Biological evaluation of novel estrogen-platinum(II) hybrid molecules on uterine and ovarian cancers-molecular modeling studies.
We have recently reported the synthesis of a series of original 17beta-estradiol-linked platinum(II) hybrid molecules. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER(+) and ER(-)) human uterine and ovarian cancers. The hybrid molecules present higher affinity than that of 17beta-estradiol for the estrogen receptor alpha (ERalpha). The cytotoxicity and the affinity of the hybrid molecules are explained using molecular modeling analysis. This study further confirms that the derivatives made of a 2-(2'-aminoethyl)pyridine ligand displayed superior activity against the cell lines particularly when the connecting arm is 8-10 carbon atoms long. Molecular modeling shows that a long side chain can facilitate the access of the platinum(II) moiety to DNA. The novel compounds also prove to be moderately cytotoxic against platinum resistant endometrial and ovarian cancer cell lines.
Gagnon
Véronique
V
Département de Chimie-Biologie, GRBCM, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec, Canada G9A 5H7.
St-Germain
Marie-Eve
ME
Descôteaux
Caroline
C
Provencher-Mandeville
Josée
J
Parent
Sophie
S
Mandal
Sanat K
SK
Asselin
Eric
E
Bérubé
Gervais
G
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004958:Estradiol / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017671:Platinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding / Q000502:physiology; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D017671:Platinum Compounds; D004958:Estradiol