Synthesis and Structure Activity Relationship of Organometallic Steroidal Androgen Derivatives

Abstract

We present here the synthesis and the structure activity relationship of a series of organometallic complexes of the steroidal androgens testosterone and dihydrotestosterone (DHT) substituted at the C-17 position of the steroid skeleton with an ethynyl substituent grafted with various sandwich or semisandwich organometallic units [ferrocenyl, (η 5 -C 5 H 4 )-Re(CO) 3, (η 5 -C 5 H 4 )-Mn(CO) 3, (η 6 -C 6 H 5 )-Cr(CO) 3 ] and of 3β-androstanediol substituted at C-16 and C-17 respectively by a ferrocenyl vinyl and a ferrocenyl ethynyl unit. In contrast to the estradiol series, there are currently very few examples of organometallic steroidal androgens in the literature. The ethynyltestosterone derivatives were obtained via a Stille coupling reaction between the appropriate iodo-organometallics and 17β-ethynyltestosterone stannyl derivatives. The ethynyl-DHT derivatives were synthesized by addition of the corresponding acetylide to the C-17 carbonyl of the steroid. The crystal structures of two ferrocenyl and one rhenium complexes were determined by X-ray diffraction and had confirmed that the organometallic moiety points toward the α face of the steroid skeleton. All the complexes retain a modest affinity for the androgen receptor. The ferrocenyl derivatives of ethynyl testosterone, 8 and 12, show a strong antiproliferative effect on the hormone-independent prostate cancer cells PC-3 with IC 50 values of respectively 4.7 and 8.3 μM. These values are very similar, for 12, or slightly better, for 8, than those found recently for the most active ferrocenyl derivative of the nonsteroidal antiandrogen nilutamide (IC 50 value of 5.4 μM). The ferrocenyl complexes described here are the first examples of organometallic steroidal androgens possessing a strong antiproliferative activity on prostate cancer cells.