DOCSLIB.ORG

2011/058582 Al O

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
2011/058582 Al O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date i 1 m 19 May 2011 (19.05.2011) 2011/058582 Al (51) International Patent Classification: Road, Sholinganallur, Chennai 600 119 (IN). CHEN- C07C 259/06 (2006.01) A61P 31/00 (2006.01) NIAPPAN, Vinoth Kumar [IN/IN]; Orchid Research C07D 277/46 (2006.01) A61K 31/426 (2006.01) Laboratories Ltd., R & D Centre: Plot No: 476/14, Old C07D 277/48 (2006.01) A61K 31/55 (2006.01) Mahabalipuram Road, Sholinganallur, Chennai 600 119 C07D 487/08 (2006.01) (IN). GANESAN, Karthikeyan [IN/IN]; Orchid Re search Laboratories Ltd., R & D Centre: Plot No: 476/14, (21) International Application Number: Old Mahabalipuram Road, Sholinganallur, Chennai 600 PCT/IN20 10/000738 119 (IN). NARAYANAN, Shridhar [IN/IN]; Orchid Re (22) International Filing Date: search Laboratories Ltd., R & D Centre: Plot No: 476/14, 12 November 2010 (12.1 1.2010) Old Mahabalipuram Road, Sholinganallur, Chennai 600 119 (IN). (25) Filing Language: English (74) Agent: UDAYAMPALAYAM PALANISAMY, (26) Publication Language: English Senthilkumar; Orchid Chemicals & Pharmaceuticals (30) Priority Data: LTD., R & D Centre: Plot No: 476/14, Old Mahabalipu 2810/CHE/2009 16 November 2009 (16. 11.2009) IN ram Road, Sholinganallur, Chennai 600 119 (IN). (71) Applicant (for all designated States except US): OR¬ (81) Designated States (unless otherwise indicated, for every CHID RESEARCH LABORATORIES LTD. [IN/IN]; kind of national protection available): AE, AG, AL, AM, Orchid Towers, 313, Valluvar Kottam High Road, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, Nungambakkam, Chennai 600 034 (IN). CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (72) Inventors; and HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (75) Inventors/ Applicants (for US only): RAJAGOPAL, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, Sridharan [IN/IN]; Orchid Research Laboratories Ltd., R ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, & D Centre: Plot No: 476/14, Old Mahabalipuram Road, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, Sholinganallur, Chennai 600 119 (IN). THANGA- SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, PAZHAM, Selvakumar [IN/IN]; Orchid Research Labo TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. ratories Ltd., R & D Centre: Plot No: 476/14, Old Maha balipuram Road, Sholinganallur, Chennai 600 119 (IN). (84) Designated States (unless otherwise indicated, for every PAUL-SATYASEELA, Maneesh [IN/IN]; Orchid Re kind of regional protection available): ARIPO (BW, GH, search Laboratories Ltd., R & D Centre: Plot No: 476/14, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Old Mahabalipuram Road, Sholinganallur, Chennai 600 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 119 (IN). BALASUBRAMANIAN, Gopalan [IN/IN]; TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Orchid Research Laboratories Ltd., R & D Centre: Plot EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, No: 476/14, Old Mahabalipuram Road, Sholinganallur., LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Chennai 600 119 (IN). SHAKTI SINGH, Solanki SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, TG). [IN/IN]; Orchid Research Laboratories Ltd., R & D Cen GW, ML, MR, NE, SN, TD, tre: Plot No: 476/14, Old Mahabalipuram Road, Sholin Declarations under Rule 4.17 : ganallur, Chennai 600 119 (IN). KUPPUSAMY, — of inventorship (Rule 4.1 7(iv)) Bharathimohan [IN/IN]; Orchid Research Laboratories Ltd., R & D Centre: Plot No: 476/14, Old Mahabalipuram Published: Road, Sholinganallur, Chennai 600 119 (IN). KACHHA- — with international search report (Art. 21(3)) DIA, Virendra [IN/IN]; Orchid Research Laboratories Ltd., R & D Centre: Plot No: 476/14, Old Mahabalipuram [Continued on next page] (54) Title: HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF FUNGAL INFECTIONS :2 4 ∞ (I) ∞ o (57) Abstract: Described are bridged compounds of the formula (I), their analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and pro- drugs thereof. The invention relates to compositions and methods to treat fungal infection. These compounds are selective HDAC Q inhibitors that act as inherent antifungal compounds or enhance the activity of other antifungal compounds such as azoles. w o 2011/058582 A l II 11 II I 1 Illlll I lll l l ll l l II il II I II before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF