DNA interaction with novel antitumor estradiol-platinum(II) hybrid molecule: a comparative study with cisplatin drug.
Platinum(II)-based anticancer drugs are effective for the management and treatment of several types of cancer. Cis-diamminedichloroplatinum(II) (cisplatin) exerts its antitumor activity by binding to DNA via intrastrand cross-links to d(GpG) (dG = deoxyguanosine) and to d(ApG) (dA = deoxyadenosine), causing DNA bending and interfering with DNA replication and transcription. However, the exact binding modes of other platinum(II)-based antitumor drugs to DNA duplex and their mechanism of action have not been clearly investigated. The aim of this study was to examine the binding of a novel anticancer estradiol-platinum(II) hybrid molecule (CD-37) with calf-thymus DNA in vitro and to compare the results with those obtained with cisplatin drug. Solutions containing various CD-37 or cisplatin concentrations were reacted with DNA at physiological pH. Then, using Fourier transform infrared, ultraviolet-visible, and circular dichroism spectroscopic methods, it was possible to characterize the drug binding mode, the binding constant, and structural variations of DNA in aqueous solution. Spectroscopic evidence showed that cisplatin binds to guanine N7 site with minor perturbations of the backbone phosphate group with an overall binding constant of K(cisPt) = 5.73 (+/- 0.45) x 10(4) M(-1). CD-37 binds to DNA duplex via H-bonding network at low drug concentrations with minor perturbations of guanine N7 site at high drug content and with a binding constant of K(CD-37) = 1.0 (+/- 0.15) x 10(4) M(-1). DNA aggregation occurs at high drug concentration, while DNA remains in the B-family structure.
N'soukpoé-Kossi
Christophe N
CN
Département de Chimie-Biologie, Groupe de Recherche en Biologie Végétale, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
Descôteaux
Caroline
C
Asselin
Eric
E
Tajmir-Riahi
Heidar-Ali
HA
Bérubé
Gervais
G
D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D002942:Circular Dichroism; D002945:Cisplatin / Q000493:pharmacokinetics*; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D007364:Intercalating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D008954:Models, Biological; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D017550:Spectroscopy, Fourier Transform Infrared
D000970:Antineoplastic Agents; C527992:CD-37 compound; D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D004958:Estradiol; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin