New Isomeric Azine-Bridged Dinuclear Platinum(II) Complexes Circumvent Cross-Resistance to Cisplatin

Abstract

Four new isomeric azine-bridged complexes ([{cis-Pt(NH 3 ) 2 Cl} 2 (µ-pzn)]Cl 2 (1a) (pzn ) pyrazine) and its corresponding nitrate salt (1b), [{cis-Pt(NH 3 ) 2 Cl} 2 (µ-pmn)]Cl 2 (2) (pmn ) pyrimidine), and [{cis-Pt(NH 3 ) 2 Cl} 2 (µ-pdn)](NO 3 ) 2 (3) (pdn ) pyridazine) have been newly synthesized as potential anticancer compounds. These complexes have been characterized by 1 H and 195 Pt NMR spectroscopy, and also the X-ray crystal structure of 1b has been determined. The reactions of 1a, 2, and 3 with guanosine-5′-monophosphate (GMP) have been monitored and kinetically investigated in D 2 O solutions at 310 K using 1 H NMR spectroscopy. Both 1a and 2 react with 2 equiv of GMP to form 1:2 complexes. The reactions involve a stepwise direct substitution of chloride ligands by GMP, with similar reaction rates for both complexes. On the other hand, the reaction of 3 with GMP results in the cleavage of one of the Pt-N(pyridazine) bonds to form an N7,O6-platinated polymer. The reaction products have been separated and have been characterized by 1 H and 195 Pt NMR spectroscopy. A cytotoxicity assay of the azinebridged complexes (1a, 1b, 2, and 3) has been performed on human tumor cell lines and two L1210 murine leukemia cell lines (one sensitive to and one resistant to cisplatin). In general, the complexes show lower cytotoxicity than cisplatin for the human tumor cell lines except for the IGROV cell line. Their cytotoxicity for the mouse cell lines is comparable to or higher than that of cisplatin. Furthermore, these complexes appeared to largely or partly overcome the cross-resistance to cisplatin. Implications of these findings are discussed in the context of a structure-activity relationship for this class of compounds.

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5′-GMP

“…and À2380 ppm were observed for compounds 1, 2 and 3 respectively, indicative of a [PtN 4 ] chromophore [39][40][41][42][43]. The interaction of the three complexes with stoichiometric amount (1:2) of GMP (Supp.…”

Synthesis, Structure, and Biological Activity of New Azine‐Bridged Dinuclear Platinum(II) Complexes − a New Class of Anticancer Compounds

“…One of them was initially tentatively assigned to the hydrolyzed intermediate IVb. However, no peaks corresponding to the platinum nucleus in the [N 3 O] coordination environment [19,23,25] were found in the 195 Pt NMR spectrum. Thus, IVb is not present in the reaction mixture, and the signals at δ ϭ 8.08 and 8.18 ppm can only be assigned to the non-equivalent H8 protons of the two guanine bases in the disubstituted product IV.…”

“…As compared to the reaction with GMP [t 1/2 (GMP) ϭ 100 min] previously described, [23] binding of 9EtG to 1 is slower than GMP binding to this complex. A certain amount of the monosubstituted complex was observed in the case of 9EtG, indicating a slower substitution of the second chloride ion as compared to the reaction with GMP.…”

“…[23] In all cases the formation of the desired compounds was accompanied by a series of side reactions, and repeated recrystallizations were necessary to purify the complexes.…”

“…[22] Recently, we described a new class of dinuclear platinum() complexes with azines as bridging ligands. [23] These complexes present a combination of the two above-mentioned types of compounds: they utilize rigid aromatic rings of azines as linkers between two platinum atoms, featuring (6) at the same time non-bridging chloride ions as leaving groups. These compounds exhibit considerable activity in vitro in several human tumor cell lines.…”