Withanolides are a group of naturally occurring C28- steroidal lactones. They contain four cycloalkane ring structures, three cyclohexane rings and one cyclopentane ring.[3] Withaferin A is highly reactive because of the ketone-containing unsaturated A ring, the epoxide in the B ring, and the unsaturated lactone ring. The double bond in ring A and the epoxide ring are mainly responsible for the cytotoxicity. The 22nd and 26th carbons of the ergostane skeleton in withaferin A and related steroidal compounds are oxidized to form a six-membered delta lactone unit. NMR spectral analysis identifies C3 in the unsaturated A ring as the main nucleophilic target site for ethyl mercaptan, thiophenol and L-cysteine ethyl esterin vitro.[3] A library of 2, 3-dihydro-3β-substituted derivatives are synthesized by regio/stereoselective Michael addition to ring A.
In the withania somnifera plant, the withanolide, Withaferin A, is present in the leaves. Withanolides are terpenoids, which are synthesized in plants using isoprenoids as precursors. Isoprenoids can be synthesized through mevalonate or 1-deoxy-D-xylulose 5-phosphate pathways. Isoprenogenesis significantly governs withanolide synthesis.[6]
Isoprenoids form squalene, which then goes through a variety of intermediate steps to form 24-methylenecholesterol - the sterol precursor of the withanolides.[7]
The biosynthesis of withaferin A uses enzymes such as squalene epoxidase (SQE), cycloartenol synthase (CAS), sterol methyl transferase (SMT), obtusifoliol-14 –demethylase (ODM).[8]
Lactone ring formation in Withaferin A biosynthesis.
To produce withaferin A from 24-methylene cholesterol, the molecule undergoes several functional changes including formation of a ketone, epoxide, 2 hydroxyl groups, and lactone ring.[9]
^Kupchan, S. M.; Anderson, W. K.; Bollinger, P.; Doskotch, R. W.; Smith, R. M.; Renauld, J. A.; Schnoes, H. K.; Burlingame, A. L.; Smith, D. H. (1969-12-01). "Tumor inhibitors. XXXIX. Active principles of Acnistus arborescens. Isolation and structural and spectral studies of withaferin A and withacnistin". The Journal of Organic Chemistry. 34 (12): 3858–3866. doi:10.1021/jo01264a027. PMID 5357526.
^ abMohan, R; Hammers, HJ; Bargagna-Mohan, P; Zhan, XH; Herbstritt, CJ; Ruiz, A; Zhang, L; Hanson, AD; et al. (2004). "Withaferin A is a potent inhibitor of angiogenesis". Angiogenesis. 7 (2): 115–122. doi:10.1007/s10456-004-1026-3. PMID 15516832. S2CID 8095820.
^ abVanden Berghe, Wim; Sabbe, Linde; Kaileh, Mary; Haegeman, Guy; Heyninck, Karen (2012-11-15). "Molecular insight in the multifunctional activities of Withaferin A". Biochemical Pharmacology. 84 (10): 1282–1291. doi:10.1016/j.bcp.2012.08.027. PMID 22981382.
^Braun, Lesley; Cohen, Marc (2015-03-30). Herbs and Natural Supplements, Volume 2: An Evidence-Based Guide. Elsevier Health Sciences. ISBN9780729581738.
^Prasanna Kumar, S; Shilpa, P; Salimath Bharati, P (2009). "Withaferin A suppresses the expression of vascular endothelial growth factor in Ehrlich ascites tumor cells via Sp1 transcription factor". Current Trends in Biotechnology and Pharmacy. 3 (2): 138–148. ISSN 0973-8916.
