Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

International Journal of Molecular Sciences
Ming-Yu SongJin-Ming Gao

Abstract

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

References

Jul 4, 1990·Journal of the National Cancer Institute·P SkehanM R Boyd
Apr 1, 1995·British Journal of Cancer·J A WoodsA T McGown
Mar 1, 1996·Medicinal Research Reviews·E Hamel
Jul 23, 2003·Current Medicinal Chemistry·Nguyen-Hai Nam
Aug 28, 2004·Expert Opinion on Investigational Drugs·Scott L Young, David J Chaplin
May 26, 2006·Journal of Medicinal Chemistry·Gian Cesare TronArmando A Genazzani
May 26, 2006·Journal of Medicinal Chemistry·Daniele SimoniClaudio Pisano
Aug 18, 2006·Journal of Medicinal Chemistry·Tracey PiraliArmando A Genazzani
Sep 25, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Silvio AprileGiorgio Grosa
Jan 29, 2013·European Journal of Medicinal Chemistry·Evelia RasolofonjatovoMouad Alami
Feb 2, 2013·Bioorganic & Medicinal Chemistry·Nancy TyJean-Claude Florent
Apr 1, 2014·European Journal of Medicinal Chemistry·Mohamed Ali SoussiMouad Alami
Jun 26, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alla V LipeevaAndrey G Pokrovsky
Jan 1, 2011·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yinghua JinHongrui Song
Apr 14, 2017·Bioorganic & Medicinal Chemistry·Yanqing PangXingshu Li
Mar 17, 2019·International Journal of Molecular Sciences·Natalia Piekuś-SłomkaStanisław Sobiak

❮ Previous
Next ❯

Citations

Jun 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gökçe Şeker KaratoprakEduardo Sobarzo-Sánchez

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR
X-ray
column chromatography
Assay
flow cytometry

Software Mentioned

Cellquest
USCF Chimera
Sybyl
Surflex
Dock
GraphPad Prism

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis