cis-[PtCl2(4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine)2]: A Sterically Restrictive New Cisplatin Analogue. Reaction Kinetics with Model Nucleobases, DNA Interaction Studies, Antitumor Activity, and Structure−Activity Relationships

TLDR: The results and those obtained from reaction of 1 with 9-EtGH suggest that the platinum compound binds the N7 atoms of two guanines of the same strand, forming intrastrand cross-linked adducts.

Abstract: The formation and isolation of the antitumor drug cisplatin analogue cis-[PtCl2(Hmtpo-N3)2]·2H2O (1) (where Hmtpo = 4,7-H-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine) by reaction of Hmtpo with K2[PtCl4] in HCl (0.5 N) is reported. This complex crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 15.215(2) A, b = 9.629(1) A, c = 13.115(3) A, β = 97.40(2)°, and Z = 4. The molecular structure shows that Pt is in an almost square planar environment, PtN2Cl2, which has a cis configuration. The Hmtpo ligands show a head to head orientation in the solid state and nonrestricted rotation about the Pt−N bonds in solution. The reactivity of the complex to model nucleobases 9-ethylguanine (9-EtGH) and 1-methylcytosine (1-MeC) has been investigated by 1H NMR spectroscopy at 45 °C in aqueous media. The results show that 1 reacts slowly with 9-EtGH (t1/2 ≈ 5 days) by displacement of Cl-, producing cis-[Pt(mtpo-N3)2(9-EtGH-N7)2], which is similar to the major cross-link adduct of cisplatin wi...