Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring PtII chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand

Abstract

Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH=diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4-5.4-fold) of [PtCl(2)(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (approximately 1.5-fold) of [PtCl(2)(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(2)(cis-1,4-DACH)] with glutathione (approximately 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media (approximately 2-fold); (v) similar sequence preference of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand cross-linking efficiency (6%); (vii) similar bending (32 degrees) and enhanced local unwinding (approximately 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(2)(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(2)(cis-1,4-DACH)] from DNA.

DNA fragment conformations in adducts with Kiteplatin

“…Because the bulk of the cis-1,4-DACH carrier ligand does not have a dramatic effect on conformer stability or structure, the main local effect of the ligand, namely the impeded rotation of the guanine bases with respect to the Pt-N7 bond, could contribute to the markedly different biological activity of kiteplatin [69][70][71] as compared to those of cisplatin and oxaliplatin. [69][70][71]79 Alternatively, and perhaps more likely, the shape and bulk of the carrier ligand, as it projects out away from the DNA helix, will influence interactions with nucleic acid binding proteins or repair enzymes, thereby influencing activity.…”

“…[69][70][71]79 Alternatively, and perhaps more likely, the shape and bulk of the carrier ligand, as it projects out away from the DNA helix, will influence interactions with nucleic acid binding proteins or repair enzymes, thereby influencing activity.…”

“…More recently, [PtCl 2 (cis-1,4-DACH)] (Kiteplatin, Chart 2) was extensively reinvestigated by some of us, and it was found to have potential application against colorectal cancer (including oxaliplatin-resistant phenotypes). 65,[69][70][71][72][73] In this work, (cis-1,4-DACH)Pt(d(GpG)), (cis-1,4-DACH)Pt-(d(GGTTT)), and (cis-1,4-DACH)Pt(d(TGGT)) adducts were investigated by employing 1 H and 31 P NMR spectroscopy complemented with a combination of molecular mechanics and semi-empirical quantum-chemical calculations. It should be noted that the triplet GGT present in the latter two adducts is also part of the repetitive sequence in single-strand telomeres, which could also be potential targets for platinum drugs.…”

Platinum–bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis

“…In this context, it is also important to recall that platinum complexes with cis-1,4-DACH carrier ligand are, in general, active also against cisplatin-resistant cell lines [18,20,35,36].…”

Platinum(II) complexes with thiourea derivatives containing oxygen, sulfur or selenium in a heterocyclic ring: computational studies and cytotoxic properties

“…They are used for the treatment of a variety of human solid tumors and form the largest class of anticancer drugs. They destroy malignant cells by interfering with the DNA, via inter-and intrastrand crosslinks, where platinum binds primarily to the adjacent guanine-N7 sites [1][2][3][4][5], thereby preventing cell division and growth. The most frequently used platinum-containing drugs are cisplatin and carboplatin (first-generation drugs) or oxaliplatin, proplatin and spiroplatin (second generation).…”