Abstract
Abstract For the drug discovery, generation of chemical libraries has been required. Natural products are utilized for drug-lead discovery because of their structural diversity, and indeed, many natural products and their derivatives have been used as approved drugs historically. Here, we generated a natural product-derived chemical library named “Natural Unnatural Product (NUP) library”. To generate NUP library, chemical reagent was added in microbial broth extracts, and many microbial metabolites in the broths extracts were converted into their derivatives. After this reaction, newly synthesized components, NUPs, in the reaction mixtures were detected and isolated by LC-MS system to give a NUP library. On the other hand, X-linked inhibitor of apoptosis (XIAP) is an endogenous direct inhibitor of caspase-3, -7 and -9. Overexpression of XIAP is often seen in several types of human tumor, and it contributes tumor malignancy by inhibiting apoptosis. Therefore, XIAP is considered as a promising molecular target for cancer therapies, and we searched for the compound that inhibited anti-caspase activity of XIAP from our NUP library. As results, three compounds, C38OX3, C38OX6 and C38OX8, were found to restore XIAP-suppressed enzymatic activity of caspase-3 in a dose dependent manner in vitro. Next, we examined whether these XIAP inhibitors could accelerate apoptosis induced with death ligands or anticancer drugs. C38OX6 overcame XIAP-mediated resistance of HeLa cells against TRAIL and anticancer drugs. These findings suggest that our NUPs contain potential drug-leads for the development of new class of anticancer drugs such as XIAP inhibitors. In conclusion, we generated NUP library as source for drug-lead of anticancer drugs and identified three NUPs as XIAP inhibitors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B157.
Published Version
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