Phenothiazine- and Carbazole-Cyanochalcones as Dual Inhibitors of Tubulin Polymerization and Human Farnesyltransferase.

Abstract

In the search for innovative approaches to cancer chemotherapy, a chemical library of 49 cyanochalcones, 1a-r, 2a-o, and 3a-p, was designed as dual inhibitors of human farnesyltransferase (FTIs) and tubulin polymerization (MTIs) (FTIs/MTIs), two important biological targets in oncology. This approach is innovative since the same molecule would be able to interfere with two different mitotic events of the cancer cells and prevent these cells from developing an emergency route and becoming resistant to anticancer agents. Compounds were synthesized by the Claisen-Schmidt condensation of aldehydes with N-3-oxo-propanenitriles under classical magnetic stirring and under sonication. Newly synthesized compounds were screened for their potential to inhibit human farnesyltransferase, tubulin polymerization, and cancer cell growth in vitro. This study allowed for the identification of 22 FTIs and 8 dual FTIs/MTIs inhibitors. The most effective molecule was carbazole-cyanochalcone 3a, bearing a 4-dimethylaminophenyl group (IC50 (h-FTase) = 0.12 µM; IC50 (tubulin) = 0.24 µM) with better antitubulin activity than the known inhibitors that were previously reported, phenstatin and (-)-desoxypodophyllotoxin. The docking of the dual inhibitors was realized in both the active site of FTase and in the colchicine binding site of tubulin. Such compounds with a dual inhibitory profile are excellent clinical candidates for the treatment of human cancers and offer new research perspectives in the search for new anti-cancer drugs.