Synthesis of flexible purine analog inhibitors of NCp7

In recent years, the use of FDA approved Highly Active Antiretroviral Therapies (HAARTs) has shown great promise in the treatment of Human Immunodeficiency Virus Type 1 (HIV-​1)​. A large majority of FDA approved HIV-​1 chemotherapies target the viral enzymes essential for viral replication. Unfortunately, monotherapy-​based treatments have been plagued with rapid loss of efficacy due to the virus' ability to adapt and mutate. Thus, the use of combination therapies is now the preferred mode of treatment of HIV-​1 since the rate of mutation development decreased significantly in the presence of multiple drugs, although it has not been completely halted. Consequently, the development of new drugs that work through alternative modes of action are needed. The objective of this project is to synthesize a series of flexible guanine nucleobase analogs (Flex-​bases) to selectively inhibit the highly conserved nucleic acid (NA) binding domain of the HIV-​1 nucleocapsid protein (NCp7)​. The rotational flexibility of the Flex-​base analogs is installed by "splitting" the purine base into its imidazole and pyrimidine counterparts with a single C-​C bond. Previous results obtained by the Seley-​Radtke lab suggest that this flexibility may endow the nucleobase with the ability to overcome active site mutations in NCp7 as well as adapt to potential binding site repositioning. Previously reported NCp7 inhibitors have not been entirely successful due to significant toxicity, caused by their non-​specific zinc-​ejecting properties. Preliminary computational studies have indicated that the target compds. should work through an alternative mechanism that will not involve zinc ejection. This should endow them with significant advantages over known NCp7 inhibitors. We propose to synthesize several series of these Flex-​bases using palladium-​catalyzed coupling techniques in order to fully study the effects of flexibility on this new class of NCp7 inhibitors.