Withaferin A

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Withaferin A
Withaferin A.svg
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
PubChem CID
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.

Contents

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 Biosynthesis of Withaferin A.png
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. Lactone Ring Withanolide.png
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

Related Research Articles

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A steroid is an organic compound with four fused rings arranged in a specific molecular configuration.

<span class="mw-page-title-main">Mevalonate pathway</span> Series of interconnected biochemical reactions

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

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<span class="mw-page-title-main">Smith–Lemli–Opitz syndrome</span> Medical condition

Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.

<span class="mw-page-title-main">Hopanoids</span> Class of chemical compounds

Hopanoids are a diverse subclass of triterpenoids with the same hydrocarbon skeleton as the compound hopane. This group of pentacyclic molecules therefore refers to simple hopenes, hopanols and hopanes, but also to extensively functionalized derivatives such as bacteriohopanepolyols (BHPs) and hopanoids covalently attached to lipid A.

<i>beta</i>-Sitosterol Chemical compound

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<span class="mw-page-title-main">Triterpene</span> Class of chemical compounds

Triterpenes are a class of terpenes composed of six isoprene units with the molecular formula C30H48; they may also be thought of as consisting of three terpene units. Animals, plants and fungi all produce triterpenes, including squalene, the precursor to all steroids.

(<i>E</i>)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate Chemical compound

(E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP or HMB-PP) is an intermediate of the MEP pathway (non-mevalonate pathway) of isoprenoid biosynthesis. The enzyme HMB-PP synthase (GcpE, IspG) catalyzes the conversion of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP) into HMB-PP. HMB-PP is then converted further to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).

The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The currently preferred name for this pathway is the MEP pathway, since MEP is the first committed metabolite on the route to IPP.

<span class="mw-page-title-main">Andrographolide</span> Chemical compound

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<span class="mw-page-title-main">Farnesyl-diphosphate farnesyltransferase</span> Class of enzymes

Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH. Catalysis by SQS is the first committed step in sterol synthesis, since the squalene produced is converted exclusively into various sterols, such as cholesterol, via a complex, multi-step pathway. SQS belongs to squalene/phytoene synthase family of proteins.

<span class="mw-page-title-main">Squalene monooxygenase</span> Mammalian protein found in Homo sapiens

Squalene monooxygenase is a eukaryotic enzyme that uses NADPH and diatomic oxygen to oxidize squalene to 2,3-oxidosqualene. Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. In humans, squalene epoxidase is encoded by the SQLE gene. Several eukaryote genomes lack a squalene monooxygenase encoding gene, but instead encode an alternative squalene epoxidase that performs the same task.

<span class="mw-page-title-main">Lanosterol synthase</span> Mammalian protein found in Homo sapiens

Lanosterol synthase (EC 5.4.99.7) is an oxidosqualene cyclase (OSC) enzyme that converts (S)-2,3-oxidosqualene to a protosterol cation and finally to lanosterol. Lanosterol is a key four-ringed intermediate in cholesterol biosynthesis. In humans, lanosterol synthase is encoded by the LSS gene.

<span class="mw-page-title-main">Isopentenyl-diphosphate delta isomerase</span> Class of enzymes

Isopentenyl pyrophosphate isomerase, also known as Isopentenyl-diphosphate delta isomerase, is an isomerase that catalyzes the conversion of the relatively un-reactive isopentenyl pyrophosphate (IPP) to the more-reactive electrophile dimethylallyl pyrophosphate (DMAPP). This isomerization is a key step in the biosynthesis of isoprenoids through the mevalonate pathway and the MEP pathway.

<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

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<span class="mw-page-title-main">Withanolide</span>

Withanolides are a group of at least 300 naturally occurring steroids built on an ergostane skeleton. They occur as secondary metabolites primarily in genera of the Nightshade family, for example in the tomatillo.

<span class="mw-page-title-main">Viridin</span> Chemical compound: furanosteroid

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<span class="mw-page-title-main">Oxidosqualene cyclase</span>

Oxidosqualene cyclases (OSC) are enzymes involved in cyclization reactions of 2,3-oxidosqualene to form sterols or triterpenes.

<span class="mw-page-title-main">Arglabin</span> Chemical compound

Arglabin is a sesquiterpene lactone belonging to the guaianolide subclass bearing a 5,7,5-tricyclic ring system which is known to inhibit farnesyl transferase. It is characterized by an epoxide on the cycloheptane as well as an exocyclic methylene group that is conjugated with the carbonyl of the lactone. Arglabin is extracted from Artemisia glabella, a species of wormwood, found in the Karaganda Region of Kazakhstan. Arglabin and its derivatives are biologically active and demonstrate promising antitumor activity and cytoxocity against varying tumor cell lines.

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. 1 2 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. 1 2 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.
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