Natural Products as Anti-HIV agents: Synthesis of Przewalskin B

Kristy Tran, California Institute of Technology, Pasadena
Mentor: Brian Stoltz
Training in Basic Biomedical Sciences
Postdoctoral Fellowship Award

Since the discovery of HIV as the cause of AIDS in 1983, significant breakthroughs have been made in the treatment of this disease. For the past 25 years, small molecule pharmaceutical agents have changed the face of HIV/AIDS care in developed nations. As a result, those living with HIV/AIDS can now look forward to longer lifetimes and improved standards of living. Within California as of October 2008, HIV/AIDS case-fatality rates are down to 5-10% from near certainty (>90%) in the early 1990s. However, despite significant gains, HIV/AIDS remains a formidable disease. Now considered a pandemic, an estimated 33 million people are living with HIV/AIDS, approximately 2.5 million people became newly infected and about 2.1 million AIDS related deaths occurred in 2007 alone.Treatment options, such as highly active antiretroviral therapies, only postpone the onset of AIDS and are expensive and cumbersome to administer requiring around the clock dosing of a cocktail of drugs. In contrast with other eukaryotic DNA polymerases, HIV reverse transcriptase has no error correction ability during the transcription of RNA to viral DNA. Given the number of replication cycles and length of the HIV genome, there is the possibility of every possible point mutation at least once per day in a single patient. As a consequence, HIV is highly prone to mutation and there are more than 200 known drug resistant mutants. Although non-adherence to treatment exacerbates the threat, even with perfect usage, patients are prone to developing drug resistance and have limited treatment options thereafter. As a result, new small molecule anti-retrovirals are urgently needed.

Natural products are one source of inspiration for new types of pharmacophores for the treatment of HIV/AIDS. Przewalskin B is a diterpeniod that was isolated in 2007 from a Chinese medicinal plant Salvia przewalskii Maxim. Przewalskin B possesses a unique structural core and anti-HIV-1 activity with an EC50 = 30 micrograms/mL. The highly compact molecular framework consists of a decalin ring system, three contiguous stereocenters, two all carbon quaternary centers, a tertiary and secondary carbinol and an all carbon spirocyclic ring junction. As a part of an overarching program to develop new methods for the synthesis of biologically relevant polycyclic ring systems, a total synthesis of przewalskin B, employing a Pauson-Khand/Nazarov cyclization cascade, is proposed. Closer inspection of the natural product reveals at least two important functional groups: a cyclopentanone and a gamma-lactone which may allow the natural product to behave a Michael acceptor or for the system to undergo gamma-lactone nucleophilic ring opening. A synthesis of the natural product that incorporates a method to quickly access these two important functionalities and furnish many derivatives is a worthy goal. In collaboration with the laboratories of Nouri Neamati at University of Southern California, the biological activity of the natural product will be studied along with derivatives possessing the butenolide spirocycle. By virtue of their distinct skill set, organic chemists offer a unique opportunity in the ongoing fight against HIV/AIDS. Synthesis of natural products with therapeutic properties may lead to new technologies in chemistry but more importantly are a stepping stone to new treatment options for those living with HIV/AIDS.