The structure-activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode.

Bioorganic & Medicinal Chemistry
Maris A CinelliMark Cushman

Abstract

Aromathecins are inhibitors of human topoisomerase I (Top1). These compounds are composites of several heteroaromatic systems, namely the camptothecins and indenoisoquinolines, and they possess notable Top1 inhibition and cytotoxicity when substituted at position 14. The SAR of these compounds overlaps with indenoisoquinolines, suggesting that they may intercalate into the Top1-DNA complex similarly. Nonetheless, the proposed binding mode for aromathecins is purely hypothetical, as an X-ray structure is unavailable. In the present communication, we have synthesized eight novel series of A-ring-substituted (positions 1-3) aromathecins, through a simple, modular route, as part of a comprehensive SAR study. Certain groups (such as 2,3-ethylenedioxy) moderately improve Top1 inhibition, and, often, antiproliferative activity, whereas other groups (2,3-dimethoxy and 3-substituents) attenuate bioactivity. Strikingly, these trends are very similar to those previously observed for the A-ring of camptothecins, and this considerable SAR overlap lends further support (in the absence of crystallographic data) to the hypothesis that aromathecins bind in the Top1 cleavage complex as interfacial inhibitors in a 'camptothecin-like' pose.

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Citations

Mar 1, 2012·Organic and Medicinal Chemistry Letters·Mohammed Hussaini BohariGarikapati Narahari Sastry
Jun 7, 2013·Medicinal Research Reviews·Ling ZhangCheng-He Zhou
Apr 25, 2013·Expert Opinion on Therapeutic Patents·Daulat B Khadka, Won-Jea Cho
Aug 15, 2018·Antimicrobial Agents and Chemotherapy·Nathaniel P NenortasTheresa A Shapiro
Nov 11, 2019·BMC Veterinary Research·Rosa M RegueraYolanda Pérez-Pertejo
Apr 13, 2017·MedChemComm·Imran AliHaasan Y Aboul-Enein
Jan 22, 2021·Expert Opinion on Therapeutic Patents·Asier SelasConcepción Alonso
Jul 14, 2021·European Journal of Medicinal Chemistry·Shuli ManWenyuan Gao

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