title: R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II.
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'-NH(2) 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 H(22) 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 IIalpha. 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.
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Xu-Hong
authors.initials: XH
authors.lastname: Qian
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Xu
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Qin
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Cai
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000225:Adenine; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D053644:Naphthalimides / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013876:Thiophenes / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C524136:2-(2-dimethylamino)-6-thia-2-azabenzo(def)chrysene-1,3-dione; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007094:Imides; D007546:Isoquinolines; D053644:Naphthalimides; D063065:Organophosphonates; D013876:Thiophenes; D059005:Topoisomerase II Inhibitors; C037020:amonafide; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D004250:DNA Topoisomerases, Type II; D000225:Adenine