Synthesis andin vitroAntitumor Potency of(Cyclohexane-1,2-Diamine)Platinum(II) Complexeswith Aminotris(Methylenephosphonic Acid) as Bone-Seeking Ligand

摘要

In order to develop platinum complexes with selective activity in primary and secondary bonemalignancies and with the aim to optimize antitumor activity, platinum(II) complexes withaminotris(methylenephosphonic acid) as bone-seeking (osteotropic) ligand have been synthesized,characterized and tested in the cisplatin-sensitive ovarian carcinoma cell line CH1. As non-leaving diamineligands, which are decisive for the cellular processing of DNA adducts,cis-R,S-cyclohexane-1,2-diamine,trans-S,S-cyclohexane-1,2-diamine andtrans-R,R-cyclohexane-1,2-diamine have been used, resulting incomplexes 1, 2, and 3, respectively. The cytotoxicity of the complexes under investigation decreases in theorder 3>2>1 which is in accord with structure-activity relationships with other (cyclohexane-1,2-diamine)platinum(II) and platinum(IV) complexes: Bothtranscomplexes (2 and 3) display a higherin vitropotency than the correspondingcisisomer (I), with thetrans-R,Risomer (3) being the most active in thisseries. In comparison to the analogous (cyclohexane-1,2-diamine)platinum(II) complexes withbis(phosphonomethyl)aminoacetic acid as osteotropic carrier ligand, the cytotoxicity of 1-3 was found to be1.5 – 2 fold higher, which is explainable by a different coordination mode of the phosphonic acid ligands(acetato versus phosphonato).