Design and synthesis of novel tranilast analogs: Docking, antiproliferative evaluation and in-silico screening of TGFβR1 inhibitors

The discovery of the antiproliferative potential of tranilast prompted additional studies directed at understanding the mechanisms of tranilast action. Its inhibitory effect on cell proliferation depends principally on the capacity of tranilast to interfere with transforming growth factor beta (TGFβR1) signaling. This work summarizes design, synthesis and biological evaluation of sixteen novel tranilast analogs on different tumors such as PC-3, HepG-2 and MCF-7 cell lines. The in vitro cytotoxicity was evaluated using MTT assay showed that, twelve compounds out of sixteen showed higher cytotoxic activities (IC₅₀'s 1.1-6.29 µM), than that of the reference standard, 5-FU (IC₅₀ 7.53 µM). The promising cytotoxic hits (4b, 7a, b and 14c-e), proved to be selective to Cancer cells when their cytotoxicity's are examined on human normal cell line (WI-38). Then they are investigated for their possible mode of action as TGFβR1 inhibitors; remarkable inhibition of TGFβR1 by these hits was observed at the range of IC₅₀ 0.087-3.276 μM. The cell cycle analysis of the most potent TGFβR1 inhibitor, 4b revealed cell cycle arrest at G₂/M phase on prostate Cancer cells. Additionally, it is clearly indicated Apoptosis induction at Pre-G1 phase, this is substantiated by significant increase in the expression on the tumor suppressor gene, p53 and up regulation the level of Apoptosis mediator, Caspase-3. In addition, in silico study was performed for validating the physicochemical and ADME properties which revealed that, all compounds are orally bioavailable with no side effects complying with Lipinski rule. The proposed mode of action can be further explored on the light of molecular modeling simulation of the most potent compounds, 4b and 14e which were docked into the active sites of TGFβR1 to predict their affinities toward the receptor.