Potent Antitumor Activities and Structure Basis of the Chiral β-Lactam Bridged Analogue of Combretastatin A-4 Binding to Tubulin

Zhou, Pengfei; Liu, Yan; Zhou, Lu; Zhu, Kongkai; Feng, Kechang; Zhang, Hao; Liang, Yuru; Jiang, Hualiang; Luo, Cheng; Liu, Mingming; Wang, Yang

doi:10.1021/acs.jmedchem.6b01268

Cited by 81 publications

(34 citation statements)

References 22 publications

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“…Therefore, crystals containing two heterodimers of tubulin (T 2 ), the stathmin-like domain of RB3 (R) and TTL were solved at 2.6–1.8 Å resolution 26 , 27 . In the last two to three years, the number of solved complexes has increased significantly 11 , 28 – 30 . This information could facilitate the structure-based optimization of the described ligands.…”

Section: Introductionmentioning

confidence: 99%

High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design

Bueno

Estévez-Gallego

Martins

et al. 2018

Sci Rep

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Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub μM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a Kb value of 2.87 × 108 M−1 which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.

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Section: Introductionmentioning

confidence: 99%

High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design

Bueno

Estévez-Gallego

Martins

et al. 2018

Sci Rep

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“…37 In other investigations, trisubstituted azetidinone derivatives were designed as cis-restricted CA-4 analogues and evaluated for antitumour activity under in vitro and in vivo conditions. 38,39 Thiazolidinones were also reported to mimic the cis-olefinic bond of CA-4 and amongst them compound 18 was the most potent with IC 50 values of 1.21 and 2.12 μM against tumor cell proliferation and tubulin polymerization inhibition, respectively. 40 Guan and coworkers synthesised a series of CA-4 analogues containing a maleic anhydride/N-substituted maleimide moiety by employing a microwave-assisted process and further evaluated them for antiproliferative activities against three tumour cell lines.…”

Section: Recent Developments In Ca-4 Based Analoguesmentioning

confidence: 99%

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

et al. 2017

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The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development. Combretastatin A-4 (CA-4), an inhibitor of tubulin polymerization isolated from natural sources, is a lead molecule with significant cytotoxicity against tumour cells. Owing to its non polar nature it exhibits low solubility in natural biological fluids, thereby prompting the development of new CA-4 based derivatives. The modification of this lead molecule was mostly carried out by keeping the crucial -orientation of the double bond intact, along with a trimethoxyphenyl aromatic ring, by employing different approaches. The issue of solubility was also addressed by the development of water soluble prodrugs of CA-4. The present review highlights the investigations into the parallel development of both new CA-4 based derivatives and prodrugs in the past few years.

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“…Thus, an extensive focus of research was directed towards the rational modifications of the unstable olefinic bond as the main pursued strategy. Various olefinic linkers including silicon [14], butadiene [15], cyclopropane [16], cyclopropyl [17], chiral-lactam [18], furan [19], furazan [20], imidazole [21], 2,3-diarylthiophene [22], isoxazole and terphenyl [23], triazoles [24,25], thiazole [26,27] and 1,2,4-triazolo-4,3-b-pyridazines [28] has unveiled novel agents endowed with cytotoxic activity. The structure-activity relationships (SARs) have made clearly important features of maintaining the tubulin interaction for CA-4.…”

Section: Introductionmentioning

confidence: 99%

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

Song

Wang

et al. 2020

IJMS

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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.

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Potent Antitumor Activities and Structure Basis of the Chiral β-Lactam Bridged Analogue of Combretastatin A-4 Binding to Tubulin

Cited by 81 publications

References 22 publications

High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design

High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

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

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