Synthesis and structure-activity relationships of the first ferrocenyl-aryl-hydantoin derivatives of the nonsteroidal antiandrogen nilutamide.
We present here the first synthesis of organometallic complexes derived from the nonsteroidal antiandrogen nilutamide, bearing a ferrocenyl substituent at position N(1) or at C(5) of the hydantoin ring; for comparison, we also describe the C(5) p-anisyl organic analogue. All of these complexes retain a modest affinity for the androgen receptor. The N-substituted complexes show a weak or moderate antiproliferative effect (IC 50 around 68 microM) on hormone-dependent and -independent prostate cancer cells, while the C(5)-substituted compounds exhibit toxicity levels 10 times higher (IC 50 around 5.4 microM). This strong antiproliferative effect is probably due to a structural effect linked to the aromatic character of the ferrocene rather than to its organometallic feature. In addition, it seems connected to a cytotoxic effect rather than an antihormonal one. These results open the way toward a new family of molecules that are active against both hormone-dependent and hormone-independent prostate cancer cells.
Payen
Olivier
O
Ecole Nationale Supérieure de Chimie de Paris, Laboratoire de Chimie et Biochimie des Complexes Moléculaires, UMR CNRS 7576, 11 rue Pierre et Marie Curie, Paris Cedex 05, France.
Top
Siden
S
Vessières
Anne
A
Brulé
Emilie
E
Plamont
Marie-Aude
MA
McGlinchey
Michael J
MJ
Müller-Bunz
Helge
H
Jaouen
Gérard
G
D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000737:chemistry* / Q000494:pharmacology; D048289:Imidazolidines / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000813:Anilides; D005296:Ferrous Compounds; D006827:Hydantoins; D048289:Imidazolidines; D009570:Nitriles; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D014105:Tosyl Compounds; C021277:nilutamide; C053541:bicalutamide