An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα and Potent Anticancer Agent

Marine Drugs

Linfeng Li²  Adedoyin D. Abraham²  Qiong Zhou²  Hadi Ali²  Jeremy V. O𠆛rien²  Brayden D. Hamill²  John J. Arcaroli¹  Wells A. Messersmith¹ 

[1] Division of Medical Oncology, School of Medicine, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; E-Mails:;Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; E-Mails:

关键词: marine natural product;    pyridoacridine;    neoamphimedine;    total synthesis;    topoisomerase II;    cytotoxicity;    colorectal cancer;    cancer therapeutics;   

DOI  :  10.3390/md12094833

来源: mdpi

【 摘 要 】

Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC₅₀ values) in all, with significant potency against colorectal cancer (lowest IC₅₀ = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.