NEW STRATEGIES TO GENERATE NEW CHEMICAL DIVERSITY FOR DRUG DISCOVERY

Hidayat Hussain

Center for Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, 92093-0204, USA and UoN Chair of Oman’s Medicinal Plants and Marine Natural Products, University of Nizwa, P.O Box 33, Postal Code 616, Nizwa, Sultanate of Oman

Abstract

Natural products have an excellent track record in the discovery of lead compounds to treat cancer and infectious diseases. A characteristic feature of natural products is their chemical diversity, which is created by a sequence of enzymatic reactions in the producing organisms. Different classes of compounds are produced by different biosynthetic pathways. Sometime different biosynthetic pathways takes place within one compound and leads to functional group modification, combination of monomers to dimers, and occurrences of open chain and ring close natural products. The phytochemical investigations of plants and fungi provided a continuous supply of the natural products of interest but with limited number of their derivatives. Moreover synthetic chemistry can be employed to generate chemical diversity from bioactive natural products in order to prepare more derivatives for further biological screening.

We have isolated number of natural products from fungi and plants which have interesting chemical diversity. Moreover these natural products demonstrated significant anticancer, antimalarial, and antimicrobial effects. Various analogs of bioactive natural products have been prepared via natural product inspired diversity oriented synthesis strategy with the objective to obtain analogues with greater anticancer and antimalarial activities. In addition to simple chemical modification, various monomers, homodimers and heterodimers of bioactive natural products were also prepared in order to enhance the biological effects as well as to create interesting Structure Activity Relationships (SARs) among synthesized compounds. It is noteworthy that these natural product inspired scaffolds display very potent antimalarial and anticancer effects towards various cancer cells viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma) and A375 (malignant melanoma). A detail discussion about natural and synthetic chemical diversity and their role in drug discovery will be presented.