focuses specifically on spirocyclic oxindoles Open Access Article. Published on 06 January 2021. Downloaded 3/11/2021 10:31:59 AM. Hub, White City Campus, Wood Lane, London W12 0BZ, UK. E-mail: [email protected] (spirooxindoles or spiroindolones). These are a widespread Alexander Boddy graduated from Dr James Bull is a University Durham University with an Research Fellow at Imperial MChem with Industrial Training College London. His research in 2016, including a final year focuses on the development of placement at Infineum UK. He synthetic and catalytic methods completed his PhD in the labora- to access medicinally relevant tory of Dr James A. Bull at structural motifs and hetero- Imperial College London in cycles. He obtained his MSci 2020. His PhD research, in col- degree from the University of laboration with AstraZeneca, Cambridge, then spent a year at developed new synthetic method- GlaxoSmithKline. He returned to ologies to access saturated het- University of Cambridge for his Alexander J. Boddy erocycles for potential use in James A. Bull PhD with Professor Steven Ley. drug discovery. Alexander is now In 2007 he joined Université de a Senior Scientist in Chemical Montréal as a postdoc with Professor André Charette. He started a Development at GlaxoSmithKline. Ramsay Memorial Fellowship at Imperial College in 2009, an EPSRC Career Acceleration Fellowship in 2011, and in 2016 was awarded a Royal Society University Research Fellowship. 1026 | Org. Chem. Front.,2021,8,1026–1084 This journal is © the Partner Organisations 2021 View Article Online Organic Chemistry Frontiers Review motif within modern organic synthesis, drug discovery and 5- and 6-membered rings (silver and gold in Fig. 2) dominates natural product chemistry. Stereoselective synthetic methods the contribution to this total. However, in the last decade the towards this privileged class of spirocycles have seen enor- relative contribution of 3-, 4- and 7-membered spirocycles mous development in recent years. This review aims to (dark/light blues and orange) has increased. combine the analysis of recent synthetic strategies with an We also analysed the frequency of the different types of overview of the importance of these scaffolds for medicinal rings which feature in this review (Fig. 3). Considering 3-mem- chemistry and in natural product synthesis. Since 1950 there bered spirocycles, we can see that cyclopropane rings are have been 6896 publications containing spirooxindoles, 3283 much more common than their aziridine or epoxide ana- of these publications have appeared since 2012.15 Oxindoles logues. Similarly, cyclobutanes far outnumber azetidines or are often used as rigid scaffolds for testing new asymmetric oxetanes. Notably the number of oxetanes is surprisingly low, synthetic methodology and due to the demand of discovery especially, when compared to azetidines. The position of the chemistry for controlled and modular syntheses, and with the heteroatom has a significant influence on the frequency of a plethora of publications in this area, we will focus on stereo- certain ring. This may generally correlate with ease of synthesis selective processes. This review examines spirocyclic oxindoles or lower complexity, i.e. 3,4′-spirotetrahydropyran oxindoles far containing a spiro-(3 to 8)-membered ring, in turn, analysing outnumber the 3,2′- or 3,3′-analogues. 7-Membered rings are carbocyclic then monoheteroatom nitrogen-containing and generally underrepresented when bridged examples are dis- oxygen-containing spirocycles. The review will cover recent counted (these will generally have been counted in the developments from 2013, following major work by Singh and numbers for other ring sizes as these are a less significant con- Desta,6 until April 2020. Specific bioactivity and applications tribution). There is only one example of a non-bridged mono- of each ring system will be discussed at the start of the relevant heteroatom containing 8-membered spirooxindole in the lit- section and provide a reference work for the preparation of erature (synthesised as an analogue of cipargamin).16 different spirocyclic patterns. Within each section, the discus- Although there will be a clear correlation between the Creative Commons Attribution 3.0 Unported Licence. sion is split by the reaction type employed to construct the number of publications for each ring size, we have tried to spirocycle. discuss each ring type on an equal basis, though inevitably the Fig. 1 shows a representative set of each ring system, which 5-membered nitrogen section is largest. will be covered in this review, as they feature in