Our work in the previous funding period was inspired by synthetic challenges inherent in molecules that directly bind to the ribosome or indirectly impact its function. Structure-activity relationship studies are difficult in these classes of molecules, due to lack of flexible synthetic methods to enable flexible changes to the positioning, stereochemistry and steric environments of key amine and alcohol groups that engage in H- bonding or electrostatic interactions with the binding site; the same is true for altering alkyl and aryl groups that participate in hydrophobic or ?-? interactions. Our versatile methods streamline syntheses of stereochemically complex amine 'triads' present in natural products that inhibit protein synthesis, including aminocyclitols, anthracyclines, and tetracyclines. This enables us to construct 'unnatural products' inspired by bioactive natural products, where diversity can be achieved in: 1) heteroatoms installed in the amine 'triad' building blocks, 2) stereochemical relationships amongst the three contiguous, heteroatom-bearing sp3 carbon centers of the triad, and 3) densely functionalized carbo- and heterocyclic scaffolds. A library of >1000 unique compounds in novel amine chemical space displaying significant stereochemical complexity has shown promising activities against drug-resistant malaria and tuberculosis, Chaga's disease, hepatocellular carcinoma, and other biological targets. This renewal builds on our expertise in securing complex, densely functionalized amine motifs to investigate structure-activity relationships in molecules that impact protein synthesis, primarily through interactions with the ribosome. Analogs of the potent antimalarial natural product jogyamycin will be prepared to probe how binding to the ribosome is impacted; these studies are key to the design of simpler synthetic amine scaffolds that show similar bioactivity, but better selectivity for parasitic vs. eukaryotic mitochondrial ribosomes, lowered toxicity, and less propensity to develop resistance. In the same manner, our expertise in complex amine synthesis will be applied to the design of 'hybrid' anthracyclines that mitigate the toxicity and multi-drug resistance seen in the widely-used antitumor drug doxorubicin (DOX) and other related drugs of significance to the treatment of cancer. We have secured the aid of several collaborators to assess the biological activities of our compounds and provide insight into the design of 2nd-generation libraries, including the Eli Lilly Open Innovation program, GSK (in progress), Corteva Agrisciences, several academic colleagues (Prof. Taifo Mahmud, Prof. Dev Arya, Prof. Silvia Cavagnero, Dr. Desiree Bates), and the University of Wisconsin Medicinal Chemistry Center.
Synthetic compounds able to selectively target prokaryotic over eukaryotic ribosomes to impede protein synthesis are rare. Challenges with pathogens developing resistance towards ribosomal-binding therapeutics, coupled with the synthetic complexity of drugs based on natural products, have reignited interest in 'unnatural products' capable of fulfilling this function. This proposal utilizes versatile synthetic methods to explore new amine chemical space with promising bioactivities that may be related to targeting the ribosome.
