Study on natural products for drug development

Abstract

The ubiquitin-proteasome system (UPS) plays a major role in selective protein degradation and regulates various cellular events. Approval of bortezomib for the treatment of multiple myeloma validated the proteasome as an anticancer target. In order to find drug candidates targeting the ubiquitin-dependent protein degradation, we paid an attention to inhibitors against three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), which are required for polyubiquitination of proteins and prerequisite to proteasome-mediated protein degradation. We succeeded in isolating various compounds with three distinct inhibitory activities against an E1 enzyme reaction, Ubc13 (E2)-Uev1A interaction, and p53-HDM2 (E3) interaction as well as the proteasome inhibitors. We also isolated new alkaloids, notoamides, from a marine-derived Aspergillus sp. Among them, notoamide B and stephacidin A contain a bicyclo[2.2.2] diazaoctane ring in their structures. We proposed this ring is constructed from notoamide E by the intramolecular Diels-Alder (IMDA) reaction. Recently, the isolation of the antipodes of notoamides from the terrestrial Aspergillus has been reported. We propose that each enantiomer is generated by a distinct face-selective IMDA. © 2010 The Pharmaceutical Society of Japan.