Theoretical studies on QSAR and mechanism of 2‐indolinone derivatives as tubulin inhibitors

Abstract

The theoretical studies on three-dimensional quantitative structure activity relationship (3D-QSAR) and action mechanism of a series of 2-indolinone derivatives as tubulin inhibitors against human breast cancer cell line MDA-MB-231 have been carried out. The established 3D-QSAR model from the comparative molecular field analysis (CoMFA) shows not only significant statistical quality but also predictive ability, with high correlation coefficient (R 2 ϭ 0.986) and cross-validation coefficient (q 2 ϭ 0.683). In particular, the appropriate binding orientations and conformations of these 2-indolinone derivatives interacting with tubulin are located by docking study, and it is very interesting to find that the plot of the energy scores of these compounds in DOCK versus the corresponding experimental pIC 50 values exhibits a considerable linear correlation. Therefore, the inhibition mechanism that 2-indolinone derivatives were regarded as tubulin inhibitors can be theoretically confirmed. Based on such an inhibition mechanism along with 3D-QSAR results, some important factors improving the activities of these compounds were discussed in detail. These factors can be summarized as follows: the H atom adopted as substituent R 1 , the substituent R 2 with higher electropositivity and smaller bulk, the substituents R 4 -R 6 (on the phenyl ring) with higher electropositivity and larger bulk, and so on. These results can offer useful theoretical references for understanding the action mechanism, designing more potent inhibitors, and predicting their activities prior to synthesis.

Methoxy and bromo scans onN-(5-methoxyphenyl) methoxybenzenesulphonamides reveal potent cytotoxic compounds, especially against the human breast adenocarcinoma MCF7 cell line

“…The 3,5-and 3,4dimethoxyphenyl are the mono demethoxylated analogs of the TMP, and have been previously shown to result in severe potency reductions, with occasional exceptions such as in the 3,5-dimethoxyphenyl triazole analogs of combretastatin A-4 34 . The 2,5dimethoxyphenyl substitution pattern has as well yielded modest results at best 15,[35][36][37][38] , and only combined with bulky and hydrophobic B ring derivatives such as the carbazolesulphonamides 38,39 or quinazolinone sulfamates 40 achieved good antiproliferative results.…”

3D‐QSAR studies and molecular design on a novel series of pyrimidine benzimidazoles as Lck inhibitors

“…QSAR methodology, which quantitatively describes the correlations between biological activities and molecular structures or properties, is one of the most effective approaches for understanding the action mechanism of drugs and designing new drugs . 3D‐QSAR methods, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indexes analysis (CoMSIA), have furthered the understanding of pharmacological properties of studied compounds and modern drug design . 3D‐QSAR models further the understanding of the non‐covalent interaction characteristics between the drug molecule and the target protein, because they are vivid and robust ones.…”

Ferrocene–indole hybrids for cancer and malaria therapy

“…Modifications of the structure of the antimitotic 2-phenylindole-3-carbaldehydes by substitution of the 3-formyl group gave rise to methylene propanedinitrile [12c] and hydrazone [12d] derivatives that did not inhibit tubulin polymerization but were still able to block the cell cycle in G 2 /M phase. QSAR [13], CoMFA, and docking studies [14] have been carried out upon 2-phenylindole derivatives to find out the structural requirements for more active antimitotic agents.…”