Dinuclear complexes of platinum having anticancer properties. DNA-binding studies and biological activity of bis(4,4'-dipyrazolylmethane-N,N')- bis[dichloroplatinum(II)] and related complexes.

Some DNA-binding experiments employing a selected number of novel dinuclear platinum complexes with the 4,4'-dipyrazolylmethane (dpzm) ligand are reported. A DNA-cleavage assay using Eco RI and Bam HI restriction endonucleases to probe the binding of the complexes at or near their unique restriction sequences of pUC9 DNA has been examined. The complex beta-[Cl2Pt(dpzm)2PtCl2] has a greater affinity for DNA at the Eco RI restriction sequence over the Bam HI site. To our knowledge, the preferential inhibition of Eco RI activity is unprecedented for any platinum species reported to date. Further, the dinuclear complexes beta-[Cl2Pt(dpzm)2PtCl2], beta-[Cl4Pt(dpzm)2PtCl4] x 0.5dmf x 0.5H2O and [Cl4Pt(dpzm)2PtCl2] are capable of inhibiting Eco RI activity to a far greater extent than the platinum anticancer drug cis-[PtCl2(NH3)2] (cisplatin). The in vivo and in vitro anticancer properties of some of the platinum complexes are also described. The complexes alpha-[Cl2Pt(dpzm)2PtCl2] x 0.5dmf and beta-[Cl2Pt(dpzm)2PtCl2] display significant activity against P388 lymphocytic leukemia in mice.

Irritancy and anti-inflammatory activity of bis(eta 5-cyclopentadienyl)titanium(IV) complexes in rats.

Dichloro-bis(eta 5-cyclopentadienyl)titanium(IV) and some related complexes were compared with cis-dichlorodiammineplatinum(II) in rats for acute anti-inflammatory activity against carrageenan paw oedema, anti-arthritic activity against developing and established adjuvant-induced polyarthritis, immunosuppressant activity in a local graft-vs. host assay, irritant effects at sites of administration (paw, skin, peritoneum) and nephro- and gastro-toxicities. These titanium complexes, like cisplatin and its hydrolysis products, in vivo exhibited both anti-inflammatory and anti-arthritic activity as well as immunosuppressant effects. Nephro- and gastro-toxicity were much less severe than in rats given platinum complexes. In vitro they selectively inhibited [3H]thymidine incorporation by isolated thymocytes and prevented the germination of radish seeds. When given intraperitoneally, the anti-inflammatory activity may partly be due to a counter-irritant phenomenon since the titanium derivatives elicited an acute peritoneal effusion if they were injected towards the omentum. However, when injected subcutaneously or applied in dimethylformamide or dimethylsulfoxide to the skin, they manifested both anti-inflammatory and anti-arthritic activity without irritancy or much local skin damage. They might therefore have the potential of being useful drugs, especially if released slowly.

cis-Platinum(II) amine complexes: some structure-activity relationships for immunosuppressive, nephrotoxic and gastrointestinal (side) effects in rats.

A local graft-versus-host reaction was established to elicit lymphoid hypertrophy in F1 hybrid PVG X Lew rats. cis-Di(amine)platinum(II) complexes were given i.p. on days 1--4 in divided doses. Overnight proteinuria and measurements of renal hypertrophy on day 5 reflected the nephrotoxicity of the test compound. Stomach weights indicated the peculiar effect on pyloric stasis causing gastric distension. Weights of thymus' and spleens together with lymph-nodes showed the lymphodepressant/immunosuppressive properties of platinum compounds. Structure activity relationships for immunosuppressant, nephrotoxic and gastric-distending activities were investigated with: (a) cis-diaquo, cis-hydroxyaquo- and cis-dichlorodi(amine)platinum(II) complexes; (b) dinuclear mu-dihydroxo-bridged di(amine)platinum(II) complexes; (c) carboxylatodi(amine)platinum(II) complexes. Nephrotoxicity was minimised (with retention of immunosuppressant activity) by (a) the use of certain N-substituted amines e.g. Dach, Me4en; (b) co-administration of selected adjuncts e.g. citrate, salicylate; (c) auxiliary treatment with a penicillin mixture (Triplopen). In vitro effects of some platinum(II) compounds on isolated rat kidney tubules were also investigated.

Platinum drugs: combined anti-lymphoproliferative and nephrotoxicity assay in rats.

A 4-day drug schedule was used to explore the efficacy and simultaneous toxicity of cisplatin and 30 other platinum (II) amines given IP to PVG x Lew F1 hybrid rats at cumulative doses of 10-300 mumol/kg. Toxic effects monitored were stomach enlargement, kidney hypertrophy with tubular necrosis and proteinuria, evident visceral mucin, and lymphoid involution (thymus, spleen). Immunosuppressive effects were monitored as inhibition of the lymph node hypertrophy induced by grafting PVG spleen cells into each paw of F1 hybrids. No significant activity/toxicity was observed with 'platinum-(pyrimidine) blues'. N-alkyl derivatives of cisplatin were less active/toxic and some had no immunosuppressant effect, though they are reported as effective antitumour agents (in mice). mu-Hydroxobridged aminoplatinum (II) dimers were highly toxic, effective immunosuppressants and their toxicity profiles were distinct from the dihalo or diaquo diaminoplatinum species. 1,2-Diaminocyclohexane platinum derivatives showed a wide range of potency, all being much less nephrotoxic than cisplatin.