medicinal or natural products.7 Notable biological activity is indicated, including use as anti-cancer agents,8 and anti-viral agents.9 Three-membered rings Some ring types are not represented in these bioactive com- pounds, i.e. aziridines, likely due to their instability relative to Spirocyclopropyl oxindoles larger ring sizes, but will nonetheless be featured in the Three-membered ring containing spiroindolones feature in This article is licensed under a review. pharmaceutical compounds as well as being used as reactive Given the importance of this structural class, spirocyclic intermediates, i.e. in ring opening reactions.17 These ring oxindoles have been featured in other reviews discussing their opening reactions can often be coupled with ring closing reac- 10 11 Open Access Article. Published on 06 January 2021. Downloaded 3/11/2021 10:31:59 AM. synthesis, including asymmetric synthesis, use of isatin tions to form spirocycles of larger ring size. There has recently starting materials12 or the synthesis of target product been an excellent review on the catalytic enantioselective syn- scaffolds.13 General reviews on spirocyclic compounds (i.e. thesis of polysubstituted spirocyclopropyl oxindoles by Cao spiroindolenes) also often contain spirocyclic oxindoles and Zhou,18 as well as a review of transition metal-free strat- without specifically focusing on these.14 We expect the analysis egies by Ashfeld.19 presented in this review of the structural types, synthesis and Applications. Spirocyclopropyl oxindoles are featured in a applications to lead to further studies, and aid in the identifi- wide variety of reports showing their bioactivity (see Fig. 1 for cation of future opportunities to expand the applications of examples). These bioactivities include examples of antitumour this fascinating class of compounds. agents,20 pain treatment,21 treatment of CNS disorders,22 anti- virals,23 among others.24 Direct methylene cyclopropanation. Direct cyclopropanation Frequency analysis of spirooxindoles methodology with unprotected oxindoles has been a synthetic challenge which has seen many recent advances (Scheme 1). To quantify the importance of spiroindolones in the medicinal In 1987, a team at Lilly synthesised spirocycle 2 as a route to a chemistry and organic synthesis literature, we analysed publi- phosphorodiesterase inhibitor (Scheme 1A).25 Since this low cations which feature spiroindolones containing up to one yielding and step-inefficient synthesis using strong base, heteroatom in the spirocycle between 1970–2020 (Fig. 2).15 The Marini reported cyclopropanation using a vinyl selenone number of
Load more

Recommended publications
  • Synthesis of Indole and Oxindole Derivatives Incorporating Pyrrolidino, Pyrrolo Or Imidazolo Moieties
    From DEPARTMENT OF BIOSCIENCES AT NOVUM Karolinska Institutet, Stockholm, Sweden SYNTHESIS OF INDOLE AND OXINDOLE DERIVATIVES INCORPORATING PYRROLIDINO, PYRROLO OR IMIDAZOLO MOIETIES Stanley Rehn Stockholm 2004 All previously published papers have been reproduced with permission from the publishers. Published and printed by Karolinska University Press Box 200, SE-171 77 Stockholm, Sweden © Stanley Rehn, 2004 ISBN 91-7140-169-5 Till Amanda Abstract The focus of this thesis is on the synthesis of oxindole- and indole-derivatives incorporating pyrrolidins, pyrroles or imidazoles moieties. Pyrrolidino-2-spiro-3’-oxindole derivatives have been prepared in high yielding three-component reactions between isatin, α-amino acid derivatives, and suitable dipolarophiles. Condensation between isatin and an α-amino acid yielded a cyclic intermediate, an oxazolidinone, which decarboxylate to give a 1,3-dipolar species, an azomethine ylide, which have been reacted with several dipolarophiles such as N- benzylmaleimide and methyl acrylate. Both N-substituted and N-unsubstituted α- amino acids have been used as the amine component. 3-Methyleneoxindole acetic acid ethyl ester was reacted with p- toluenesulfonylmethyl isocyanide (TosMIC) under basic conditions which gave (in a high yield) a colourless product. Two possible structures could be deduced from the analytical data, a pyrroloquinolone and an isomeric ß-carboline. To clarify which one of the alternatives that was actually formed from the TosMIC reaction both the ß- carboline and the pyrroloquinolone were synthesised. The ß-carboline was obtained when 3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester was treated with a tosylimine. An alternative synthesis of the pyrroloquinolone was performed via a reduction of a 2,3,4-trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions.