FUNGAL INFECTIONS Field Described are bridged compounds of the formula (I), their analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. Provided herein are also the compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors that act as inherent antifungal compounds or augment the activity of other antifungal compounds such as azoles. Background Fungal infections (mycoses), are not as frequent as bacterial or viral infections, but have nonetheless been increasing in incidence in the human population over the past several years. This trend is largely as a consequence of increased number of cancer and immunocompromised patients who, owing to weakened immune system and the chronic nature of the diseases, are at greater risk. The fungi, like bacteria, have unique characteristics, distinct from their mammalian hosts, but at the same time they being eukaryotic like mammals, are much more complex organisms. Consequently, only a few drugs are aimed at interfering with cell division and have limited use. Most antifungal drugs are targeted to the cell membrane. The principal predisposing factors for C. albicans infection are diabetes mellitus, general debility, immunodeficiency, indwelling catheters, antibiotics that alter normal bacterial flora and corticosteroids. Of these the infection of the skin occurs in moist, warm parts of the body such as the axilla, intergluteal folds, groin, or inframammary folds; it is most common in the obese and diabetic individuals. Interdigital web infection is common among those that work in wet conditions. (Jawetz Microbiology 19th ed; Antimicrobial Agents and Chemotherapy, 2002: 46(1 1): 3532- 3539). Candidiasis is treated with antifungal azoles such as topical agents and oral or intravenous fluconazole and itraconazole. The major limitation of antifungal azoles is their lack of fungicidal activity. Furthermore surviving yeasts provide a reservoir for the development of Azole resistance. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539). Azole class of antifungal agents includes the imidazoles (clotrimazole, miconazole, and ketoconazole) and the triazoles (fluconazole, itraconazole, isavucanazole, ravucanazole, posoconazole, voriconazole and terconazole). Mechanism of action: Azoles interfere with the biosynthesis of major fungal membrane component ergosterol by inhibiting sterol C14-demethylation of cytochrome P-450 3-A dependent enzyme 14-a-lanosterol-demethylase, one of the about 20 enzymes involved in the biosynthesis of ergosterol. Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth. Azole antifungals can also inhibit many mammalian cytochrome P450-dependent enzymes involved in hormone synthesis or drug metabolism. Therefore, they are particularly susceptible to clinically significant drug interactions with other medications metabolized through the cytochrome P450 pathway. One of the major differences is that the fungi rely on endogenous ergosterol biosynthesis, in contrast to mammalian cells that have the ability to incorporate exogenous sterol. This property may account for the selectivity of the azoles against fungi. (Lorian V. Antibiotics in Laboratory medicine. 4th ed; Crit. Rev. Biochem. Mol. Biol. 1999: 34:159-166; Curr. Opin. Microbiol. 2001, 4:540-545). Azole resistance has been documented in several species of Candida. The proposed mechanisms include alteration of 14-a-demethylase and upregulation of genes that encode for efflux pumps. In vitro, Azoles not only fail to kill but also fail to suppress growth of Candida completely, resulting in trailing growth as observed in broth microdilution assays. (Antimicrobial Agents and Chemotherapy, 2002; 46:3532- 3539) HDACs (Histone deacetylases) are validated targets for anticancer and antiprotozoal therapy. The chromatin at any given point of time is controlled by opposing actions of two types of enzymes: Histone acetyltransferases, which transfer an acetyl group from acetyl CoA to an ε-amino group of lysine residues of histones loosening the nucleosomes, and HDACs that catalyze the hydrolysis of acetamides by removing acetyl groups and lead to the compaction of chromatin (The Oncologist, 2003; 8:389-391). It has been recognized in recent years that histone acetylation and deacetylation play important roles in eukaryotic gene regulation. The ε-amino groups of lysine residues within the flexible amino-terminal tails of the core histones are the primary targets for acetylation.
