Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (bis-capronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development.

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The synthetic potential of the title compounds benzimidazo[1,2-a] q u i n a z o l i n e -5 ( 7H)-one 2 a and 5,7-dihydro-5-oxopyrido[3',2':5,6]pyrimido[1,2-a]benzimidazole 2b for the construction of novel polyheterocyclic frameworks is reported. Compounds 2a,b, by conversion into their thio analogues 3a,b, were used for the synthesis of tetrazole (5a,b) and triazole (7a,b) derivatives, as well as for an unexpected synthesis of triazoles 8a,b, isomers of 7a,b, resulting from the occurrence of a Dimroth rearrangement.

Diels-Alder reaction of 2-(E-2-nitroethenyl)-1H-pyrrole (2a) with 1,4-benzoquinone gave the desired benzo[e]indole-6, 9(3H)-dione (4a) in 10% yield versus a 26% yield (lit. 86% [5]) of the known N-methyl compound (4b) from the N-(or 1)-methyl compound (2b). Protection of the nitrogen of 2a with a phenylsulfonyl group (2c) gave a 9% yield of the corresponding N-(or 3)-phenylsulfonyl compound (4c). The reaction of 2b with 1,4-naphthoquinone gave in 6% yield (lit. 64% [5]) the known 3-methylnaphtho[2,3-e]-indole-6, 9(3H)-dione (6). The reaction of 2-(E-2-nitroethenyl)furan (8a) gave a small yield of the desired naphtho[2,1-b]furan-6, 9-dione (9a), recognized by comparing its NMR spectrum with that of 4b. The corresponding reaction of 2-(E-2-nitroethenyl)thiophene (8b) gave a 4% yield of naphtho[2,1-b]thiophene-6,9-dione (9b), previously prepared in 24% yield [12] in a three-step procedure involving 2-ethenylthiophene. Introducing an electron-releasing 2-methyl substituent into 8a and 8b gave 12a and 12b, which, upon reaction with 1,4-benzoquinone, gave 2-methylnaphtho[2,1-b]furan-6, 9-dione (13a) and its sulfur analog (13b) in yields of 4 and 8%, respectively.

The synthesis of the title compounds 5H, 11H‐pyrido[2′,3′:2,3]thiopyrano[4,3‐b]indoles was accomplished by the Fischer indole cyclization of some 2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐one phenylhydrazones and 7‐methyl‐2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐one phenylhydrazones. The synthesis of the new 2,3‐dihydrothiopyrano[2,3‐b]pyridin‐4(4H)‐one, which was used as one of the starting compounds, is also described.