Computer aided design of novel noscapinoids and their experimental evaluation as tubulin binding anti cancer drugs

Abstract

Microtubules are major cytoskeletal structures responsible for maintaining genetic stability during cell division The dynamics of these polymers are absolutely crucial for this function that can be described as their growth rate at the plus ends catastrophic shortening frequency of transition between the two phases pause between the two phases from the microtubule organizing center and treadmilling Interference with microtubules dynamics often leads to programmed cell death and thus microtubule binding drugs such as paclitaxel docetaxel and the vinca alkaloids are currently used to treat various malignancies in the clinic However these chemotherapy drugs are confounded by complications with serious toxicity particularly peripheral neuropathies gastrointestinal toxicity myelosuppression and immunosuppression owing to their non selective action and extreme overpolymerizing effects by taxanes or depolymerizing effects by vincas on microtubules Thus there is an urgent need to explore novel tubulin binding agents that are significantly effective and comparatively less toxic compared to currently available drugs for the treatment of human cancers Systematic screening of new compounds based on structural similarity of know drugs such as colchicines podophyllotoxin etc that interfere with microtubules has led to the discovery of noscapine an opium alkaloid that binds stoichiometrically to tubulin alters its conformation upon binding and arrests mammalian cells in mitosis It was demonstrated that unlike many other microtubule inhibitors noscapine does not significantly promote or inhibit microtubule assembly primarily by increasing the amount of time that the microtubules spend in an attenuated pause state when neither microtubule growth nor shortening is detectable newline