Rational design of novel tubulin binding anticancer agents based on chemoinformatics evaluation of noscapinoids their chemical synthesis and experimental validation and#8195;

Abstract

Microtubules are important cytoskeletal structures that preserve genetic stability during cell division. The dynamics of these polymers, which may be defined as their growth rate at the newlineplus ends, catastrophic shortening, frequency of transition between the two phases, pause between newlinethe two phases, release from the microtubule organising centre, and so on, are all critical for this newlinefunction. Interfering with microtubule dynamics results in programmed cell death. Therefore microtubule-binding agents such as paclitaxel, docetaxel, and the vinca alkaloids are utilised in clinics to treat a variety of cancers. However, because of their non-selective action, these drugs are newlineassociated with severe toxicity (especially peripheral neuropathies, gastrointestinal damage, myelosuppression, and immunosuppression) mainly by overpolymerizing (by taxanes) or depolymerizing (by vincas) the microtubules. In a quest to find new tubulin-binding compounds for the treatment of cancer, noscapine, an opium alkaloid was discovered. It was found to binds newlinestoichiometrically to tubulin, alter its conformation upon binding, and arrest mammalian cells in mitosis. Even at high doses, noscapine, unlike many other microtubule inhibitors, does not appreciably enhance or inhibit microtubule polymer mass. Instead, it alters the steady-state dynamics of microtubule assembly, principally by increasing the amount of time that microtubules spend in an attenuated (halt) state, in which neither microtubule growth nor shortening can be detected. Owing to the compromised cell cycle check points, cancer cells are preferentially newlinedestroyed by noscapine and its derivatives (together known as noscapinoids) without affecting normal cells.