Synthesis and characterization of cis -bis-heptamethyleneimine platinum(II) dicarboxylate complexes: crystal structure of cis -[Pt(heptamethyleneimine) 2 (malonate)] × /H 2 O Uday Mukhopadhyay a , John H. Thurston b , Kenton H. Whitmire b , Abdul R. Khokhar a, * a Department of Experimental Therapeutics, M.D. Anderson Cancer Center, The University of Texas, Box 353, 1515 Holcombe Boulevard, Houston, TX 77030, USA b Department of Chemistry, MS 60, Rice University, 6100 Main Street, Houston, TX 77005, USA Received 1 April 2002; accepted 5 August 2002 Abstract A series of new platinum complexes of the type cis -[Pt(L) 2 X] (where L /heptamethyleneimine and X /1,1-cyclobutanedicarboxy- late (CBDCA), oxalate, malonate, methylmalonate, ethylmalonate, dimethylmalonate, or diethylmalonate ligand) were synthesized and characterized by elemental analysis, infrared, and 195 Pt nuclear magnetic resonance spectroscopy. The crystal structure of cis - [Pt(L) 2 (malonate)] × /H 2 O was determined by X-ray crystallography. In all of the molecules, the platinum atom adopts a distorted square-planar geometry. Two of the coordination sites of the metal center are occupied by heptamethyleneimine ligands, which are arranged in a cis orientation. The coordination sphere of the metal is completed through interaction of the platinum with two of the oxygen atoms of the malonate ligand, resulting in the formation of a six-membered chelate ring. In the solid state, an intricate network of hydrogen bonds is found to exist between carbonyl oxygen atoms, amine hydrogen atoms and included solvent water. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Platinum(II) complexes; Heptamethyleneimine; Synthesis; Crystal structures 1. Introduction Very few platinum-based compounds have been approved for use in humans as anticancer agents. One of the most effective of such drugs is cisplatin, cis - Pt II Cl 2 (NH 3 ) 2 . The wide success of cisplatin in the treatment of a variety of human cancers [1], especially those of the testes, ovaries, head, and neck [2 /5], has encouraged the search for new cisplatin derivatives in an effort to improve the therapeutic index of its com- pounds, which is reduced by dose-limiting toxic effects, namely, nephrotoxicity, myelotoxicity, neurotoxicity, nausea, and vomiting [6,7]. Because of this and other limitations, understanding the mechanism and reducing the toxicity of cisplatin are important for developing more effective platinum-based drugs [8  /10]. To overcome these limitations, efforts were directed to develop new platinum-based anticancer drugs with improved clinical effectiveness, a broader spectrum of activity, and less toxicity [9,10]. This has been accom- plished by altering the pharmacokinetics of cisplatin by either replacing the labile chloro ligands with other leaving groups or extending the stable amine ligands to a series of either cyclic or acyclic amines. In this way, the second-generation platinum drug carboplatin has come into clinical use [11,12]. Like cisplatin, however, the clinical effectiveness of carboplatin is limited by under- standable side effects like nephrotoxicity, emesis, and myelosuppression [13]. Platinum complexes with 1,2- diaminecyclohexane [14] carrier ligands (such as oxali- platin and ormaplatin) and aminecyclohexylamine car- rier ligands (such as JM216) are often effective in cells resistant to platinum complexes with cis -diammine * Corresponding author. Tel.:  /1-713-792-2837; fax:  /1-713-745- 1176 E-mail address: akhokhar@mdanderson.org (A.R. Khokhar). Polyhedron 21 (2002) 2369  /2374 www.elsevier.com/locate/poly 0277-5387/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII:S0277-5387(02)01214-7