Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy

Abstract

Natural products and their derivatives represent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthesis and evaluation of three synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs as cancer therapeutic agents. Chemical synthesis of these compounds (BA-TPQ, TBA-TPQ, and TCBA-TPQ) has been accomplished and the mechanisms of action (MOA) and structure-activity relationships (SAR) have been investigated. In the past, the complexity of chemical synthesis and the lack of well-defined MOA have dampened the enthusiasm for the development of some makaluvamines. Recent discovery of novel molecular targets for these alkaloids (unrelated to inhibition of Topoisomerase II) warrant further consideration as clinical candidates in the future. In addition to the establishment of novel synthetic approaches and demonstration of in vitro and in vivo anticancer activities, we have successfully demonstrated that these makaluvamines attack several key molecular targets, including the MDM2-p53 pathway, providing ample opportunities of modulating the compound structure based on SAR and the use of such compounds in combination therapy in the future.

Key words： synthesis; marine drugs; tricyclic pyrroloquinone alkaloid; cancer therapy; MDM2; p53

Conflicts of interest

The authors declare no conflict of interest.AcknowledgementsƒThis work was supported by the National Institutes of Health (NIH) grant R01 CA186662 (to R.Z.). This work was also supported by Collaborative Programmatic Development grant from UAB Comprehensive Cancer Center and NIH National Center for Research Resources 1UL1RR025777 (to V.S.). The content is solely the responsibility of the authors, and do not necessarily represent the official views of the National Institutes of Health. This work was also supported by the American Cancer Society (ACS) grant RSG-15-009-01-CDD (to W.W.).

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