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. 2014 May 12;21(1):41.
doi: 10.1186/1423-0127-21-41.

Synthesis and activity of three new trinuclear platinums with cis-geometry for terminal metal centres

Shahnaz A Hamad, Philip Beale, Jun Q Yu, Fazlul Huq  1
Affiliations

Synthesis and activity of three new trinuclear platinums with cis-geometry for terminal metal centres

Shahnaz A Hamad et al. J Biomed Sci. .

Abstract

Background: As 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.

Results: Methods 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.

Conclusion: Among 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.

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Figures

Figure 1
Figure 1
Structures of QH4, QH7 and QH8. QH2: [{cis-PtCl(NH3)2}2 μ{trans-Pt(3-hydroxypyridine)2(H2N(CH2)4NH2)2}]Cl4; QH3: [{cis-PtCl(NH3)2}2 μ{trans-Pt(3-hydroxypyridine)(NH3)(H2N(CH2)6NH2)2}]Cl4; QH4: [{cis-PtCl(NH3)2}2 μ{trans-Pt(3-hydroxypyridine)(NH3)(H2N(CH2)4NH2)2}]Cl4.
Figure 2
Figure 2
Schema for the synthesis of QH4.
Figure 3
Figure 3
Schema for the synthesis of QH7.
Figure 4
Figure 4
Schema for the synthesis of QH8.
Figure 5
Figure 5
Total intracellular platinum levels (expressed as nmol Pt per 2x10 6 cells) found in A2780, A2780 cisR and A2780 ZD0473R cells after their exposure to 50 μM concentrations of QH4, QH7, QH8 and cisplatin for 2, 4 and 24 hours.
Figure 6
Figure 6
Levels of platinum-DNA binding expressed as nmol Pt per milligram of DNA from QH2, QH7, QH8 and cisplatin in A2780, A2780 cisR and A2780 ZD0473R cells as a function of time.
Figure 7
Figure 7
Electrophotograms applying to the interaction of pBR322 plasmid DNA with increasing concentrations of QH4, QH7, QH8 and cisplatin. Lane B applied to untreated pBR322 plasmid DNA to serve as a control, lanes 1 to 8 applied to plasmid DNA interacted with increasing concentrations of the compounds and cisplatin. The concentrations for QH4, QH8 and cisplatin were: lane 1: 0.55 μM, lane 2: 1.09 μM, lane 3: 2.19 μM, lane 4: 4.38 μM, lane 5: 8.75 μM, lane 6: 17.50 μM, lane 7: 35.00 μM, and lane 8: 70.00 μM. The concentrations for QH7 is as follows lane 1: 0.12 μM, lane 2 : 0.23 μM, lane 3: 0.47 μM, lane 4: 0.94 μM, lane 5:1.88 μM, lane 6: 3.75 μM, lane 7: 7.50 μM and lane 8: 15.00 μM.
Figure 8
Figure 8
Electrophoretograms applying to the incubated mixtures of pBR322 plasmid DNA and varying concentrations of QH4, QH7, QH8 and cisplatin followed by digestion with BamH1. Lane B1 applied to the untreated pBR322 plasmid DNA and undigested with BamH1, lane B2 applied to untreated but digestion with BamH1. Lanes 1 to 8: apply to pBR322 plasmid DNA interacted with increasing concentrations of the compounds followed by BamH1 digestion. The concentrations for QH4, QH8 and cisplatin were: lane 1: 0.55 μM, lane 2: 1.09 μM, lane 3: 2.19 μM, lane 4: 4.38 μM, lane 5: 8.75 μM, lane 6: 17.50 μM, lane 7: 35.00 μM, and lane 8: 70.00 μM. The concentrations for QH7 is as follows lane 1: 0.12, lane 2 : 0.23, lane 3: 0.47, lane 4: 0.94, lane 5:1.88, lane 6: 3.75, lane 7: 7.50 and lane 8: 15.00.
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