Load more

Recommended publications
  • Discovery of Anti-Amoebic Inhibitors from Screening the MMV Pandemic Response Box on Balamuthia Mandrillaris, Naegleria Fowleri
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.14.096776; this version posted May 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Article 2 Discovery of anti-amoebic inhibitors from screening 3 the MMV Pandemic Response Box on Balamuthia 4 mandrillaris, Naegleria fowleri and Acanthamoeba 5 castellanii 6 Christopher A. Rice1,2,Δ,†,*, Emma V. Troth2,3,†, A. Cassiopeia Russell2,3,†, and Dennis E. Kyle1,2,3,* 7 1 Department of Cellular Biology, University of Georgia, Athens, Georgia, USA. 8 2 Center for Tropical and Emerging Global Diseases, Athens, Georgia, USA. 9 3 Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA. 10 Δ Current address: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, 11 University of Georgia, Athens, Georgia, USA. 12 † These authors contributed equally to this work. 13 14 *Author correspondence: [email protected] (D.E.K) and [email protected] (C.A.R) 15 Received: date; Accepted: date; Published: date 16 Abstract: Pathogenic free-living amoebae, Balamuthia mandrillaris, Naegleria fowleri and several 17 Acanthamoeba species are the etiological agents of severe brain diseases, with case mortality rates 18 >90%. A number of constraints including misdiagnosis and partially effective treatments lead to 19 these high fatality rates. The unmet medical need is for rapidly acting, highly potent new drugs to 20 reduce these alarming mortality rates. Herein, we report the discovery of new drugs as potential 21 anti-amoebic agents.
    [Show full text]
  • Upregulation of Peroxisome Proliferator-Activated Receptor-Α And
    Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer Chih-Yang Wang, Ying-Jui Chao, Yi-Ling Chen, Tzu-Wen Wang, Nam Nhut Phan, Hui-Ping Hsu, Yan-Shen Shan, Ming-Derg Lai 1 Supplementary Table 1. Demographics and clinical outcomes of five patients with ampullary cancer Time of Tumor Time to Age Differentia survival/ Sex Staging size Morphology Recurrence recurrence Condition (years) tion expired (cm) (months) (months) T2N0, 51 F 211 Polypoid Unknown No -- Survived 193 stage Ib T2N0, 2.41.5 58 F Mixed Good Yes 14 Expired 17 stage Ib 0.6 T3N0, 4.53.5 68 M Polypoid Good No -- Survived 162 stage IIA 1.2 T3N0, 66 M 110.8 Ulcerative Good Yes 64 Expired 227 stage IIA T3N0, 60 M 21.81 Mixed Moderate Yes 5.6 Expired 16.7 stage IIA 2 Supplementary Table 2. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of an ampullary cancer microarray using the Database for Annotation, Visualization and Integrated Discovery (DAVID). This table contains only pathways with p values that ranged 0.0001~0.05. KEGG Pathway p value Genes Pentose and 1.50E-04 UGT1A6, CRYL1, UGT1A8, AKR1B1, UGT2B11, UGT2A3, glucuronate UGT2B10, UGT2B7, XYLB interconversions Drug metabolism 1.63E-04 CYP3A4, XDH, UGT1A6, CYP3A5, CES2, CYP3A7, UGT1A8, NAT2, UGT2B11, DPYD, UGT2A3, UGT2B10, UGT2B7 Maturity-onset 2.43E-04 HNF1A, HNF4A, SLC2A2, PKLR, NEUROD1, HNF4G, diabetes of the PDX1, NR5A2, NKX2-2 young Starch and sucrose 6.03E-04 GBA3, UGT1A6, G6PC, UGT1A8, ENPP3, MGAM, SI, metabolism
    [Show full text]
  • Integrated Molecular Profiling for Analyzing and Predicting Therapeutic Mechanism, Response, Biomarker and Target
    INTEGRATED MOLECULAR PROFILING FOR ANALYZING AND PREDICTING THERAPEUTIC MECHANISM, RESPONSE, BIOMARKER AND TARGET Jia Jia (B. Sci & M. Sci, Zhejiang University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2010 Acknowledgements ACKNOWLEDGEMENTS I would like to deeply thank Professor Chen Yu Zong, for his constant encouragement and advice during the entire period of my postgraduate studies. In particular, he has guided me to make my research applicable to the real world problem. This work would not have been possible without his kindness in supporting me to shape up the manuscript for publication. I am also tremendously benefited from his profound knowledge, expertise in scientific research, as well as his enormous support, which will inspire and motivate me to go further in my future professional career. I am also grateful to our BIDD group members for their insight suggestions and collaborations in my research work: Dr. Tang Zhiqun, Ms. Ma Xiaohua, Mr. Zhu Feng, Ms. Liu Xin, Ms. Shi Zhe, Dr. Cui Juan, Mr. Tu Weimin, Dr. Zhang Hailei, Dr. Lin Honghuang, Dr. Liu Xianghui, Dr. Pankaj Kumar, Dr Yap Chun wei, Ms. Wei Xiaona, Ms. Huang Lu, Mr. Zhang Jinxian, Mr. Han Bucong, Mr. Tao Lin, Dr. Wang Rong, Dr. Yan Kun. I thank them for their valuable support and encouragement in my work. Finally, I owe my gratitude to my parents for their forever love, constant support, understanding, encouragement and strength throughout my life. A special appreciation goes to all for love and support. Jia Jia August 2010 I Table of Contents TABLE OF CONTENTS 1.1 Overview of mechanism and strategies of molecular-targeted therapeutics ...................................
