Abstract

Development of New Molecules as Potential Anticancer Agents

Ahmed Kamal, Outstanding Scientist and Head, Indian Institute of Chemical Technology

Cancer is one of the dreadful diseases, which poses a significant challenge with high rates of diagnosis and mortality. In the development of anticancer drugs, leads from natural products still remains a cornerstone and a number of drugs in clinical usage are inspired from natural products. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) isolated from various Streptomyces species is a lead compound, which binds to minor groove of DNA exhibiting potent anticancer properties. Similarly, the naturally occurring podophyllotoxin lignans exhibits anticancer activity. Combrestatins isolated from the bark of Combretum caffrum is also a lead compound which binds at the colchicine site of tubulin and arrest cell proliferation. However, these lead compounds have limitations because of the lack of selectivity for tumor tissues, low water solubility and stability etc. Different strategies have been adapted which includes modification of the scaffold, design of new hydrids and prodrugs etc. to address the short comings associated with these lead structures. In our laboratory, several congeners of these leads have been designed and synthesized by conjugating with different pharmacophoric heterocyles (such as benzimidazole, quinazolinone, pyrazoles etc.), modification of the ring system in addition to dimerization of these lead moieties. Mechanistic studies have been carried out to understand their mode of action and interestingly, some of the conjugates are found to induce apoptosis. Prodrug concepts have been applied to enhance the selectivity and new -galactoside prodrugs of PBDs have been synthesized and evaluated for potential use in selective therapy of solid tumors. Moreover, some to the PBD derivatives developed in our laboratory are undergoing preclinical studies.