    [Show full text]
  • Crowdsourcing Analysis of Off-Label Intervention Usage in Amyotrophic Lateral Sclersosis
    CROWDSOURCING ANALYSIS OF OFF-LABEL INTERVENTION USAGE IN AMYOTROPHIC LATERAL SCLERSOSIS A Thesis Presented to The Academic Faculty by Benjamin I. Mertens In Partial Fulfillment of the Requirements for the Degree B.S. in Biomedical Engineering with the Research Option in the Wallace H. Coulter School of Biomedical Engineering Georgia Institute of Technology Spring 2017 1 ACKNOWLEDGEMENTS I would like to thank my research advisor, Dr. Cassie Mitchell, first and foremost, for helping me through this long process of research, analysis, writing this thesis and the corresponding article to be submitted for peer-reviewed journal publication. There is no way I could have done this, or written it as eloquently without her. Next, I would like to acknowledge Grant Coan, Gloria Bowen, and Nathan Neuhart for all helping me on the road to writing this paper. Lastly, I would like to thank Dr. Lena Ting for her consultation as the faculty reader. 2 TABLE OF CONTENTS Page ACKNOWLEDGEMENTS 2 LIST OF TABLES 4 LIST OF FIGURES 5 LIST OF ABBREVIATIONS 6 SUMMARY 7 CHAPTERS 1 Philosophy 9 2 Crowdsourced Off-label Medications to Extend ALS Disease Duration 12 Introduction 12 Methodology 15 Results 18 Discussion 25 Tables 33 Figures 38 APPENDIX A: All Table 2 Appearance in Patients and Visits 44 APPENDIX B: All Table 3 Appearance in Patients and Visits 114 REFERENCES 129 3 LIST OF TABLES Page Table 1: Database Overview 33 Table 2: Ontology of Individual Medications 34 Table 3: Ontology of Intervention Groups 36 4 LIST OF FIGURES Page Figure 1: Relational circle
    [Show full text]
  • Practice Questions of Backlog Examination - 20 Questions (2M Each) Select Correct Answer for the Following Multiple Choice Questions
    Practice Questions of backlog examination - 20 Questions (2M each) Select correct answer for the following Multiple Choice Questions. Final Year B. Pharm. (Sem-VII) (CBSGS) Pharmaceutical Chemistry III 1. One of these is a HDAC inhibitor. a. Vorinostat b. Epalristat c. Imatinib d. Oxaliplatin 2. AZT, an antiviral agent is a a. Protease inhibitor b. Nonnucleoside RT inhibitor c. Nucleoside RT inhibitor d. Entry inhibitor 3. The sugar present in digitalis glycosides is a. Sucrose b. Glucose c. Digitoxose d. Galactose 4. The active metabolite of verapamil is a product of a. O-dealkylation b. C-dealkylation c. N-dealkylation d. Reduction 5. The epimer of Qunidine has the following activity a. Anti-diabetic b. Anti-malarial c. Analgesic d. Antihypertensive 6. N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide is the IUPAC name of a. Furosemide b. Acetazolamide c. Methazolamide d. Thiazoleamide 7. Enalapril and captopril are a. ACE inhibitors b. Prodrugs c. Used in diarrhoea d. Used as a prodrug Practice Questions of backlog examination - 20 Questions (2M each) Select correct answer for the following Multiple Choice Questions. 8. The Phase -2 metabolite of one of these drugs is active a. Esmolol b. Prazocin c. Minoxidil d. Timolol 9. Which of following is anthranilic acid derivative? (a) Furosemide (b) Bumetanide (c) Ethacrynic acid (d) None 10. Aspirin is chemically a. A reverse ester of salicylic acid b. An amide of salicylic acid c. An ester of salicylic acid d. An imide of salicylic acid 11. The structure of 5-Fluorouracil, an anticancer agent has a. Purine nucleus b.
