Reversion of structure-activity relationships of antitumor platinum complexes by acetoxime but not hydroxylamine ligands.
The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl2(acetoxime)2], cis-[dichlorobis(acetoxime)platinum(II)] [1 (cis)] and trans-[dichlorobis(acetoxime)platinum(II)] [2 (trans)], as well as those of [PtCl2(hydroxylamine)2], cis-[dichlorobis(hydroxylamine)platinum(II)] [3 (cis)] and trans-[dichlorobis(hydroxylamine)platinum(II)] [4 (trans)]. We found that 2 (trans)is 16 times more cytotoxic than 1 (cis) and as cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than either cisplatin or 1 (cis) in intrinsically cisplatin-resistant colon carcinoma cells (SW480). Thus, compound 2 (trans) represents a novel type of active platinum(II) complexes of the trans geometry, whereas the hydroxylamine-containing complexes conform to the classic structure-activity relationships. The reactivity of the compounds toward dGMP and DNA and their capacity to alter the structure of double-stranded DNA and form interstrand cross-links were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (tau(1/2) = 50 h versus 8.9 h in the case of cisplatin), the low reactivity toward DNA, the comparatively small impact on DNA secondary structure, and the lack of detectable interstrand cross-linking suggest a mode of action fundamentally different from that of cisplatin. Implications of our findings for the minimal structural requirements (e.g., planarity around the nitrogen donor atom and/or ramified aliphatic moiety attached to the latter) of active trans-configured platinum complexes are discussed.
Zorbas-Seifried
Stefanie
S
Max-Planck Institute of Biochemistry, Martinsried, Germany.
Jakupec
Michael A
MA
Kukushkin
Nikolay V
NV
Groessl
Michael
M
Hartinger
Christian G
CG
Semenova
Olga
O
Zorbas
Haralabos
H
Kukushkin
Vadim Yu
VY
Keppler
Bernhard K
BK
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D019811:Hydroxylamine / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D010091:Oximes / Q000494:pharmacology*; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003848:Deoxyguanine Nucleotides; D008024:Ligands; D010091:Oximes; D017671:Platinum Compounds; D019811:Hydroxylamine; C007257:2'-deoxyguanosine 5'-phosphate; C035911:acetoxime