    [Show full text]
  • 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania Amazonensis Promastigote
    International Journal of Molecular Sciences Article 1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania amazonensis Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study Fernando Almeida-Souza 1,2,* , Verônica Diniz da Silva 3,4, Gabriel Xavier Silva 5, Noemi Nosomi Taniwaki 6, Daiana de Jesus Hardoim 2, Camilla Djenne Buarque 3, 1, , 2, Ana Lucia Abreu-Silva * y and Kátia da Silva Calabrese y 1 Pós-graduação em Ciência Animal, Universidade Estadual do Maranhão, São Luís 65055-310, Brazil 2 Laboratório de Imunomodulação e Protozoologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-900, Brazil; [email protected] (D.d.J.H.); calabrese@ioc.fiocruz.br (K.d.S.C.) 3 Laboratório de Síntese Orgânica, Pontifícia Universidade Católica, Rio de Janeiro 22451-900, Brazil; [email protected] (V.D.d.S.); [email protected] (C.D.B.) 4 Faculdade de Ciência e Tecnologia, Universidade Nova de Lisboa, 2825-149 Caparica, Portugal 5 Rede Nordeste de Biotecnologia, Universidade Federal do Maranhão, São Luís 65080-805, Brazil; [email protected] 6 Núcleo de Microscopia Eletrônica, Instituto Adolfo Lutz, São Paulo 01246-000, Brazil; [email protected] * Correspondence: [email protected] (F.A.-S.); [email protected] (A.L.A.-S.) These authors equally contributed to this work. y Received: 26 June 2020; Accepted: 14 July 2020; Published: 18 September 2020 Abstract: The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties.
    [Show full text]
  • Review Article Sporotrichosis: an Overview and Therapeutic Options
    Hindawi Publishing Corporation Dermatology Research and Practice Volume 2014, Article ID 272376, 13 pages http://dx.doi.org/10.1155/2014/272376 Review Article Sporotrichosis: An Overview and Therapeutic Options Vikram K. Mahajan Department of Dermatology, Venereology & Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda, Himachal Pradesh 176001, India Correspondence should be addressed to Vikram K. Mahajan; [email protected] Received 30 July 2014; Accepted 12 December 2014; Published 29 December 2014 Academic Editor: Craig G. Burkhart Copyright © 2014 Vikram K. Mahajan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sporotrichosis is a chronic granulomatous mycotic infection caused by Sporothrix schenckii, a common saprophyte of soil, decaying wood, hay, and sphagnum moss, that is endemic in tropical/subtropical areas. The recent phylogenetic studies have delineated the geographic distribution of multiple distinct Sporothrix species causing sporotrichosis. It characteristically involves the skin and subcutaneous tissue following traumatic inoculation of the pathogen. After a variable incubation period, progressively enlarging papulo-nodule at the inoculation site develops that may ulcerate (fixed cutaneous sporotrichosis) or multiple nodules appear proximally along lymphatics (lymphocutaneous sporotrichosis). Osteoarticular sporotrichosis or primary pulmonary sporotrichosis are rare and occur from direct inoculation or inhalation of conidia, respectively. Disseminated cutaneous sporotrichosis or involvement of multiple visceral organs, particularly the central nervous system, occurs most commonly in persons with immunosuppression. Saturated solution of potassium iodide remains a first line treatment choice for uncomplicated cutaneous sporotrichosis in resource poor countries but itraconazole is currently used/recommended for the treatment of all forms of sporotrichosis.