^Chaurasiya, N.D., Sangwan, N.S., Sabir, F. et al. “Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L.” Plant Cell Reports (2012) 31: 1889. doi:10.1007/s00299-012-1302-4
^Lockley, W.J.S., Rees, H.H., Goodwin, T.W. “Biosynthesis of steroidal withanolides in Withania Somnifera” Phytochemistry (1976) 15:937-939. doi:10.1016/S0031-9422(00)84374-5
^Pandey, S.S., Singh, S., Pandey, H. et al. “Endophytes of Withania somniferamodulate in planta content and the site of withanolide biosynthesis” Scientific Reports (2018) 8:5450. doi:10.1038/s41598-018-23716-5
^Bharitkar, Y.P., Kanhar, S., Suneel, N. et al. “Chemistry of withaferin-A: chemo, regio, and stereoselective synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A via one-pot three-component [3+2] azomethine ylide cycloaddition and their cytotoxicity evaluation” Molecular Diversity (2015) 19: 251. doi:10.1007/s11030-015-9574-6
January 10, 2024
withaferin, steroidal, lactone, derived, from, acnistus, arborescens, withania, somnifera, other, members, family, solanaceae, first, member, withanolide, class, ergostane, type, product, discovered, namesiupac, name, dihydroxy, diepoxy, ergosta, diene, diones. Withaferin A is a steroidal lactone derived from Acnistus arborescens 1 Withania somnifera 2 and other members of family Solanaceae It is the first member of the withanolide class of ergostane type product to be discovered Withaferin A NamesIUPAC name 22R 4b 27 Dihydroxy 5 6b 22 26 diepoxy 5b ergosta 2 24 diene 1 26 dioneSystematic IUPAC name 4S 4aR 5aR 6aS 6bS 9R 9aS 11aS 11bR 4 Hydroxy 9 1S 1 2R 5 hydroxymethyl 4 methyl 6 oxo 3 6 dihydro 2H pyran 2 yl ethyl 9a 11b dimethyl 5a 6 6a 6b 7 8 9 9a 10 11 11a 11b dodecahydrocyclopenta 1 2 phenanthro 8a 9 b oxiren 1 4H oneOther names Withaferine AIdentifiersCAS Number 5119 48 2 Y3D model JSmol Interactive imageChEBI CHEBI 69120ChEMBL ChEMBL1221986ChemSpider 233064PubChem CID 265237UNII L6DO3QW4K5 YCompTox Dashboard EPA DTXSID10965459InChI InChI 1S C28H38O6 c1 14 11 21 33 25 32 17 14 13 29 15 2 18 5 6 19 16 12 24 28 34 24 23 31 8 7 22 30 27 28 4 20 16 9 10 26 18 19 3 h7 8 15 16 18 21 23 24 29 31H 5 6 9 13H2 1 4H3 t15 16 18 19 20 21 23 24 26 27 28 m0 s1Key DBRXOUCRJQVYJQ CKNDUULBSA NInChI 1 C28H38O6 c1 14 11 21 33 25 32 17 14 13 29 15 2 18 5 6 19 16 12 24 28 34 24 23 31 8 7 22 30 27 28 4 20 16 9 10 26 18 19 3 h7 8 15 16 18 21 23 24 29 31H 5 6 9 13H2 1 4H3 t15 16 18 19 20 21 23 24 26 27 28 m0 s1Key DBRXOUCRJQVYJQ CKNDUULBBISMILES O C 1O C H CC C 1CO C C H C C H 6CC C H 4 C 6 C CC C H 3 C 5 C O C C C H O C 52O C H 2C C H 34 CPropertiesChemical formula C 28H 38O 6Molar mass 470 606 g mol 1Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox references Contents 1 Structure 2 Regulation 2 1 Transcription factor NF kB in vitro 3 Biosynthesis 4 See also 5 ReferencesStructure editWithanolides are a group of naturally occurring C28 steroidal lactones They contain four cycloalkane ring structures three cyclohexane rings and one cyclopentane ring 3 Withaferin A is highly reactive because of the ketone containing unsaturated A ring the epoxide in the B ring and the unsaturated lactone ring The double bond in ring A and the epoxide ring are mainly responsible for the cytotoxicity The 22nd and 26th carbons of the ergostane skeleton in withaferin A and related steroidal compounds are oxidized to form a six membered delta lactone unit NMR spectral analysis identifies C3 in the unsaturated A ring as the main nucleophilic target site for ethyl mercaptan thiophenol and L cysteine ethyl ester in vitro 3 A library of 2 3 dihydro 3b substituted derivatives are synthesized by regio stereoselective