PROJECT ABSTRACT Cyanobacteria produce secondary metabolites have been well-documented to possess potent and selective anticancer activity, which has resulted in FDA approval of a cyanobacterial antibody-drug-conjugate (ADC) for the treatment of several Hodgkin lymphomas. Even though this highlights the critical role of natural products in the drug discovery, the novelty of structural scaffolds has largely remained steady in the last two decades. Therefore, we aim to design and synthesize a pseudo-natural product library inspired by cyanobacterial metabolites with well-described anti-cancer activity to expand their molecular coverage. Our pseudo-natural product library will develop and describe uncharted chemical space that integrates privileged scaffolds while employing medicinal chemistry approaches, such as combinatorial chemistry and parallel synthesis. We will qualitatively and quantitatively characterize our library using modern computational, machine learning and metabolomic techniques, to compare it with natural products and FDA-approved drugs. The long-term goal of this research is to generate a chemical library rich in natural product scaffolds that are biased towards cancer tissue for drug discovery and development. Our main hypothesis is that our library will contain chemical architectures embedded with biological properties of privileged cyanobacterial structures that describe new chemical space.

PROJECT NARRATIVE This study will yield a comprehensive characterization of new bio-inspired chemicals to provide new molecules with anticancer properties. The computational data from this project will used to guide our navigation of chemical space, potentially providing new therapeutic agents for treating cancers, as well as a better understanding of the molecular universe and its potential for drug discovery.