Comparative studies on the mechanism of cytotoxic action of novel platinum II complexes with pyrazole ligands.
In search for new platinum-based anticancer drugs, four cisplatin analogues, which contain pyrazole rings as non-leaving ligands, have been synthesized: cis-PtCl(2)(3,5-DM HMPz)(2), cis-PtCl(2)(Pz)(2), cis-PtCl(2)(ClMPz)(2), and cis-PtCl(2)(HMPz)(2), where Pz=pyrazole, H=hydroxyl, M=methyl. We tested their cytotoxicity, apoptosis induction ability, DNA damaging and modification properties comparing them in respect to the parent compound. The cytotoxic activity of these platinum pyrazole complexes toward the murine leukemia cell line was 2.9-3.8 times lower than actvity of cisplatin. The tested compounds varied in their mechanism of action by producing different DNA lesions. The most interesting compound seems to be the complex with chloromethyl groups at N1 of pyrazole rings, which exhibited the highest ability to form bifunctional adducts with DNA in vitro.
Ciesielska
Ewa
E
Department of Molecular Pharmacology, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. chemgen@csk.umed.lodz.pl
Szulawska
Agata
A
Studzian
Kazimierz
K
Ochocki
Justyn
J
Malinowska
Katarzyna
K
Kik
Krzysztof
K
Szmigiero
Leszek
L
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002945:Cisplatin / Q000031:analogs & derivatives / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210; D051379:Mice; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D017671:Platinum Compounds; D011720:Pyrazoles; C031280:pyrazole; D004247:DNA; D002945:Cisplatin