Design, synthesis and biological evaluation of novel quinoline analogues as potential anticancer agents and tubulin inhibitors

Microtubules play an essential role in mitosis and have long been considered as an important target for the development of novel anticancer drugs. In general, antitubulin agents exert their effects by bindingto one of the three established drug domains on the tubulin heterodimer: the colchicine, the paclitaxel and the vinca alkaloid binding sites. Agents that target the colchicine’s domain (e.g., colchicine andpodophyllotoxin) or to the vinca alkaloid binding site (e.g., vincristine) are defined as inhibitors of tubulin assembly, that is, microtubule destabilizing agents. Some quinoline derivatives displayed potentanticancer activity targeting different sites like topoisomerase I, telomerase, farnasyl transferase, Src tyrosine kinase, protein kinase CK-II, aromatase, COX-2 and etc. In the present study some newquinoline derivatives have been designed and synthesized as tubulin inhibitors, these compounds all are possessing trimethoxy phenyl pharmacophore and some of our compounds possessing also 3-hydroxy4-methoxy phenyl pharmacophore which are present in some potent tubulin inhibitors1. Synthesis: A four-step reaction was used to prepare the target 5,6,7-trimethoxyquinoline derivatives, atfirst step to obtain quinolin-4-ol derivatives, trimethoxy aniline, ethyl acetoacetate and polyphosphoric acid was stirred at 130°C in THF, then reaction of quinolin-4-ols with POCl3 led to the formation of 4-chloroquinoline derivatives. In the third step 4-chloroquinolines with substituted benzaldehydes were refluxed in toluene to obtain the target compounds. The compounds were characterized by nuclearmagnetic resonance, infrared and mass spectrometry. Biological evaluation (In vitro anticancer activity): The cytotoxic activity of the synthesized compounds are under evaluation against four human cancercell lines including MCF-7 (Human Breast Cancer Cells), MCF-7/MX (Resistant human Breast Cancer Cells), A-2780 (human ovarian carcinoma) and A-2780/RCIS (Resistant human ovarian carcinoma),employing the MTT assay