    [Show full text]
  • Highly Efficient Endo'- Selective Synthesis of (Dispiro 3,2
    J. Chem. Sci. Ó (2020) 132:76 Indian Academy of Sciences https://doi.org/10.1007/s12039-020-01772-7Sadhana(0123456789().,-volV)FT3](0123456789().,-volV) REGULAR ARTICLE Highly efficient endo’- selective synthesis of (dispiro 3,20- pyrrolidinyl) bisoxindoles containing three contiguous chiral stereocenters with two contiguous quaternary spirostereocenters PANNEERSELVAM YUVARAJa,* , HUIDROM BIRKUMAR SINGHa, ARUN PRASATH LINGAM KANDAPALAMb, DEVARAJAN KATHIRVELANc and SANKARANARAYANAN NAGARAJANd aCSIR-North East Institute of Science and Technology, Branch Laboratory, Imphal, Manipur 795004, India bDepartment of Chemistry, Kamaraj College, Thoothukudi, Tamil Nadu 628003, India cDepartment of Chemistry, Indian Institute of Technology-Hyderabad, Kandi, Telangana 502285, India dDepartment of Chemistry, National Institute of Technology Manipur, Imphal 795004, India E-mail: [email protected]; [email protected] MS received 15 November 2019; revised 6 January 2020; accepted 9 January 2020 Abstract. An efficient, atom economical, one-pot synthesis of endo’- selective (dispiro 3,20-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved by three-component reaction of isatins, malononitrile (cyanoacetic ester) and 1,3- dicarbonyl compounds in water in the presence of L-proline. One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst have also been achieved in good yields. This new methodology offers many advantages of catalyst-free,
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9.260,446 B2 Cadieux Et Al
    USOO926O446B2 (12) United States Patent (10) Patent No.: US 9.260,446 B2 Cadieux et al. (45) Date of Patent: Feb. 16, 2016 (54) SYNTHETIC METHODS FOR 5,663,431 A 9, 1997 Di Malta et al. SPIRO-OXINDOLE COMPOUNDS 5,686,624 A 11/1997 Di Malta et al. 5,696,145 A 12/1997 Foulon et al. (71) Applicant: Xenon Pharmaceuticals Inc., Burnaby 5,723,625 A 3/1998 Keplinger et al. (CA) 5,726,322 A 3, 1998 Di Malta et al. Inventors: 5,728,723 A 3, 1998 Di Malta et al. (72) Jean-Jacques Alexandre Cadieux, 5,763,471 A 6/1998 Fourtillan et al. Burnaby (CA); Mikhail Chafeev, 5,767,128 A 6/1998 Guillaumet et al. Khimki (RU); Sultan Chowdhury, 5,776,936 A 7/1998 Lee et al. Surrey (CA); Jianmin Fu, Coquitlam 5,849,780 A 12/1998 Di Malta et al. (CA); Qi Ji, Burnaby (CA); Stefanie 5,886,026 A 3, 1999 Hunter et al. 5,994,350 A 11/1999 Foulon et al. Abel, Thalwil (CH); Emad El-Sayed, 6,046,341 A 4/2000 Foulon et al. Zumikon (CH); Elke Huthmann, Buchs 6,090,818 A 7/2000 Foulon et al. (CH); Thomas Isarno, Niffer (FR) 6,099,562 A 8/2000 Ding et al. 6,110,969 A 8, 2000 Tani et al. (73) Assignee: Xenon Pharmaceuticals Inc., Burnaby 6,225,347 B1 5/2001 Buchmann et al. 6,235,780 B1 5, 2001 Ohuchida et al. (CA) 6,262.293 B1 7/2001 Tani et al.
    [Show full text]
  • Enzyme Evolution in Fungal Indole Alkaloid Biosynthesis Amy E
    REVIEW ARTICLE Enzyme evolution in fungal indole alkaloid biosynthesis Amy E. Fraley1,2 and David H. Sherman1,2,3,4 1 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA 2 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 3 Department of Chemistry, University of Michigan, Ann Arbor, MI, USA 4 Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA Keywords The class of fungal indole alkaloids containing the bicyclo[2.2.2]diazaoc- biosynthesis; Diels–Alderase; natural tane ring is comprised of diverse molecules that display a range of biologi- products; nonribosomal peptides; cal activities. While much interest has been garnered due to their monooxygenase therapeutic potential, this class of molecules also displays unique chemical Correspondence functionality, making them intriguing synthetic targets. Many elegant and D. H. Sherman, Life Sciences Institute, 210 intricate total syntheses have been developed to generate these alkaloids, Washtenaw Avenue, Ann Arbor, MI 48104, but the selectivity required to produce them in high yield presents great USA barriers. Alternatively, if we can understand the molecular mechanisms Tel: +734 615 9907 behind how fungi make these complex molecules, we can leverage the E-mail: [email protected] power of nature to perform these chemical transformations. Here, we describe the various studies regarding the evolutionary development of (Received 21 August 2019, revised 24 November 2019, accepted 27 February enzymes involved in fungal indole alkaloid biosynthesis. 2020) doi:10.1111/febs.15270 Introduction to fungal indole alkaloids The fungal indole alkaloid class of natural products knowledge gaps with detailed biochemical characteri- contains molecules with unique structural properties zation.
