title: 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.
abstract: Palladium and platinum complexes with HmtpO (where HmtpO=4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine, an analogue of the natural occurring nucleobase hypoxanthine) of the types [M(dmba)(PPh3)(HmtpO)]ClO4[dmba=N,C-chelating 2-(dimethylaminomethyl)phenyl; M=Pd or Pt], [Pd(N-N)(C6F5)(HmtpO)]ClO4[N-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]2[M(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]2[Pd(C6F5)2(micro-mtpO)]2.CH2Cl2.toluene, [NBu4]2[Pt(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.
authors.affiliation: Departamento de Química Inorgánica, Universidad de Murcia, E-30071-Murcia, Spain. jruiz@um.es
authors.forename: José
authors.initials: J
authors.lastname: Ruiz
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Villa
authors.forename: Natalia
authors.initials: N
authors.lastname: Cutillas
authors.forename: Gregorio
authors.initials: G
authors.lastname: López
authors.forename: Concepción
authors.initials: C
authors.lastname: de Haro
authors.forename: Delia
authors.initials: D
authors.lastname: Bautista
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Laura
authors.initials: L
authors.lastname: Valencia
mesh_terms: D000096:Acetone / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004587:Electrophoresis, Agar Gel; D005029:Ethylenediamines / Q000737:chemistry; D006801:Humans; D018625:Microscopy, Atomic Force; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D005029:Ethylenediamines; D009944:Organoplatinum Compounds; D011744:Pyrimidinones; C005798:N,N,N',N'-tetramethylethylenediamine; D000096:Acetone; D010165:Palladium; D004247:DNA