Abstract
BackgroundAs compared to cisplatin, trinuclear platinum compounds such as BBR3464 and DH6Cl have an altered spectrum of activity possibly because they form long-range adducts with DNA as against mainly intrastrand 1,2-bifunctional adducts formed by cisplatin and its analogues. Because of the labilizing effect associated with the trans-geometry, the compounds are expected to break down inside the cell thus serving to reduce the number of long-range adducts formed. In contrast, trinuclear platinum complexes with cis-geometry for the terminal metal centres would be less subject to such breakdown and hence may produce a greater number of long-range inter- and intrastrand adducts with the DNA. This paper describes the synthesis and activity against human ovarian tumour models of of three new trinuclear platinum complexes with cis-geometry for terminal platinum centres, coded as QH4, QH7 and QH8. The paper also describes cellular accumulation of platinum, level of drug−DNA binding, and nature of interaction of the compounds with pBR322 plasmid DNA.ResultsMethods of synthesis, elemental analysis, spectral studies and molar conductivity measurements provide support to the suggested structures of the compounds. QH4 and QH8 are found to be more cytotoxic than cisplatin against the parental A2780 cell line; QH8 is more active than cisplatin against the resistant A2780cisR and A2780ZD0473R cell lines as well. The least compound QH7 shows a greater activity against the resistant cell lines than the parental cell line; it is most damaging to pBR322 plasmid DNA and most able to induce changes in DNA conformation. The variations in activity of the compounds, changes in intracellular drug accumulation and levels of Pt−DNA binding with the changes in number of planaramine ligands bound to central platinum and the length of the linking diamines, can be seen (1) to illustrate structure-activity relationships and (2) to highlight that the relationship between antitumour activity and interaction with cellular platinophiles including DNA can be quite complex as the cell death is carried out by downstream processes in the cell cycle where many proteins are involved.ConclusionAmong the three designed trinuclear platinum complexes with cis-geometry for the terminal metal centres, the most active compound QH8 is found to be more active than cisplatin against the parental A2780 and the resistant A2780cisR and A2780ZD0473R cell lines.
Highlights
As compared to cisplatin, trinuclear platinum compounds such as BBR3464 and [{trans-PtCl(NH3)2}2 μ{trans-Pt(NH3)2(H2N(CH2)6NH2)2}]Cl4 (DH6Cl) have an altered spectrum of activity possibly because they form long-range adducts with DNA as against mainly intrastrand 1,2-bifunctional adducts formed by cisplatin and its analogues
IC50 values are defined as drug concentrations required for 50% cell kill and resistance factors (RF) is defined as the ratio of the concentration of drug required for 50% cell kill in the resistant cell line to that in the parent cell line
It can be seen that [{cis-PtCl(NH3)2}2 μ{trans-Pt(3-hydroxypyridine)2(H2N(CH2)4NH2)2}]Cl4 (QH4) and [{cis-PtCl(NH3)2}2 μ{trans-Pt(3-hydroxypyridine)(NH3)(H2N(CH2)4NH2)2}]Cl4 (QH8) are more active than cisplatin against the parental A2780 cell line
Summary
Trinuclear platinum compounds such as BBR3464 and DH6Cl have an altered spectrum of activity possibly because they form long-range adducts with DNA as against mainly intrastrand 1,2-bifunctional adducts formed by cisplatin and its analogues. Cisplatin is a widely used anticancer drug [1,2], its use is limited due to intrinsic and/or acquired resistance and the presence of numerous side effects [3,4] Trinuclear platinum compounds such as BBR3464, DH6Cl, DH7Cl, TH1 and CH25 that bind with DNA differently than cisplatin (in the sense that they form long-range adducts with DNA as against mainly 1,2-bifunctional adducts formed by cisplatin) are found to be significantly more cytotoxic than cisplatin [5,6,7,8,9]. Trinuclear platinum complexes with cis-geometry for the terminal metal centres would be less subjected to such breakdown and may produce a greater number of long-range interand intrastrand adducts with DNA. Whereas the two terminal platinum ions bind covalently with DNA, the central platinum ion can only undergo non-covalent interactions including electrostatic interaction and hydrogen bonding via 3-hydroxypyridine ligand
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