    [Show full text]
  • Breaking Barriers to Novel Analgesic Drug Development
    REVIEWS Breaking barriers to novel analgesic drug development Ajay S. Yekkirala1–3, David P. Roberson1–3, Bruce P. Bean1 and Clifford J. Woolf1,2 Abstract | Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors. Pain is the primary reason why people seek medical blockbuster model of one treatment for all pain condi- Analgesics 12 Pharmacological agents or care: more than 40% of the US population is affected tions is not tenable . The poor predictability of preclin- 1 ligands that produce analgesia. by chronic pain . In the United States alone in 2013, the ical ‘pain’ models can result in candidates being selected overall cost of treating certain chronic pain conditions that do not have activity in the conditions suffered by Tolerance amounted to more than US$130 billion2. Currently avail- patients13 (BOX 1). Conversely, difficulty in ensuring A state in which the drug no analgesics longer produces the same able — nonsteroidal anti-inflammatory drugs target engagement, lack of sensitivity of clinical trials effect and a higher dose is (NSAIDs), amine reuptake inhibitors, anti epileptic and distortions induced by placebos increase the risk therefore needed.
    [Show full text]
  • Fernandez-Sanchez Et Al
    Amino Acids (2002) 23: 31–36 DOI 10.1007/s00726-001-0106-6 Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity M. T. Fernández-Sánchez 1, R. Díaz-Trelles 1, A. Groppetti 3, B. Manfredi 3, A. T. Brini 3, G. Biella 4,5, M. L. Sotgiu 5, and A. Novelli 1,2 1 Department of Biochemistry and Molecular Biology, University of Oviedo, Oviedo, Spain 2 Department of Psychology, University of Oviedo, Oviedo, Spain 3 Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy 4 Department of Science and Biomedical Technologies, University of Milan, Milan, Italy 5 Institute of Neuroscience and Bioimaging, CNR, Segrate, Italy Received June 29, 2001 Accepted August 6, 2001 Published online June 3, 2002 © Springer-Verlag 2002 Summary. Nefopam hyghochloride is a potent analgesic compound have demonstrated nefopam to be very effective in the commercialized in most Western Europe for 20 years, which pos- prevention of postoperative shivering in patients after sesses a profile distinct from that of opioids or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam general anesthesia (Rosa et al., 1995) without affecting but the detailed mechanisms remain unclear. While, nefopam struc- the recovering time between the end of anesthesia and ture resembles that of orphenadrine, an uncompetitive NMDA extubation (Piper et al., 1999). Unpleasant adverse receptor antagonist, here we report that differently from effects during therapeutic use have been also reported orphenadrine, nefopam (100 µM) failed to protect cultured cerebel- lar neurons from excitotoxicity following direct exposure of neurons including dizziness, headache, nausea, vomiting and to glutamate.
    [Show full text]
  • Small Dose... Big Poison
    Traps for the unwary George Braitberg Ed Oakley Small dose... Big poison All substances are poisons; Background There is none which is not a poison. It is not possible to identify all toxic substances in a single The right dose differentiates a poison from a remedy. journal article. However, there are some exposures that in Paracelsus (1493–1541)1 small doses are potentially fatal. Many of these exposures are particularly toxic to children. Using data from poison control centres, it is possible to recognise this group of Poisoning is a frequent occurrence with a low fatality rate. exposures. In 2008, almost 2.5 million human exposures were reported to the National Poison Data System (NPDS) in the United Objective States, of which only 1315 were thought to contribute This article provides information to assist the general to fatality.2 The most common poisons associated with practitioner to identify potential toxic substance exposures in children. fatalities are shown in Figure 1. Polypharmacy (the ingestion of more than one drug) is far more common. Discussion In this article the authors report the signs and symptoms Substances most frequently involved in human exposure are shown of toxic exposures and identify the time of onset. Where in Figure 2. In paediatric exposures there is an over-representation clear recommendations on the period of observation and of personal care products, cleaning solutions and other household known fatal dose are available, these are provided. We do not discuss management or disposition, and advise readers products, with ingestions peaking in the toddler age group. This to contact the Poison Information Service or a toxicologist reflects the acquisition of developmental milestones and subsequent for this advice.