    [Show full text]
  • Abstract #15 Drug Repurposing for Human Visceral Leishmaniasis: Screening Marketed Antifungal Azoles for Inhibition of Leishmani
    Abstract #15 Drug Repurposing for Human Visceral Leishmaniasis: Screening Marketed Antifungal Azoles for Inhibition of Leishmanial CYP5122A1 and CYP51 Enzymes Yiru Jin1, Mei Feng1, Michael Zhuo Wang1 1Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA CYP5122A1 is a novel cytochrome P450 (CYP) enzyme that is essential for the survival of Leishmania donovani, a major causative agent for human visceral leishmaniasis. Recent studies suggest that CYP5122A1 plays an important role as sterol 4-demethylase in ergosterol biosynthesis by Leishmania. Thus, CYP5122A1 inhibitors may represent a new therapeutic approach against the devastating infectious disease. To evaluate the effects of antifungal azoles on CYP5122A1, a panel of twenty marketed antifungal azoles (bifonazole, butoconazole, clotrimazole, econazole, efinaconazole, fenticonazole, fluconazole, isavuconazole, isoconazole, itraconazole, ketoconazole, miconazole, oxiconazole, posaconazole, ravuconazole, sertaconazole, sulconazole, terconazole, tioconazole, voriconazole) were screened for inhibition of CYP5122A1, as well as the lanosterol 14α-demethylase CYP51, using a fluorescence-based inhibition assay. All twenty azoles were potent inhibitors of leishmanial CYP51 with IC50 ranging from 0.031 to 0.084 M, whereas their inhibitory potencies against CYP5122A1 were much lower (0.25 to 12 M). Ravuconazole was identified as a selective CYP51 inhibitor with an IC50 value of 0.048 M and selectivity index of 250 against CYP5122A1. Interestingly, the imidazole class of antifungal azoles showed stronger inhibition against CYP5122A1 compared with the triazole class. These results can provide insights toward rational drug design of CYP5122A1 inhibitors. Future studies will attempt to obtain X-ray crystal structures of several select protein-ligand complexes and confirm the proposed biochemical roles of CYP5122A1 and CYP51 by treating parasites with selective inhibitors, followed by HPLC-MS/MS-based sterol analysis.
    [Show full text]
  • Microspore Embryogenesis: Targeting the Determinant Factors of Stress- Induced Cell Reprogramming for Crop Improvement
    1 2 3 4 Microspore embryogenesis: targeting the determinant factors of stress- 5 induced cell reprogramming for crop improvement 6 7 8 Pilar S. Testillano 9 10 Pollen Biotechnolgy of Crop Plants group. Biological Research Center, CIB-CSIC. 11 Ramiro de Maeztu 9, 28040 Madrid. Spain 12 E-mail: [email protected] 13 Phone: +34-918373112 (Ext: 4366) 14 15 Date of submission: October 31, 2018 16 Number of figures: 5. 17 Word count: 6312. 18 19 Running title: 20 Determinant factors of stress-induced microspore embryogenesis in crops 1 21 ABSTRACT 22 23 Under stress, isolated microspores are reprogrammed in vitro towards embryogenesis, 24 producing doubled haploid plants, useful biotechnological tools in plant breeding as a 25 source of new genetic variability, fixed in homozygous plants in only one generation. 26 Stress-induced cell death and low rates of cell reprogramming are major factors that 27 reduce the process yield. Knowledge gained in recent years has revealed that 28 microspore embryogenesis initiation and progression involve a complex network of 29 factors, whose roles are not yet well understood. Autophagy and cell-death proteases are 30 crucial players in the response to stress, while cell reprogramming and totipotency 31 acquisition are regulated by hormonal and epigenetic mechanisms. Auxin biosynthesis, 32 transport and action are required for microspore embryogenesis. Initial stages involve 33 DNA hypomethylation, H3K9 demethylation, and H3/H4 acetylation. Cell wall 34 remodelling, with pectin de-methylesterification and AGP expression, is necessary for 35 embryo development. We will review recent findings regarding the determinant factors 36 underlying stress-induced microspore embryogenesis, focusing on the role of 37 autophagy, cell death, auxin, chromatin modifications, and cell wall.
