Preparation, characterization, and anticancer activity of a series of cis-PtCl2 complexes linked to anthraquinone intercalators

• Published in: Journal of medicinal chemistry 1991-01, Vol.34 (1), p.414-420
• Main Authors: Gibson, Dan, Gean, Keria Fiorella, Katzhendle, Jehoshua, Ben-Shoshan, Raphael, Ramu, Avner, Ringel, Israel
• Format: Article
• Language: English
• Subjects: Animals; Anthraquinones - chemical synthesis; Anthraquinones - pharmacology; Anthraquinones - therapeutic use; Antineoplastic Agents - chemical synthesis; Cisplatin - analogs & derivatives; Cisplatin - chemical synthesis; Cisplatin - pharmacology; Cisplatin - therapeutic use; Drug Screening Assays, Antitumor; Indicators and Reagents; Intercalating Agents - chemical synthesis; Intercalating Agents - pharmacology; Intercalating Agents - therapeutic use; Leukemia P388 - drug therapy; Mice; Mice, Inbred DBA; Molecular Structure; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00105a063

A new series of complexes of the type cis-PtL2X2 [where L is a monodentate AQ-Y(CH2)nNH2 and L2 is a bidentate AQ-Y(CH2)nNH(CH2)2NH2; AQ = anthraquinone, X = Cl, I, Y = NH, O] in which anthraquinone intercalators are tethered to the cis-PtCl2 unit via an (aminoalkyl)amino, (oxyalkyl)amino, or polyethylene glycol (aminoethyl)amino linker chains was prepared and screened in vitro against P388 leukemia. In vivo toxicity studies were carried out on selected complexes. All complexes were characterized by means of elemental analysis, 195Pt NMR spectroscopy, and FTIR. The 1:1 Pt-intercalator complexes displayed much higher in vitro cytotoxic activities than the 1:2 Pt-intercalator complexes. The dichloride complexes were consistently more active than their diiodide counterparts. Among the 1:1 Pt-intercalator complexes those with the shorter linker chains (n = 2, 3) exhibited the highest cytotoxic activities. Three compounds, [[2-[[2-(anthraquinon-1- ylamino)ethyl]amino]ethyl]amine-N,N']dichloroplatinum(II), [[2-[[3-(anthraquinon-1-ylamino)propyl]amino]ethyl]amine- N,N']dichloroplatinum(II), and [[2-[[3-anthraquinon-1- yloxy)propyl]amino]ethyl]amine-N,N']dichloroplatinum(II), were as active in vitro as cisplatin (ED50 = 2-4 x 10(-7) M) while on a molar basis their acute in vivo toxicity was significantly lower than that of cisplatin. In vivo screening against P388 leukemia indicated that these complexes have activity comparable to cisplatin.