    [Show full text]
  • Prebiotic Formation of Cyclic Dipeptides Under Potentially Early Earth
    www.nature.com/scientificreports OPEN Prebiotic formation of cyclic dipeptides under potentially early Earth conditions Received: 10 October 2017 Jianxi Ying1, Rongcan Lin1, Pengxiang Xu1, Yile Wu 1, Yan Liu1 & Yufen Zhao1,2 Accepted: 27 December 2017 Cyclic dipeptides, also known as 2,5-diketopiperazines (DKPs), represent the simplest peptides Published: xx xx xxxx that were frst completely characterized. DKPs can catalyze the chiral selection of reactions and are considered as peptide precursors. The origin of biochemical chirality and synthesis of peptides remains abstruse problem believed to be essential precondition to origin of life. Therefore, it is reasonable to believe that the DKPs could have played a key role in the origin of life. How the formation of the DKPs through the condensation of unprotected amino acids in simulated prebiotic conditions has been unclear. Herein, it was found that cyclo-Pro-Pro could be formed directly from unprotected proline in the aqueous solution of trimetaphosphate (P3m) under mild condition with the yield up to 97%. Other amino acids were found to form proline-containing DKPs under the same conditions in spite of lower yield. During the formation process of these DKPs, P3m promotes the formation of linear dipeptides in the frst step of the mechanism. The above fndings are helpful and signifcant for understanding the formation of DKPs in the process of chemical evolution of life. As one of the simplest peptide derivatives in nature1,2, Cyclic dipeptides, also known as 2, 5-diketopiperazines (DKPs), which were ubiquitously observed in microorganism, plants and animals3–10, have been found to have many biological activities (e.g., antiviral, antibiotic, anticancer)11–14 and chiral catalysis properties15.
    [Show full text]
  • Facile Synthesis of 3-Spiropyrrolizidine Oxindoles and 3-Spirotetrahydroquinoline Oxindoles Via [3+2] and [4+2] Cycloaddition Reactions
    id2143625 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com OOrrggaanniicc ISSN: 0974 - 7516 Volume 8 Issue 3 CCHHEEMMAn IIInSSdiTTan RRJouYrYnal Trade Science Inc. Full Paper OCAIJ, 8(3), 2012 [94-102] Facile synthesis of 3-spiropyrrolizidine oxindoles and 3-spirotetrahydroquinoline oxindoles via [3+2] and [4+2] cycloaddition reactions A.Sudhakara1, H.C.Kiran Kumar2, H.Jayadevappa1, K.M.Mahadevan2* 1Department of Chemistry, Sahyadri Science College, Shimoga, Karnataka, 577 203, (INDIA) 2Department of Postgraduate Studies and Research in Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, Karnataka, 577 451, (INDIA) E-mail: [email protected] Received: 22nd June, 2011 ; Accepted: 22nd July, 2011 ABSTRACT KEYWORDS A rapid and efficient synthesis of a number of functionalized 3- Isatin; spiropyrrolizidine oxindoles from [3+2] cycloaddition of azomethine ylide Imino Diels-Alder; and 3-spirotetrahydroquinoline oxindoles from [4+2] imino Diels-Alder re- Antimony(III)chloride; action; catalyzed by Antimony(III)chloride in excellent yields are reported. Spiropyrrolizidine oxindoles; 2012 Trade Science Inc. - INDIA Spirotetrahydroquinoline- oxindoles. INTRODUCTION sor for the synthesis of biologically active indole de- rivatives and natural products[2]. The Spirooxindoles core Heterocyclic compounds containing isatin (1H-in- is featured in a number of natural products and recently dole-2, 3-dione) scaffold have a wide range of biologi- has been the subject of significant synthetic interest[3]. cal activities[1] and also serves as an important precur- Oxindoles derivatized like Spirotryprostatin B, Horsfiline O Me H H O NH MeO N Me N N H MeO O H O O N N N O Me H H Spirotryprostatin B Horsfiline Alstonisine Spirooxindole alkaloid natural products Figure 1 : Spirotryprostatin B, horsfiline and alstonisine are alkaloids present in nature and are elegant targets in the organic synthesis due to their significant biological activities.
    [Show full text]
  • Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery
    fphar-07-00121 May 7, 2016 Time: 11:45 # 1 REVIEW published: 10 May 2016 doi: 10.3389/fphar.2016.00121 Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery Paola Imbrici1*, Antonella Liantonio1, Giulia M. Camerino1, Michela De Bellis1, Claudia Camerino2, Antonietta Mele1, Arcangela Giustino3, Sabata Pierno1, Annamaria De Luca1, Domenico Tricarico1, Jean-Francois Desaphy3 and Diana Conte1 1 Department of Pharmacy – Drug Sciences, University of Bari “Aldo Moro”, Bari, Italy, 2 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, Bari, Italy, 3 Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, Edited by: disabling, or life-threatening. In spite of this, ion channels are the primary target of only Maria Cristina D’Adamo, University of Perugia, Italy about 5% of the marketed drugs suggesting their potential in drug discovery. The current Reviewed by: review summarizes the therapeutic management of the principal ion channelopathies Mirko Baruscotti, of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and University of Milano, Italy Adrien Moreau, pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion Institut Neuromyogene – École channels.
    [Show full text]