    [Show full text]
  • Epigenetic Malleability at Core Promoter Regulates Tobacco PR-1A
    bioRxiv preprint doi: https://doi.org/10.1101/2021.07.24.453639; this version posted July 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Research article: 2 Epigenetic Malleability at Core Promoter Regulates Tobacco PR-1a 3 Expression after Salicylic Acid Treatment 4 5 Authors: Niraj Lodhi1*, Mala Singh1, Rakesh Srivastava1, Samir V. Sawant1, and Rakesh 6 Tuli1,3 7 8 1. National Botanical Research Institute, Council of Scientific and Industrial Research, Rana 9 Pratap Marg, Lucknow-226001, India 10 2. Present address: University Institute of Engineering & Technology (UIET), Sector 25, 11 Panjab University, Chandigarh 160014, India 12 13 14 *Corresponding Author: 15 Niraj Lodhi, Ph.D. 16 Lead, Clinical Research (Research and Development Division) 17 Genesis DiaGnostics 18 LanGhorne, PA 19047 19 Ph: 267-212-2000 Ext. 156 20 Fax: 267-212-2005 21 E-mail: [email protected] 22 23 24 25 SUMMARY 26 Histone methylation and acetylation regulation of tobacco PR-1a promoter are significant for 27 disassembly of the nucleosome and repressor proteins during induction. 28 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.07.24.453639; this version posted July 25, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 29 ABSTRACT 30 • Tobacco’s PR-1a gene is induced by pathogen attack or exogenous application of 31 Salicylic Acid (SA). However, the epigenetic modifications of the most important 32 inducible promoter of the PR-1a gene are not understood clearly.
    [Show full text]
  • Novel Insights Into P450 BM3 Interactions with FDA-Approved Antifungal Azole Drugs Received: 1 August 2018 Laura N
    www.nature.com/scientificreports OPEN Novel insights into P450 BM3 interactions with FDA-approved antifungal azole drugs Received: 1 August 2018 Laura N. Jefreys1, Harshwardhan Poddar1, Marina Golovanova1, Colin W. Levy2, Accepted: 14 November 2018 Hazel M. Girvan1, Kirsty J. McLean1, Michael W. Voice3, David Leys1 & Andrew W. Munro1 Published: xx xx xxxx Flavocytochrome P450 BM3 is a natural fusion protein constructed of cytochrome P450 and NADPH- cytochrome P450 reductase domains. P450 BM3 binds and oxidizes several mid- to long-chain fatty acids, typically hydroxylating these lipids at the ω-1, ω-2 and ω-3 positions. However, protein engineering has led to variants of this enzyme that are able to bind and oxidize diverse compounds, including steroids, terpenes and various human drugs. The wild-type P450 BM3 enzyme binds inefciently to many azole antifungal drugs. However, we show that the BM3 A82F/F87V double mutant (DM) variant binds substantially tighter to numerous azole drugs than does the wild-type BM3, and that their binding occurs with more extensive heme spectral shifts indicative of complete binding of several azoles to the BM3 DM heme iron. We report here the frst crystal structures of P450 BM3 bound to azole antifungal drugs – with the BM3 DM heme domain bound to the imidazole drugs clotrimazole and tioconazole, and to the triazole drugs fuconazole and voriconazole. This is the frst report of any protein structure bound to the azole drug tioconazole, as well as the frst example of voriconazole heme iron ligation through a pyrimidine nitrogen from its 5-fuoropyrimidine ring. Te cytochromes P450 (P450s or CYPs) are a superfamily of heme b-binding enzymes that catalyze the oxidative modifcation of a huge number of organic substrates1.
    [Show full text]
  • Gene Expression-Based Chemical Genomics Identifies Potential Therapeutic Drugs in Hepatocellular Carcinoma
    Gene Expression-Based Chemical Genomics Identifies Potential Therapeutic Drugs in Hepatocellular Carcinoma Ming-Huang Chen1., Wu-Lung R. Yang2., Kuan-Ting Lin3,4., Chia-Hung Liu4,5., Yu-Wen Liu1., Kai-Wen Huang6., Peter Mu-Hsin Chang1, Jin-Mei Lai7, Chun-Nan Hsu4,8, Kun-Mao Chao2,5, Cheng-Yan Kao2,5, Chi-Ying F. Huang1,3,9* 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, 2 Department of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan, 3 Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan, 4 Institute of Information Science, Academia Sinica, Taipei, Taiwan, 5 Graduate Institute of Biomedical Electronic and Bioinformatics, National Taiwan University, Taipei, Taiwan, 6 Department of Surgery & Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan, 7 Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan, 8 Information Sciences Institute, University of Southern California, Marina del Rey, California, United States of America, 9 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan Abstract Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Currently, only sorafenib is approved by the FDA for advanced HCC treatment; therefore, there is an urgent need to discover candidate therapeutic drugs for HCC. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of HCC, it might have the potential to inhibit HCC-related pathways and thereby treat HCC. To test this hypothesis, we first built an integrative platform, the ‘‘Encyclopedia of Hepatocellular Carcinoma genes Online 2’’, dubbed EHCO2, to systematically collect, organize and compare the publicly available data from HCC studies.
