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

doi:10.1007/s11705-016-1562-6

Front. Chem. Sci. Eng.

2016, Vol. 10

Issue (1) : 1-15 https://doi.org/10.1007/s11705-016-1562-6

REVIEW ARTICLE

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

Wei Wang^1,², Bhavitavya Nijampatnam³, Sadanandan E. Velu³(

), Ruiwen Zhang^1,²(

)

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

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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.

Keywords synthesis marine drugs tricyclic pyrroloquinone alkaloid cancer therapy MDM2 p53

Corresponding Author(s): Sadanandan E. Velu,Ruiwen Zhang

Online First Date: 23 February 2016 Issue Date: 29 February 2016

Cite this article:

Wei Wang,Bhavitavya Nijampatnam,Sadanandan E. Velu, et al. Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy[J]. Front. Chem. Sci. Eng., 2016, 10(1): 1-15.

URL:

https://academic.hep.com.cn/fcse/EN/10.1007/s11705-016-1562-6
https://academic.hep.com.cn/fcse/EN/Y2016/V10/I1/1

Fig.1 Marine natural product analogs used in cancer therapy

Fig.2 Naturally occurring tricyclic pyrroloquinone (TPQ) alkaloids

Fig.3 Tricyclic pyrroloquinone synthetic analogs

Fig.4 TPQ analogs

Scheme 1 Synthesis of TPQ intermediate compound 3

Scheme 2 Synthesis of TPQ analogs

Fig.5 Benzyl and phenethyl analogs of TPQ alkaloids

Fig.6 Most potent benzyl and phenethyl amino analogs of TPQ alkaloids

Fig.7 Mechanism of action of TPQ alkaloids

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