Frontiers of Chemical Science and Engineering >
Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy
Received date: 09 Dec 2015
Accepted date: 18 Jan 2016
Published date: 29 Feb 2016
Copyright
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
Wei Wang , Bhavitavya Nijampatnam , Sadanandan E. Velu , Ruiwen Zhang . Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy[J]. Frontiers of Chemical Science and Engineering, 2016 , 10(1) : 1 -15 . DOI: 10.1007/s11705-016-1562-6
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