Synthesis and anti-breast cancer activity of novel indibulin related diarylpyrrole derivatives

Abstract

Background During recent years, a number of anti-tubulin agents were introduced for treatment of diverse types of cancer. Despite their potential in the treatment of cancer, drug resistance and adverse toxicity, such as peripheral neuropathy, are some of the negative effects of anti-tubulin agents. Among anti-tubulin agents, indibulin was found to cause minimal peripheral neuropathy. Thus far, however, indibulin has not entered clinical usage, caused in part by its poor aqueous solubility and other developmental problems in preclinical evaluation. Objectives With respect to need for finding potent and safe anticancer agents, in our current research work, we synthesized several indibulin-related diarylpyrrole derivatives and investigated their anti-cancer activity. Methods Cell cultur studies were perfomred using the MTT cell viability assay on the breast cancer cell lines MCF-7, T47-D, and MDA-MB231 and also NIH-3 T3 cells as representative of a normal cell line. The activity of some of the synthesized compounds for tubulin interaction was studied using colchicine binding and tubulin polymerization assays. The annexin V-FITC/PI method and flow cytometric analysis were used for studying apoptosis induction and cell cycle distribution. Results and conclusion Two of the synthesized compounds, 4f and 4 g, showed high activity on the MDA-MB231 cell line (IC 50 = 11.82 and 13.33 μM, (respectively) and low toxicity on the normal fibroblast cells (IC 50 > 100 μM). All of the tested compounds were more potent on T47-D cancer cells and less toxic on NIH-3 T3 normal cells in comparison to reference compound, indibulin. The tubulin polymerization inhibition assay and [ 3 H]colchicine binding assay showed that the main mechanism of cell death by the potent synthesized compounds was not related to an interaction with tubulin. In the annexin V/PI staining assay, the induction of apoptosis in the MCF-7 and MDA-MB231 cell lines was observed. Cell cycle analysis illustrated an increased percentage of sub-G-1 cells in the MDA-MB231 cell line as a further indication of cell death through induction of apoptosis.

From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin

“…Indibulin was tested in a concentration range of 0.39-3.13 µM, where 3.13 µM was the highest soluble concentration in embryo medium (1% DMSO) (Figure 9F-I). Indibulin is characterized by low water solubility [50] and consequently tested at the maximum soluble concentration instead of the MTC. Neither after 2 h of exposure, nor after 18 h, did the functional analogues show activity against EKP-induced seizure behavior compared to VHC-treated zebrafish larvae (p > 0.05, Figure 9).…”

Synthesis and Cytotoxic Activity Study of Novel 2-(Aryldiazenyl)-3-methyl-1H-benzo[g]indole Derivatives

“…Nitrogen-containing heterocyclic compounds are a class of compounds that have recently attracted an increased interest within the pharmaceutical community due to their widespread and often diverse biological activities [3]. The indolebased compounds in particular are common building blocks for many medicinally active drugs and are considered as target pharmacophores for the development of therapeutic agents [4][5][6][7][8][9]. During the last decade, various benzo[g]indoles have been synthesized and found to exhibit a broad spectrum of biological activities, among which the interchelating anti-tumor activity is of considerable pharmaceutical interest [10].…”