Withaferin A

Withaferin A
Names
IUPAC name
(22R)-4β,27-Dihydroxy-5,6β:22,26-diepoxy-5β-ergosta-2,24-diene-1,26-dione
Systematic 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)-one
Other names
Withaferine A
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
  • 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/s1
    Key: DBRXOUCRJQVYJQ-CKNDUULBSA-N
  • InChI=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/s1
    Key: DBRXOUCRJQVYJQ-CKNDUULBBI
  • 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)C
Properties
C28H38O6
Molar mass 470.606 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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.

Structure

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 ester in vitro.[3] A library of 2, 3-dihydro-3β-substituted derivatives are synthesized by regio/stereoselective Michael addition to ring A.

Regulation

Transcription factor NF-κB in vitro

NF-κB is a transcription factor that regulates many genes involved in cell survival, growth, immune response and angiogenesis. Withaferin A inhibits NF-κB 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

Biosynthesis of Withaferin A

In the Withania somnifera plant, the 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]

See also

References

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ Braun, Lesley; Cohen, Marc (2015-03-30). Herbs and Natural Supplements, Volume 2: An Evidence-Based Guide. Elsevier Health Sciences. ISBN 978-0-7295-8173-8.
  5. ^ 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.
  6. ^ Chaurasiya, Narayan D.; Sangwan, Neelam S.; Sabir, Farzana; Misra, Laxminarain; Sangwan, Rajender S. (2012). "Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L. (Dunal)". Plant Cell Reports. 31 (10): 1889–1897. doi:10.1007/s00299-012-1302-4. PMID 22733207. S2CID 253817403.
  7. ^ Lockley, William J.S.; Rees, Huw H.; Goodwin, Trevor W. (1976). "Biosynthesis of steroidal withanolides in Withania somnifera". Phytochemistry. 15 (6): 937–939. Bibcode:1976PChem..15..937L. doi:10.1016/S0031-9422(00)84374-5.
  8. ^ Pandey, Shiv S.; Singh, Sucheta; Pandey, Harshita; Srivastava, Madhumita; Ray, Tania; Soni, Sumit; Pandey, Alok; Shanker, Karuna; Babu, C. S. Vivek; Banerjee, Suchitra; Gupta, M. M.; Kalra, Alok (2018). "Endophytes of Withania somnifera modulate in planta content and the site of withanolide biosynthesis". Scientific Reports. 8 (1): 5450. Bibcode:2018NatSR...8.5450P. doi:10.1038/s41598-018-23716-5. PMC 5882813. PMID 29615668.
  9. ^ Bharitkar, Yogesh P.; Kanhar, Satish; Suneel, Neradibilli; Mondal, Susanta Kumar; Hazra, Abhijit; Mondal, Nirup B. (2015). "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. 19 (2): 251–261. doi:10.1007/s11030-015-9574-6. PMID 25749788. S2CID 254831740.