Synthesis, activity and binding with DNA of [{trans-PtCl(NH(3))(2)}(2)micro-{trans-Pd(4-hydroxypyridine) (2) (H(2)N(CH(2))(6)NH(2))(2)]Cl(4) (TH8).

This paper describes the synthesis, characterization, cytotoxicity of a new trinuclear Pt-Pd-Pt complex code named TH8 containing two 4-hydroxypyridine ligands bound to the central metal ion. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R), cell uptake, level of DNA-binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. TH8 is found to be less active than cisplatin against the parent cell line A2780 but is more active against the cisplatin-resistant cell line A2780(cisR). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH8 are 1.4 and 2.1. The results suggest that TH8 has been better able to overcome the resistance operating in A2780(cisR) cell line. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH8 is expected to bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation.

Synthesis and activity of a trinuclear platinum complex: [{trans-PtCl(NH3)2}2mu-{trans-Pt(3-hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in ovarian cancer cell lines.

This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 plasmid DNA have been determined. TH1 is found to be significantly more cytotoxic than cisplatin - two times more active than cisplatin against the parent cell line A2780, thirteen times more active against the cisplatin-resistant cell line A2780(cisR) and 11.5 times more active against the cell line A2780(ZD0473R). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH1 are 1.98 and 0.5. The results suggest that TH1 has been able to significantly overcome resistance in A2780(cisR) and A2780(ZD0473R) cell lines. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH1 should bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin.

Studies on the activity of three palladium(II) compounds of the form: trans-PdL2Cl2 where L=2-hydroxypyridine, 3-hydroxypyridine, and 4-hydroxypyridine.

Three planaraminepalladium(II) complexes of the form: trans-PdCl(2)L(2), code named TH5, TH6 and TH7 where L=3-hydroxypyridine, 2-hydroxypyridine and 4-hydroxypyridine respectively have been investigated for antitumour activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R). Although the compounds are generally found to be less active than cisplatin, they are often found to be more active against the resistant cell lines than the parent cell line. Among TH5, TH6 and TH7, TH6 which has two 2-hydroxypyridine non-labile ligands is found to be most active against the three cell lines. Variations in activity of TH5, TH6 and TH7 indicate that non-covalent interactions may be playing a significant role in activity. In particular, the results indicate that small changes in planaramine ligands such as the position of the polar OH group can have a more profound effect on activity of the compounds. Palladium compounds are generally found to be toxic rather tumour active because of much higher reactivity. Low but significant activity of trans-palladium(II) complexes TH5, TH6 and TH7 against the ovarian cancer cell lines indicates that it is believed to be associated with the decrease in their reactivity due to the presence of two sterically hindered planaramine ligands.

Studies on the synthesis, characterization, binding with DNA and activities of two cis-planaramineplatinum(II) complexes of the form: cis-PtL(NH3)Cl2 where L = 3-hydroxypyridine and 2,3-diaminopyridine.

BACKGROUND: Cis-planaramineplatinum(II) complexes like their trans isomers are often found to be active against cancer cell lines. The present study deals with the synthesis, characterization and determination of activity of new cis-planaramineplatinum(II) complexes. RESULTS: Two cis-planaramineplatinum(II) complexes: cis-(3-hydroxypyridine)(ammine)dichloroplatinum(II) (code named AH3) and cis-(2,3-diaminopyridine)(ammine)dichloroplatinum(II) (code named AH7) have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1H NMR spectral measurements. The interactions of the compounds with pBR322 plasmid DNA have been investigated and their activity against ovarian cancer cell lines: A2780, A2780cisR and A2780ZD047Rhave been determined. Like cisplatin, AH3 and AH7 are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of a DNA strand. As a result, gel mobility of the DNA changes. Both AH3 and AH7 are found to be less active than cisplatin against the three cell lines with AH3 being the more active compound of the two. The higher activity of AH3 is in line with its lower molar conductivity value corresponding to a lower degree of dissociation. CONCLUSION: The differences in activity of AH3, AH7 and cisplatin against the cell lines illustrate structure-activity relationship.

Synthesis, characterisation, activities, cell uptake and DNA binding of [[trans-PtCl(NH3)2] [mu-(H2N(CH2)6NH2)] [trans-PdCl(NH3)2](NO3)Cl.

The dinuclear complex: [[trans-PtCl(NH(3))(2)] [mu-(H(2)N(CH(2))(6)NH(2))] [trans-PdCl(NH(3))(2)](NO(3))Cl (code named DHD) has been synthesized and characterized. The activity against human cancer cell lines including ovarian: A2780, A2780(cisR), cell up take, level of binding with DNA and nature of interaction of the compound with pBR322 plasmid and salmon sperm DNAs have been determined. The compound is found to exhibit significant anticancer activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R)--about two times as active as cisplatin against A2780 cell line, about five times as active as cisplatin against A2780(cisR) and A2780(ZD0473R) cell lines. The higher activity of DHD suggests that the compound is able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. DHD is believed to form a range of interstrand GG adducts with duplex DNA that induces global changes in the DNA conformation, unlike cisplatin and ZD0473 that form mainly intrastrand adducts that induces a local kink in a DNA strand. Increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of DHD provides support to the idea that the interstrand binding of DHD with pBR322 plasmid DNA brings about global changes in DNA conformation.