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

作　　者：Wei Wang Bhavitavya Nijampatnam Sadanandan E. Velu Ruiwen Zhang 

机构地区：[1]Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA [2]Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA [3]Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA

出　　处：《Frontiers of Chemical Science and Engineering》2016年第1期1-15,共15页化学科学与工程前沿（英文版）

摘　　要：Natural products and their derivatives repre- sent 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.Natural products and their derivatives repre- sent 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.

关 键 词：synthesis marine drugs tricyclic pyrroloqui- none alkaloid cancer therapy MDM2 p53 

分 类 号：O629.3[理学—有机化学] Q781[理学—化学]