Combretastatin A-4
{{Use dmy dates|date=August 2024}}
{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 460106710
| Name = Combretastatin A-4
| ImageFile = Combretastatin A4.svg
| ImageSize =
| PIN = 2-Methoxy-5-[(1Z)-2-(3,4,5-trimethoxyphenyl)ethen-1-yl]phenol
| OtherNames = Combretastatin A4
CA-4
1-(3,4,5-Trimethoxyphenyl)-2-(3′-hydroxy-4′-methoxyphenyl)ethene
3,4,5-Trimethoxy-3′-hydroxy-4′-methoxystilbene
| Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 117048-59-6
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 16U6OP69RQ
| PubChem = 5351344
| SMILES = COC1=C(C=C(C=C1)C=CC2=CC(=C(C(=C2)OC)OC)OC)O
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4508364
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 67
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = HVXBOLULGPECHP-WAYWQWQTSA-N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI =1S/C18H20O5/c1-20-15-8-7-12(9-14(15)19)5-6-13-10-16(21-2)18(23-4)17(11-13)22-3/h5-11,19H,1-4H3/b6-5-
}}
| Section2 = {{Chembox Properties
| Formula = C18H20O5
| MolarMass = 316.34 g/mol
| Appearance =
| Density =
| MeltingPtC = 116
| BoilingPt =
| Solubility = insoluble
| Solvent = DMSO, Ethanol
| SolubleOther = DMSO : 63 mg/mL, Ethanol : 34 mg/mL{{Cite web |title=Selleck Chem|url=https://www.selleckchem.com/products/combretastatin-a4.html |access-date=2025-04-25 |website=www.selleckchem.com}}
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| Section3 = {{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
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Combretastatin A-4 is a combretastatin and a stilbenoid. It can be isolated from Combretum afrum, the Eastern Cape South African bushwillow tree or in Combretum leprosum, the mofumbo, a species found in Brazil.Determination of Combretastatin A-4 in Combretum leprosum. SCN Queiroz, MR Assalin, S Nobre, IS Melo, RM Moraes, VL Ferracini and AL Cerdeira, Planta Med, 2010, volume 76, pages 53, {{doi|10.1055/s-0030-1251815}}{{Cite journal|last1=Gill|first1=Rupinder|last2=Kaur|first2=Ramandeep|last3=Kaur|first3=Gurneet|last4=Rawal|first4=Ravindra|last5=Shah|first5=Anamik|last6=Bariwal|first6=Jitender|title=A Comprehensive Review on Combretastatin Analogues as Tubulin Binding Agents|journal=Current Organic Chemistry|volume=18|issue=19|pages=2462–2512|doi=10.2174/138527281819141028114428|year=2014}}
Function
Tubulin represents a potent target in cancer chemotherapy, given its role in cell division. Combretastatin is a naturally occurring well known tubulin polymerization inhibitor. Combretastatin A-4 comes in two stereoisomers (cis (shown top right), and trans); The cis form binds much better to the 'colchicine' site on tubulin to inhibit polymerization.{{Cite web|url=http://www.cell.com/chem/pdf/S2451-9294(16)30270-4.pdf|title=Structural Basis of cis- and trans-Combretastatin Binding to Tubulin. Gaspari. 2017}}
Derivatives
Combretastatin A-4 is the active component of combretastatin A-4 phosphate, a prodrug designed to damage the vasculature (blood vessels) of cancer tumors causing central necrosis.{{citation needed|date=February 2023}}
A large number of synthetic derivatives have been reported,{{cite journal |title=Synthesis and biological evaluation of Combretastatin A-4 derivatives containing a 3'-O-substituted carbonic ether moiety as potential antitumor agents. |journal = Chemistry Central Journal|volume = 7|issue = 1|pages = 179|author=Ma|display-authors=et al |year=2013 |doi=10.1186/1752-153X-7-179 |pmid = 24304592|pmc=3878987 | doi-access=free }}{{Cite journal|last1=Richter|first1=Michael|last2=Boldescu|first2=Veaceslav|last3=Graf|first3=Dominik|last4=Streicher|first4=Felix|last5=Dimoglo|first5=Anatoli|last6=Bartenschlager|first6=Ralf|last7=Klein|first7=Christian D.|date=2019|title=Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1-Activated Prodrugs as Antiviral Agents|journal=ChemMedChem|language=en|volume=14|issue=4|pages=469–483|doi=10.1002/cmdc.201800641|pmid=30605241|issn=1860-7187|doi-access=free|hdl=20.500.12684/4730|hdl-access=free}} including beta-lactam based compounds.{{cite journal|last=O'Boyle|first=N|author2=Miriam Carr |author3=Lisa M. Greene |author4=Orla Bergin |author5=Seema M. Nathwani |author6=Thomas McCabe |author7=David G. Lloyd |author8=Daniela M Zisterer |author9=Mary J. Meegan |journal=Journal of Medicinal Chemistry|year=2010|volume=53|issue=24|pages=8569–8584|doi=10.1021/jm101115u |pmid=21080725 |title=Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents.|hdl=2262/81779|hdl-access=free }}
Pharmacokinetics
CA4 has a half life of 1.8-4.2h in humans. CA4P(a prodrug) has a half life of 0.22-0.36h in humans.{{Cite journal |last=Xu |first=Xiao-Ping |last2=Wu |first2=Xiao-Dong |last3=Liang |first3=Gui-Lun |last4=Huang |first4=Wen-Sheng |last5=Wang |first5=Li |last6=Jing |first6=Hai-Ying |last7=Zhong |first7=Shi-Long |date=2012-06-01 |title=Pharmacokinetics, excretion, and distribution of combretastatin A4 phosphate in rats |url=https://www.ingentaconnect.com/content/govi/pharmaz/2012/00000067/00000006/art00011 |journal=Die Pharmazie |volume=67 |issue=6 |pages=529–533 |doi=10.1691/ph.2012.1647}}
See also
- Ombrabulin, a combretastatin A-4 derivative in clinical trials for treatment of cancer
References
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