Synthesis, cytotoxicity, and DNA interactions of new cisplatin analogues containing substituted benzimidazole ligands.
Six new platinum(II) complexes with 1-H or methyl-2-chloromethyl or acetoxymethyl or 2'-hydroxyethylbenzimidazole carrier ligands were synthesized and evaluated for their reactivity against model nucleophile I(-), cellular uptake, and in vitro antiproliferative activities against the human MCF-7 breast and HeLa cervix cancer cell lines. The effect of the compounds on pBR322 plasmid DNA was studied by gel electrophoretic mobility measurements. Flow cytometric analysis was also carried out to study the effect of representative compounds 1 and 2, bearing 2-chloromethyl or -acetoxymethylbenzimidazole carrier ligands, on the cell cycle distribution of MCF-7 and HeLa cells, respectively. In general, it was found that Pt(II) complexes were less cytotoxic than cisplatin and were comparable to carboplatin. The results of the plasmid DNA interaction and the restriction studies suggest that changing the chemical structure of the benzimidazole ligands may modulate DNA binding mode and the sequence selectivity. Compounds 1 and 2 had no significant effect on the cell cycle profile of the cells used. However, compound 2 induced a significant increase in the SubG1 cell population at a concentration of 20 microM.
Gümüş
Fatma
F
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey. fgumus@gazi.edu.tr
Eren
Gökçen
G
Açik
Leyla
L
Celebi
Ayten
A
Oztürk
Fatma
F
Yilmaz
Sükran
S
Sagkan
Rahşan Ilikçi
RI
Gür
Sibel
S
Ozkul
Aykut
A
Elmali
Ayhan
A
Elerman
Yalçin
Y
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D010957:Plasmids; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D008024:Ligands; D004247:DNA; D002945:Cisplatin