Dataset Information

Molecular modeling study, synthesis and biological evaluation of combretastatin A-4 analogues as anticancer agents and tubulin inhibitors.

ABSTRACT: As the major structural component of microtubules, tubulin is an interesting target for the development of anticancer agents. In this study, 64 tubulin polymerization inhibitors of five-membered heterocycle-based combretastatin A-4 analogues were studied by a combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were established with desirable statistical parameters and excellent predictive ability. 20 ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. Combining the binding free energy calculations and 3D-QSAR results, some new heterocycle-based combretastatin A-4 analogues were designed. Three of them were synthesized and biologically evaluated. Compound 13a displayed potent antiproliferative activity (IC50 value of 1.31 ?M against HepG2 cells, IC50 value of 1.37 ?M against A549 cells) and inhibition of tubulin polymerization activity (IC50 value of 0.86 ?M). Compound 13b also presented good activity against HepG2 cells (IC50 value of 4.75 ?M). The experimental results demonstrated that the built models were effective for the development of novel anticancer agents and tubulin inhibitors.

SUBMITTER: Quan YP

PROVIDER: S-EPMC6083788 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular modeling study, synthesis and biological evaluation of combretastatin A-4 analogues as anticancer agents and tubulin inhibitors.

Quan Yang Ping YP Cheng Li Ping LP Wang Tian Chi TC Pang Wan W Wu Fan Hong FH Huang Jin Wen JW

MedChemComm 20171206 2

As the major structural component of microtubules, tubulin is an interesting target for the development of anticancer agents. In this study, 64 tubulin polymerization inhibitors of five-membered heterocycle-based combretastatin A-4 analogues were studied by a combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) model ...[more]

PMID: 30108925

Similar Datasets

Project description:The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 ?M), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 ?M) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.

Dataset Information

Molecular modeling study, synthesis and biological evaluation of combretastatin A-4 analogues as anticancer agents and tubulin inhibitors.

Publications

Molecular modeling study, synthesis and biological evaluation of combretastatin A-4 analogues as anticancer agents and tubulin inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure