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Research Articles: Therapeutics, Targets, and Development

R16, a novel amonafide analogue, induces apoptosis and G₂-M arrest via poisoning topoisomerase II

¹ Division of Anti-Tumor Pharmacology, ² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; ³ Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, Shanghai, P.R. China; and ⁴ Department of Pharmacology and Glycobiology, Marine Drug and Food Institute, Ocean University of China, Qingdao, P.R. China

Requests for reprints: Jian Ding, Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P.R. China. Fax: 86-21-50806722. E-mail: jding{at}mail.shcnc.ac.cn

Abstract

Amonafide, a naphthalimide derivative, although selected for exploratory clinical trials for its potent anticancer activity, has long been challenged by its unpredictable side effects. In the present study, a novel amonafide analogue, 2-(2-dimethylamino)-6-thia-2-aza-benzo-[def]-chrysene-1,3-diones (R16) was synthesized by substituting 5'-NH₂ of the naphthyl with a heterocyclic group to amonafide, with additional introduction of a thiol group. In a panel of various human tumor cell lines, R16 was more cytotoxic than its parent compound amonafide. It was also effective against multidrug-resistant cells. Importantly, the i.p. administration of R16 inhibited tumor growth in mice implanted with S-180 sarcoma and H₂₂ hepatoma. The molecular and cellular machinery studies showed that the R16 functions as a topoisomerase II (topo II) poison via binding to the ATPase domain of human topo II. The superior cytotoxicity of R16 to amonafide was ascribed to its potent effects on trapping topo II–DNA cleavage complexes. Moreover, using a topo II catalytic inhibitor aclarubicin, ataxia-telangiectasia-mutated (ATM)/ATM- and Rad3-related (ATR) kinase inhibitor caffeine and topo II–deficient HL-60/MX2 cells, we further showed that R16-triggered DNA double-strand breaks, tumor cell cycle arrest, and apoptosis were in a topo II–dependent manner. Taken together, R16 stood out by its improved anticancer activity, appreciable anti–multidrug resistance activities, and well-defined topo II poisoning mechanisms, as comparable with the parent compound amonafide. All these collectively promise the potential value of R16 as an anticancer drug candidate, which deserves further development. [Mol Cancer Ther 2007;6(2):484–95]

Grant support: National Natural Science Foundation of China grant 30572201.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Unpublished data.

Received 9/19/06; revised 11/ 2/06; accepted 12/28/06.

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