Synthesis of trans-(4-hydroxypyridine)(ammine)dichloroplatinum(II) and its activity in the human ovarian tumour models.
As a part of our continued studies on trans-planaramineplatinum(II) complexes, we report here the synthesis and in vitro activity in the human ovarian tumour models of trans-(4-hydroxypyridine)(ammine)dichloroplatinum(II)] (coded as DH1). Although less active than cisplatin against the parent ovarian A2780 and the resistant A2780cisR and A2780ZD0473R cell lines, it has much lower resistant factors than cisplatin. The results indicate that at the level of its activity, DH1 has been better able to overcome the mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. When platinum-DNA binding levels at 24 h in the A2780, A2780cisR and A2780ZD0473R cell lines are compared it is found that DH1 has higher levels of platinum binding with the DNA than cisplatin even though it has lower activity than cisplatin. The lack of correlation between activity and the platinum-DNA binding level as applied to cisplatin and DH1 may not be so unexpected when we note that the two compounds will differ in their nature of interaction with the DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH1 is expected to form more of 1,2-interstrand Pt(GG) and monofunctional Pt(G) and Pt(A) adducts, thus bringing about different conformational changes in the DNA. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion showed that DH1 was less able to prevent BamH1 digestion than cisplatin, indicating that cisplatin caused a greater conformational change in the DNA than DH1. Lower activity of DH1 as compared to analogous trans-platinums containing ligands such as 3-hydroxypyridine, 2-hydroxypyridine and imidazo(1,2-α-pyridine) can be seen to illustrate structureactivity relationships. In particular, it supports the idea that, in trans-planaramineplatinum(II) complexes, the ligands 2- hydroxypyridine, 3-hydroxypyridine and imidazo(1,2-α-pyridine) are much more activating towards antitumour activity than 4-hydroxypyrine.
Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Australia.
Narjes
N
Deqnah
Jun
J
Qing Yu
Philip
P
Beale
Keith
K
Fisher
Fazlul
F
Huq
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008024:Ligands; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010984:Platinum; D013329:Structure-Activity Relationship
C588070:(4-hydroxypyridine)(ammine)dichloroplatinum(II); D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA