Palladium(II) and platinum(II) organometallic complexes with 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine. Antitumor activity of the platinum compounds

Palladium and platinum complexes with HmtpO (where HmtpO=4,7-dihydro-5-methyl-7-oxo1,2,4]triazolo1,5-a]pyrimidine, an analogue of the natural occurring nucleobase hypoxanthine) of the types M(dmba)(PPh3)(HmtpO)]ClO4dmba=N,C-chelating 2-(dimethylaminomethyl)phenyl; M=Pd or Pt], Pd(N-N)(C6F5)(HmtpO)]ClO4N-N=2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (Me2bpy), or N, N, N', N'-tetramethylethylenediamine (tmeda)] and cis-M(C6F5)2(HmtpO)2] (M=Pd or Pt) (head-to-head atropisomer in the solid state) have been obtained. Pd(II) and Pt(II) complexes with the anion of HmtpO of the types Pd(tmeda)(C6F5)(mtpO)], Pd(dmba)(micro-mtpO)] 2, and NBu4]2M(C6F5)2(micro-mtpO)]2(M=Pd or Pt) have been prepared starting from the corresponding hydroxometal complexes. Complexes containing simultaneously both the neutral HmtpO ligand and the anionic mtpO of the type NBu4]M(C6F5)2(HmtpO)(mtpO)] (M=Pd or Pt) have been also obtained. In these mtpO-HmtpO metal complexes, for the first time, prototropic exchange is observed between the two heterocyclic ligands. The crystal structures of Pd(dmba)(PPh 3)(HmtpO)]+, cis-Pt(C6F5)2(HmtpO)2].acetone, Pd(C6F5)(tmeda)(mtpO)].2H2O, Pd(dmba)(micro-mtpO)]2, NBu4]2Pd(C6F5)2(micro-mtpO)]2.CH2Cl2.toluene, NBu4]2Pt(C6F5)2(micro-mtpO)](2).0.5(toluene), and NBu4]Pt(C6F5)2(mtpO)(HmtpO)] have been established by X-ray diffraction. Values of IC50 were calculated for the new platinum complexes cis-Pt(C6F5)2(HmtpO)2] and Pt(dmba)(PPh3)(HmtpO)]ClO4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR), lung (NCI-H460), and breast cancers (T47D). At 48 h incubation time, both complexes were about 8-fold more active than cisplatin in T47D and show very low resistance factors against an A2780 cell line, which has acquired resistance to cisplatin. The DNA adduct formation of cis-Pt(C6F5)2(HmtpO)2] and Pt(dmba)(PPh3)(HmtpO)]ClO4 was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by these platinum complexes on plasmid DNA pB R322 were also obtained.