    [Show full text]
  • (ESI) for Integrative Biology. This Journal Is © the Royal Society of Chemistry 2017
    Electronic Supplementary Material (ESI) for Integrative Biology. This journal is © The Royal Society of Chemistry 2017 Table 1 Enriched GO terms with p-value ≤ 0.05 corresponding to the over-expressed genes upon perturbation with the lung-toxic compounds. Terms with corrected p-value less than 0.001 are shown in bold. GO:0043067 regulation of programmed GO:0010941 regulation of cell death cell death GO:0042981 regulation of apoptosis GO:0010033 response to organic sub- stance GO:0043068 positive regulation of pro- GO:0010942 positive regulation of cell grammed cell death death GO:0006357 regulation of transcription GO:0043065 positive regulation of apop- from RNA polymerase II promoter tosis GO:0010035 response to inorganic sub- GO:0043066 negative regulation of stance apoptosis GO:0043069 negative regulation of pro- GO:0060548 negative regulation of cell death grammed cell death GO:0016044 membrane organization GO:0042592 homeostatic process GO:0010629 negative regulation of gene ex- GO:0001568 blood vessel development pression GO:0051172 negative regulation of nitrogen GO:0006468 protein amino acid phosphoryla- compound metabolic process tion GO:0070482 response to oxygen levels GO:0045892 negative regulation of transcrip- tion, DNA-dependent GO:0001944 vasculature development GO:0046907 intracellular transport GO:0008202 steroid metabolic process GO:0045934 negative regulation of nucle- obase, nucleoside, nucleotide and nucleic acid metabolic process GO:0006917 induction of apoptosis GO:0016481 negative regulation of transcrip- tion GO:0016125 sterol metabolic process GO:0012502 induction of programmed cell death GO:0001666 response to hypoxia GO:0051253 negative regulation of RNA metabolic process GO:0008203 cholesterol metabolic process GO:0010551 regulation of specific transcrip- tion from RNA polymerase II promoter 1 Table 2 Enriched GO terms with p-value ≤ 0.05 corresponding to the under-expressed genes upon perturbation with the lung-toxic compounds.
    [Show full text]
  • Antifungal Reference Materials
    Antifungal reference materials Antifungal (antimycotic) agents These infections can be potentially lethal in are used for prophylaxis and immunocompromised patients such as those with HIV/AIDS or transplant recipients taking treatment of fungal, yeast and medications to suppress their immune system. mould infections. These can range The successful management of invasive from superficial infections including fungal infections poses a difficult challenge to athlete’s foot, ringworm, vaginal clinicians. Antifungal agents have important thrush and fungal nail infections, limitations in their spectrum of activity and can be associated with unpredictable bioavailability, through to the more serious significant pharmacokinetic variability, intolerance, invasive infections such as systemic considerable acute and chronic toxicity and candidiasis, pulmonary aspergillosis potential for drug-drug interactions. Therapeutic and cryptococcal meningitis. Drug Monitoring can assist in optimising the efficacy and safety of certain antifungal therapy. LGC now offer an extensive range of antifungal agents. LGC Quality - ISO Guide 34 • GMP/GLP • ISO 9001 • ISO/IEC 17025 • ISO/IEC 17043 Reference materials Product code Description Unit 1 Unit 2 Imidazoles TRC-B690273 Butoconazole Nitrate 10 mg 100 mg TRC-B690272 Butoconazole (rac)-d5 Nitrate 1 mg 10 mg LGCFOR0015.00 Clotrimazole 10 mg TRC-C587402 Clotrimazole-d5 1 mg 10 mg LGCFOR0524.00 Econazole Nitrate 10 mg TRC-F279250 Fenticonazole Nitrate 100 mg 1 g LGCFOR0541.00 Isoconazole Nitrate 10 mg LGCFOR0145.00
    [Show full text]