Methoxy-Substituted 3-Formyl-2-phenylindoles Inhibit Tubulin Polymerization

Abstract

The aim of this study was the identification of the essential structural elements in the 12-formyl-5,6-dihydroindolo[2, 1-a]isoquinoline system required for the inhibition of tubulin polymerization which is understood to be the predominant mode of action of this class of cytostatics. Since 2-phenylindole forms the main fragment of this tetracycle, it was used as the basic structure and modified with respect to the number and positions of the oxygen functions in the aromatic rings. Further modifications related to the nitrogen, which was both replaced by oxygen and sulfur and alkylated. All derivatives were tested for cytostatic activity in human breast cancer cells (MDA-MB 231, MCF-7) and inhibition of tubulin polymerization. The spectrum of activity ranged from inactive to IC50 values of 35 nM (cell growth inhibition) and 1.5 microM (tubulin polymerization), respectively, for the most active derivative 3e (3-formyl-6-methoxy-2-(4-methoxyphenyl)indole). Although the correlation between antiproliferative activity and inhibition of tubulin polymerization was not very pronounced, all of the potent cytostatic agents in this study disrupted microtubule assembly completely at the standard concentration of 40 microM. By fluorescence microscopy it was demonstrated that the derivative 3e degrades the cytoskeleton in a similar fashion as colchicine does leading to the condensation of the microtubules around the nucleus after treatment. The comparison between hydroxy and methoxy derivatives revealed a striking difference between the 2-phenylindole derivatives and the indoloisoquinolines. In the 2-phenylindole series, the methoxy compounds were much more effective than the free phenols, whereas in the tetracyclic system the effect of the hydroxy derivatives exceeded that of the methylated compounds by 1 order of magnitude. Preliminary studies on the binding mode showed that both the 2-phenylindole derivatives and the indoloisoquinolines bind to the colchicine site on tubulin.

Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones

“…[47][48][49] The colchicine-binding site in tubulin is mainly buried in the b-subunit of tubulin, whilst maintaining some limited interactions with the a-subunit. The H7 and H8 a-helices, the T7 loop and the S8 and S9 b-strands contribute to the binding site and interact with the colchicine-site ligand.…”

CoMFA and docking studies of 2-phenylindole derivatives with anticancer activity

“…A series of 2-phenylindole derivatives with well-expressed cytotoxicity against human breast cancer cell line MDA-MB 231 [13][14][15], were selected to perform the present study. The structural formula of the studied compounds is shown in Fig.…”

“…In addition to its potent cytotoxicity, CA-4 is one of the few tubulin targeting agents reported to have selective vascular-disrupting activity [11,12]. Recently, von Angerer and coworkers have synthesized a series of 2-phenylindole derivatives and assessed their anticancer activities in human breast cancer cell lines [13][14][15]. They found that these compounds prevent the polymerization of the a/b-tubulin dimers to functional microtubules by binding to the colchicine-binding site and all have pronounced cytotoxicity, demonstrating the great potential of developing 2-phenylindole derivatives as a new class of anticancer drug.…”

“…In this work, CoMFA and docking studies of 43 tubulin inhibitors, 2-phenylindole derivatives with anticancer activity against human breast cancer cell line MDA-MB 231 [13][14][15], were carried out. The purpose of this article focuses to establish an optimal 3D-QSAR model for these compounds by using the CoMFA method and explore the inhibition mechanism via docking analysis combined with 3D-QSAR.…”

Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives

“…Recent literature survey reveals that antitumor activities of indole derivatives [9][10][11] possessed a unique photoresponsive activity [12] used in light-emitting electrochemical cells [13], solid-state lasers, fluorescent labels, etc. 2-Phenyl-1H-indole-3-carbaldehyde derivatives inhibited the growth of MDA-MB-231 and MCF7 breast cancer cells by combining indole and barbituric acid, and new hybrid molecules were synthesized and evaluated for anticancer activity [14][15][16][17][18]. Fan Zhang et al synthesized and evaluated in vitro antitumor activity of 2-amino-3-cyano-6-(1H-indole-3-yl)-4-phenylpyridine derivatives.…”