The goal of this proposal is synthesize a class of structurally novel oligomeric terpenoids which are presented here to have previously unreported potent and selective anti-trypanosomal activity, and to determine their biological target and structure-activity relationship (SAR.) Our long-term goal is to produce new drug leads for the treatment of chronic infections of Trypanosoma cruzi (T. cruzi,) the causative agent of Chagas disease, and demonstrate their therapeutic value through in-vitro and in-vivo testing. The proposed research comprises the development of a new class of polyene capable of rapid, highly regio- and diastereo-selective formation of fused polycyclic polyene monomers; new methods for the controlled oligomerization of these monomeric species; and application of this chemistry to short, scalable and modular syntheses of the family of terpenoids presented herein. This chemistry will be used to explore the biological impact of various moieties within the context of their terpenoid frameworks through SAR discovery, to determine how the unique chemical reactivities of these polycyclic and macrocyclic systems are related to their resulting biological activities (including the possibility of prodrug degradation into reactive intermediates within T. cruzi,) and to determine the target(s) of these compounds in collaboration with the Genomics Institute of Novartis Research Foundation (GNF.) The first phase of research concerns the streamlined development of a novel chiral dienophile, as well as a new application of the polarized dendritic polyenes - Danishefsky Dendralenes - developed in our lab which undergo highly regio- and stereoselective Diels-Alder reactions to rapidly construct the polycyclic skeleton of these monomeric terpenoids. All available literature precedent indicates that these monomeric species will have widespread utility in the rapid construction of larger complex carbocycles. The second phase of research draws inspiration from a hypothesis regarding the biogenetic origin of this complex family of terpenoids being traced back to variations on a single monomeric unit. We will explore regioselective and stereoselective strategies of controlled oligomerization of the monomeric terpenoids into the desired poly- and macrocyclic oligomers, employing a strongly substrate-directed Diels-Alder approach as well as an unprecedented formal head-to-tail macrocyclization. To achieve these cyclizations, we will investigate thermal, photochemical, and Lewis-base mediated strategies as well as solid and solution phase approaches. The third phase of research, conducted in collaboration with GNF/Novartis, involves the elucidation of the structural basis for anti-trypanosomal activity within this class of terpenoid oligomers and the determination of their mechanism of action. We present preliminary data that show the potent and selective cytotoxicity of these compounds against T. cruzi parasites.
Chagas disease is a tropical parasitic infection for which no treatment exists against the most health-threatening chronic phase, and is considered a neglected disease of the poor. The objective of this proposal is to develop a scalable synthetic approach to a class of terpenoid oligomers which show promising activity and selectivity against Trypanosoma cruzi, the protozoan causative agent of Chagas disease. With a streamlined synthetic strategy in hand, we will be able to elucidate the structural attributes of these molecules which lead to their activity, determine their biological target(s,) and demonstrate to the biopharmaceutical community that this class of molecules has the promise to be the basis for a drug discovery process aimed at developing therapeutics for this disease, as well as a potential lead for other related trypanosomal illnesses.
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