Harnessing Atropisomerism in beta-Carbolines for the Discovery of New Reactions and Small Molecule Probes

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Project Summary New therapeutics that have potential for treating disease are among the public health goals that are central to the mission of the NIH. While traditional strategies have had remarkable success, molecules with novel structures and new modes of action are still needed to serve as drug leads. In this work, we wish to study the unique stereochemical property of small molecules known as atropisomerism. Chiral molecules with an atropisomeric axis, once seen by the scientific community as too risky for development, are now becoming increasingly common in drug discovery and medicinal chemistry because of improvements made to compound potency, selectivity, stability, and pharmacokinetics. In this proposal, our team of undergraduate student researchers at Providence College will continue to shift the paradigm by exploiting stable atropisomerism in the nitrogen-containing heterocycle known as the β-carboline. We have identified 1-aryl-substituted-β-carbolines with antibacterial, neuropharmacological, and DNA-binding activity, which make them appropriate for study through the National Institute of General Medical Sciences. Our main focus is on the atropisomeric behavior of 1-aryl-substituted-β-carbolines, in which we have observed barriers to rotation greater than 30 kcal/mol. Given the remarkable configurational stability of these molecules, we will establish three new strategies for harnessing their potential as chiral molecules for improving human health and well-being. Our first goal will be to develop a kinetic resolution strategy for rapidly accessing the individual enantiomers of 1-aryl-substituted-β-carbolines. We will use β-turn peptides to perform an asymmetric N-oxidation of these molecules, work which will be aided by a continuing collaboration with colleagues at Yale University in the laboratory of Professor Scott Miller. The second goal of the project will be the synthesis of the natural product chaetogline F, a β-carboline natural product with known inhibitory activity of acetylcholinesterase. We will prepare the natural product, resolve the enantiomers, and perform a structure-activity relationship study of this molecule which will shed light on the importance of atropisomerism in target binding. The third goal is to develop a new asymmetric N,P-ligand based on the β- carboline scaffold. We will synthesize the new ligand via a cross-coupling strategy and then assess its ability to induce asymmetry in the synthesis of neuroactive alkaloids via alkyne additions to iminium ions. Finally, this proposal will expose undergraduate students at Providence College to impactful research, which will both improve the culture of scientific inquiry in a liberal arts setting and inspire students to continue in a STEM or health-related field upon graduation.