Cisplatinum and transplatinum complexes with benzyliminoether ligands; synthesis, characterization, structure-activity relationships, and in vitro and in vivo antitumor efficacy.
New benzyliminoether derivatives [PtCl2{N(H)=C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups.
Sbovata
Silvia Mazzega
SM
Department of Chemical Processes of Engineering, University of Padova, Via F. Marzolo 9, 35131 Padova, Italy.
Bettio
Frazia
F
Mozzon
Mirto
M
Bertani
Roberta
R
Venzo
Alfonso
A
Benetollo
Franco
F
Michelin
Rino A
RA
Gandin
Valentina
V
Marzano
Christine
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004987:Ethers; D007097:Imines; D008024:Ligands; D009944:Organoplatinum Compounds; D012313:RNA; D004247:DNA; D002945:Cisplatin