Synthesis and Structure–Activity Relationships of the First Ferrocenyl-Aryl-Hydantoin Derivatives of the Nonsteroidal Antiandrogen Nilutamide

Abstract

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.

Reaction of Hydantoin with Boronic Acids

“…Hydantoins (¼ imidazolidine-2,4-diones), a class of cyclic imides, are an interesting family of compounds with potent pharmacological properties, including antitumor, fungicidal, herbicidal, anti-inflammatory, anti-HIV, and antihypertensive activities [7] [8]. A number of (phenylmethylidene)hydantoins, prepared by the base-catalyzed condensation of hydantoins with substituted benzaldehydes, possess good anticonvulsant activity and are being examined as a potential treatment for epilepsy [8] as well as prostate cancer [9].…”

Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens, the (cyclobutadiene)cobalt analogues of hydroxytamoxifen

“…These cobalt sandwich molecules will also be tested for activity against prostate cancer cell lines, for which ferrocenylsubstituted aryl-hydantoins have recently been shown to be antiproliferative [33].…”

Estimating octanol/water partition coefficient for selected ferrocene derivatives using XlogPv2.0 approach

“…Our method for the prediction of logP for substituted ferrocene is validated using eleven different ferrocene derivatives (mainly selected from literature sources) [12][13][14][15]. Calculations were carried out in three decimals, with the final result rounded to two decimals.…”