Michael addition to ring A Regulation editTranscription factor NF kB in vitro edit NF kB is a transcription factor that regulates many genes involved in cell survival growth immune response and angiogenesis Withaferin A inhibits NF kB at a very low concentration by targeting the ubiquitin mediated proteasome pathway UPP in endothelial cells 2 In vitro experiments demonstrated that withaferin A inhibits other transcription factors including Ap1 4 and Sp1 5 Biosynthesis edit nbsp Biosynthesis of Withaferin AIn the withania somnifera plant the withanolide Withaferin A is present in the leaves Withanolides are terpenoids which are synthesized in plants using isoprenoids as precursors Isoprenoids can be synthesized through mevalonate or 1 deoxy D xylulose 5 phosphate pathways Isoprenogenesis significantly governs withanolide synthesis 6 Isoprenoids form squalene which then goes through a variety of intermediate steps to form 24 methylenecholesterol the sterol precursor of the withanolides 7 The biosynthesis of withaferin A uses enzymes such as squalene epoxidase SQE cycloartenol synthase CAS sterol methyl transferase SMT obtusifoliol 14 demethylase ODM 8 nbsp Lactone ring formation in Withaferin A biosynthesis To produce withaferin A from 24 methylene cholesterol the molecule undergoes several functional changes including formation of a ketone epoxide 2 hydroxyl groups and lactone ring 9 See also editWithanolideReferences edit Kupchan S M Anderson W K Bollinger P Doskotch R W Smith R M Renauld J A Schnoes H K Burlingame A L Smith D H 1969 12 01 Tumor inhibitors XXXIX Active principles of Acnistus arborescens Isolation and structural and spectral studies of withaferin A and withacnistin The Journal of Organic Chemistry 34 12 3858 3866 doi 10 1021 jo01264a027 PMID 5357526 a b Mohan R Hammers HJ Bargagna Mohan P Zhan XH Herbstritt CJ Ruiz A Zhang L Hanson AD et al 2004 Withaferin A is a potent inhibitor of angiogenesis Angiogenesis 7 2 115 122 doi 10 1007 s10456 004 1026 3 PMID 15516832 S2CID 8095820 a b Vanden Berghe Wim Sabbe Linde Kaileh Mary Haegeman Guy Heyninck Karen 2012 11 15 Molecular insight in the multifunctional activities of Withaferin A Biochemical Pharmacology 84 10 1282 1291 doi 10 1016 j bcp 2012 08 027 PMID 22981382 Braun Lesley Cohen Marc 2015 03 30 Herbs and Natural Supplements Volume 2 An Evidence Based Guide Elsevier Health Sciences ISBN 9780729581738 Prasanna Kumar S Shilpa P Salimath Bharati P 2009 Withaferin A suppresses the expression of vascular endothelial growth factor in Ehrlich ascites tumor cells via Sp1 transcription factor Current Trends in Biotechnology and Pharmacy 3 2 138 148 ISSN 0973 8916 Chaurasiya N D Sangwan N S Sabir F et al Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L Plant Cell Reports 2012 31 1889 doi 10 1007 s00299 012 1302 4 Lockley W J S Rees H H Goodwin T W Biosynthesis of steroidal withanolides in Withania Somnifera Phytochemistry 1976 15 937 939 doi 10 1016 S0031 9422 00 84374 5 Pandey S S Singh S Pandey H et al Endophytes of Withania somniferamodulate in planta content and the site of withanolide biosynthesis Scientific Reports 2018 8 5450 doi 10 1038 s41598 018 23716 5 Bharitkar Y P Kanhar S Suneel N et al Chemistry of withaferin A chemo regio and stereoselective synthesis of novel spiro pyrrolizidino oxindole adducts of withaferin A via one pot three component 3 2 azomethine ylide cycloaddition and their cytotoxicity evaluation Molecular Diversity 2015 19 251 doi 10 1007 s11030 015 9574 6 Retrieved from https en wikipedia org w index php title Withaferin A amp oldid 1178837733, wikipedia, wiki, book, books, library,
