Description
Sansalvamide A (SanA) is a cyclic depsipeptide isolated from a marine fungus that exhibits anti-tumor activity in the NCI-60 human tumor cell line panel. Our laboratory has synthesized over 100 peptide derivatives of this molecule that have aided in the development of the structure activity relationship (SAR) for this compound. Further, our lab has concluded that the protein target of SanA peptide and its derivatives is Heat shock protein 90, a well established oncogenic target. The author contributed six compounds for the study of SAR by synthesizing SanA peptide derivatives via two approaches: solution phase and solid phase peptide chemistry. A convergent synthetic approach was employed via solution phase synthesis, where a di- and a tri- peptide were constructed to form a linear pentapeptide precursor. The linear pentapeptide was then cyclized in a head to tail manor. SanA peptides synthesized via solid phase occurred in a stepwise manor, from the C to N-terminus. The linear pentapeptide precursor was then cleaved from the resin and cyclized in solution. Finally, cyclized SanA derivatives were tested for their cytotoxicity against numerous cancer cell lines. To better understand how our compounds interact with Hsp90, the author synthesized two lead SanA derivatives that contained a biotin tag that will be used in affinity purification assays to confirm that their protein target is Hsp90. Competitive binding assays were also completed to determine if there was a correlation between cytotoxicity and binding to Hsp90. In addition, several Hsp90 client protein binding assays were completed to determine what client proteins were disrupted via binding of several SanA peptide derivatives.
