Antiproliferative activity in vitro of new malatoplatinum(ll) complexes.

The results of studies on antiproliferative activity in vitro of nine new platinum(II) complexes against cells of eight human and six murine neoplastic cell lines are described. New complexes with the anionic rest originating from enantiomeric forms of hydroxydicarboxylic malic acid were synthesized to obtain agents with increased water solubility and decreased toxicity. Three compounds, coded 1-3, with ethylenediamine as a neutral ligand, showed cytotoxic activity against 12 out of 14 target cell lines. Their cytotoxic activity was similar or even slightly higher than that of the reference carboplatin. The remaining six compounds, coded 4-9, with 1-alkylimidazole as a neutral ligand, revealed rather low cytotoxic activity, and only against the cells of the human bladder cancer cell line Hu1703He, ovarian cancer cell line OAW-42 and mouse leukemia P388. Most of them appeared to be negative against all other cell lines. No compounds, including reference carboplatin, showed any cytotoxicity against the cells of the T47D human breast cancer cell line or B16F-10 mouse melanoma cell line. The results obtained are in accordance with common opinion, i.e. that the presence of neutral amine ligands with NH groups is required for the cytotoxic activity of platinum complexes. Compounds with a primary amine (ethylenediamine) showed higher cytotoxic activity in vitro than complexes with a tertiary amine (1alkylimidazole).

Differential anti-proliferative properties of novel hydroxydicarboxylatoplatinum(II) complexes with high or low reactivity with thiols.

We have examined the anti-proliferative effect of 13 recently synthesised platinum dicarboxylate complexes, very similar in their chemical, structural and kinetic properties to carboplatin. We used the L5178Y model: two murine lymphoma sublines, which differ in nucleotide excision repair ability and hence, in sensitivity to those platinum complexes that react with DNA. The anti-proliferative effect of the examined compounds mainly depends on the kind of amine ligand. Complexes with the primary amine (ethylenediamine) are more effective than complexes containing the tertiary amine (1-alkylimidazole). The ethylenediaminemalatoplatinum(II) complexes show a differential in vitro anti-proliferative activity in the L5178Y model; hence, it may be expected that they inflict DNA lesions that are repaired by the nucleotide excision system. The cytotoxicity of these complexes is directly correlated with reactivity with glutathione (GSH). The 1-alkylimidazole complexes are of low toxicity and moderate to low reactivity with GSH; in contrast to the ethylenediaminemalatoplatinum(II) complexes, their cytotoxicity is inversely correlated with reactivity with GSH. Two of the 1-alkylimidazole complexes, bis(1-ethylimidazole)(L-malato)platinum(II) and bis(1-propylimidazole (L-malato)platinum(II), show a considerable ability to arrest cells in G2 phase. We expect that the properties of these two groups of platinum complexes may be exploited in combined platinum complex treatment and irradiation.

Impact of K2PtCl4 on the structure of human serum albumin and its binding ability of heme and bilirubin.

Absorption, CD, gel-filtration chromatography, and immunological tests were used to evaluate the interactions of K2PtCl4 with human serum albumin. Multidentate coordination of Pt(II) to HSA causes distinct variations in the protein conformation including a considerable decrease of the helical structure. The high excess of Pt(II) ions leads to dimerization of the protein. The metal ion binding weakness the interactions of HSA with other molecules like heme or bilirubin.

In vitro primary antitumor screen of imidazole platinum complexes.

The cytostatic activity in vitro of six cis-platinum analogs with imidazole ligands was examined. The tests were performed on 60 lines of human neoplastic cells in the NCI Preclinical Antitumor Drug Screening Program. The results obtained from 10 the most sensitive lines were analyzed and the structure-activity relationship was deduced. The cytotoxic activity of the active complexes seems to correlate with the hydrophobic properties of neutral imidazole ligands and with kinetic properties of anionic ligands.

Relationship between topological properties and biological activity of platinum (II) complexes.

A graph-theoretical method is applied to model of the relations between structure and biological activity of the anticancer Pt(II) complexes. Values of LD50, ID90, TI and % of ILS resulted from the treatment of animals bearing experimentalis ADJ/PC6 or L1210 tumors, available in the literature, were used as parameters characterizing the antitumor activity of platinum complexes. The results indicate that it is possible to find a topological description of these complexes which could be useful in their structure - activity investigations.

Cytostatic activity in vitro of new cis-dichlorodiammineplatinum (II) analogs.

Cytostatic activity of 6 new cis-dichlorodiammineplatinum (II)--(DDP) derivatives were tested against human HeLa S3, Chang Liver and Lu-106 cell lines in vitro. The tests were performed according to the recommended international protecol for screening of synthetics in cell culture system. One of the tested compounds appeared to be more active than DDP, used as referential agent. The activity of the remained compounds was lower than DDP.