Synthesis of HIV Integrase Inhibitors Integrastatin A and B

Pamela Michele Tadross, California Institiute of Technology
Dissertation Award

Since its discovery in 1981, the United Nations and World Health Organization have estimated that HIV/AIDS has claimed more than 25 million lives, placing it among the most destructive pandemics in history. With approximately 39 million people living with HIV/AIDS worldwide, the unabated spread of the HIV/AIDS pandemic is one of the most pressing issues confronting the scientific community in modern times. In 2006 alone, roughly 4.3 million people were newly infected with HIV and another 2.9 million died of the virus. The urgency of thematter is emphasized by the extraordinary growth over the past 25 years of research gearedtoward the development of new therapies aimed at disabling viral replicative processes. Despite this growth, new drugs are constantly needed to combat the toxicity of the current HIV protease and reverse transcriptase inhibitors, while minimizing the potential for the emergence of drugresistant virus strains. Toward this end, the synthesis of small molecule inhibitors has become central to the development new chemotherapeutics. Because of the potential these compounds hold for the advancement of HIV therapy, we propose to synthesize the naturally occurring integrase inhibitors, integrastatin A and B, as well as related structural analogs for biological screening.

Natural products have historically served as excellent sources for the discovery of biologically active agents that act as the basis for lead candidates in drug development. Inparticular, integrastatin A and B display inhibitory activity against HIV-1 integrase at micromolar concentrations and are thus attractive targets for new therapeutic development. Integrastatins A and B were isolated as racemic compounds in 2002 and both display potent inhibition of the strand transfer reaction of recombinant HIV-1 integrase at micromolar concentrations. IC50 values for integrastatin A and B are 1.1 M and 2.5 M, respectively. Synthetic access to these naturally occurring inhibitors would allow for more thorough biological testing as well asstructure-activity relationship (SAR) studies to optimize potency and antiviral activity. We propose to apply the acyl-alkylation of arynes, developed in 2005 by our lab, to the synthesis of the HIV-1 integrase inhibitors integrastatin A and B. The use of Sharpless dihydroxylation methodology will permit enantioselective syntheses of both antipodes of each natural product. Application of aryne insertion methodology allows for concise, modular, and highly convergent syntheses of these targets. Upon completion of the syntheses of integrastatin A and B and subsequent biological screening, we plan to design and synthesize structural analogs for additional biological activityand SAR studies. These and other proposed studies will be performed in collaboration with thelaboratories of Nouri Neamati at University of Southern California School of Pharmacy.

We anticipate that the proposed research will have a substantial impact extending beyond the realm of synthetic organic chemistry, and pervade the manifold scientific endeavors aimed at eradicating the HIV/AIDS crisis.