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Mar. Drugs 2014, 12(9), 4833-4850; doi:10.3390/md12094833

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

1
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
2
Division of Medical Oncology, School of Medicine, The University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
*
Author to whom correspondence should be addressed.
Received: 5 August 2014 / Revised: 25 August 2014 / Accepted: 5 September 2014 / Published: 19 September 2014
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Abstract

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. View Full-Text
Keywords: marine natural product; pyridoacridine; neoamphimedine; total synthesis; topoisomerase II; cytotoxicity; colorectal cancer; cancer therapeutics marine natural product; pyridoacridine; neoamphimedine; total synthesis; topoisomerase II; cytotoxicity; colorectal cancer; cancer therapeutics
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Li, L.; Abraham, A.D.; Zhou, Q.; Ali, H.; O'Brien, J.V.; Hamill, B.D.; Arcaroli, J.J.; Messersmith, W.A.; LaBarbera, D.V. 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. Mar. Drugs 2014, 12, 4833-4850.

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