Research Projects

India is making tremendous strides in realizing its potential in the integrated fields of organic chemistry and drug discovery translating into disease therapeutics. This ARG proposal, under the newly vitalized Anusandhan National Research Foundation, is targeted at advancing fundamental natural products chemistry to address stereo, regio and enantiocontrolled isoprenylation reactions to alkaloid total synthesis. They inspire new organic chemistry methods. It is also an interdisciplinary effort between the PI, Prof. Rajesh Viswanathan’s synthetic and medicinal chemistry lab and that of Dr. Sanjay Kumar, a cancer biologist (as Co-PI) at IISER Tirupati. We target the development of original total biomimetic synthesis efforts to some of the most complex pyrroloindoline natural products that are potent anticancer agents. As the world is witnessing emergence of resistance as a serious threat to human health, we offer a viable strategy to increase disease treatment success rates. Overarching Rationale: • Pyrroloindolines constitute a privileged scaffold for asymmetric synthesis and medicinal chemistry. • The area of cyclic-dipeptides with L/D-Tryptophan as dimers flanking both sides of the DKP ring has been minimally explored as bioactive natural product scaffold. • Chaetocin A/B, Nocardioazine A/B, Griseocazines and Fumitremorgins are complex DKP target molecules that challenge us to create highly stereo- and regioselective C-C & C-N bond-forming reaction methods. • Enzyme-like Bronsted acid-mediated / Pd-(II)-catalysed isoprenylations and Co-(II)-catalysed dimerization reactions offer concise gram-scale syntheses, without using protecting groups. • One of the major causes of treatment failure in cancer is the emergence of chemotherapeutic resistance to existing cancer drugs. • Inhibition of Pgp-mediated drug efflux, could dramatically reverse cancer resistance and disease relapse, and therefore, identifying non-toxic inhibitors is of utmost urgency to rejuvenate cancer therapy. Hypothesis: The development of biomimetic approaches to the total synthesis of these anticancer agents holds lot of promise for medicinal chemistry. Our projected path to gaining insightful results in the above two objectives will guide us towards a collaborative effort with the co-PI to study the effects of these DKP inhibitors against cancer stemness and disease relapsing characters as a model in Ovarian cancers. Honorary collaborators’ lab (Dr. Koji Itahana, NUS-Duke Cancer Center, Singapore) will also test our molecules to report on the most effective ABC transporter inhibitors through part of the next Objective in the proposal. Natural products, and their carefully designed analogs, serve as excellent drug leads. More than 30 to 50% of existing approved drugs trace their origins to natural products. Along the line of a priority for the nation building, we envision new research paths targeted at developing strategies to target ABC transporter proteins, will have a long-lasting trail of innovation not only for the Institute, but overall, for the country. This project has potential for creating new Active Pharmaceutical Ingredients and Patents that will help create new pharmaceutical drugs. The PI’s lab is envisioning studies proposed here as a new paradigm towards devising natural products that were earlier supported by SERB through Grant # (DST-SERB CRG 2020/005008/OC).