Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor) Cl]+

Abstract

A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.

Third row transition metals for the treatment of cancer

“…The complex that gave the best results, far better than those of oxaliplatin, was cationic cis-diamminepyridinechloroplatinum(II), also referred to as cDPCP or pyriplatin (figure 1) [27]. The anti-cancer activity of this compound had been investigated previously in an animal model [28], but only a small number of follow-up studies on related compounds were performed [29]. In addition to significant organic character and cationic charge, pyriplatin is of interest because only one labile chloride ligand is present in the coordination sphere.…”

Dichlorobis(cycloalkylamin)platin(II)-Komplexe. Struktur ? Wirkungsbeziehungen an der menschlichen MDA-MB-231 Brustkrebszellinie

“…This perturbation should influence the recognition and the repair of platinum-DNA adducts of 9 and 10 (compare Refs. [21] and [25]). …”

“…Likewise, the rule that monofunctional platinum(II) complexes, which contain 3 amine ligands and only one leaving group such as CI-, are inactive, has been disproved by Hollis et al [25]. The authors showed that such complexes inhibit the growth of several tumor models, inspite of their ability to react only with one nucleophilic center of the DNA.…”

Chloro(ethylenediamine)(6-phenylimidazo[2,1-b]thiazole-N7)platinum(II) Nitrate

“…The procedure used for synthesis is a modification of the methods of Lippert (Lippert et al, 1981) and Hollis (Hollis et al, 1989). 300 mg (1 mmol) of PtC12(C2HsN2) was dissolved in 20 ml of dimethylformamide (DMF).…”