Design, synthesis and biological evaluation of estradiol-PEG-linked platinum(II) hybrid molecules: comparative molecular modeling study of three distinct families of hybrids.
The synthesis of a series of 17β-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2'-aminoethyl)pyridine ligand. They are prepared from estrone in only 5 chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231). The novel PEG-hybrids are also compared in terms of activities with two other families of 17β-estradiol-platinum(II) hybrids that we reported in previous studies. Molecular modeling study performed on a representative member of each family of hybrids reveals distinct molecular interactions with the estrogen receptor α which further corroborates their notably contrasting cytocidal activities on breast cancer cell lines. This study also shows that lipophilicity and the orientation of the tether chain between the estrogenic portion and the platinum(II) core contribute markedly to the biological activity of the various families of hybrids. The most active hybrids are those possessing an alkyl tether chain at position 16β of the steroid nucleus. For example, derivative 3 (p=6) is about 16 times more potent on MCF-7 breast cancer cells than the corresponding 16α-PEG-hybrids (2b) made in this study.
Provencher-Mandeville
Josée
J
Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Département de Chimie-Biologie, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec, Canada.
Debnath
Chhanda
C
Mandal
Sanat K
SK
Leblanc
Valérie
V
Parent
Sophie
S
Asselin
Eric
E
Bérubé
Gervais
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D009942:Organometallic Compounds; D011092:Polyethylene Glycols; D010984:Platinum; D004958:Estradiol