Selective Estrogen‐Receptor Modulators (SERMs) in the Cyclopentadienylrhenium Tricarbonyl Series: Synthesis and Biological Behaviour

Abstract

A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (eta(5)-C(5)H(4))Re(I)(CO)(3) unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely (99m)Tc and (188)Re. In these molecules the beta-phenyl group of OH-Tam has been replaced by the (eta(5)-C(5)H(4))Re(CO)(3) moiety, and the length of the dimethylamino side chain --O(CH(2))(n)N(CH(3))(2) was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P(o/w)=4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERalpha and ERbeta). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERalpha and 16.8 % for ERbeta. The antiproliferative effects of two pairs of isomers, (Z)- and (E)-7 b (n=3) and (Z)- and (E)-7 d (n=5), were studied at a molarity of 1 microM on two breast-cancer cell lines, MCF7 (ERalpha positive) and MDA-MB231 (ERalpha negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.

The Chemistry of Technetium–Water Complexes within the Manganese Triad: Challenges and Perspectives

“…[104][105][106] Complexes of the type [(Cp-R) 99m Tc(CO) 3 ] would be particularly interesting since it has been shown many times in bioorganometallic chemistry that pianostool-structured compounds can topologically mimic phenyl rings in pharmaceuticals. [107][108][109] Whereas cyclopentadiene is insoluble and unstable in water, we found acetylcyclopentadiene (AHCp) to have a pK a in water of about 8 and to decompose only very slowly. Consequently, some AHCp was soluble in water and reacted with [ 99m Tc(OH 2 ) 3 -(CO) 3 ] + like a normal "Werner-type ligand" with the formation of [(ACp)Tc(CO) 3 ].…”

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

“…1 H NMR (300 MHz, CDCl 3 , 25°C): d 7.44 (d,8H,J = 7.5 Hz,C 4 Ph 4 ),7.20 (m,12H,C 4 Ph 4 ), 6.95,6.87,6.78,6.69 (each d,8H,J = 8 Hz,C 6 H 4 OMe),4.39,4.37 (each d,2 Hz,Cp), 3.79, 3.76 (each s, OCH 3 ), 1.83 (q, J = 7.5 Hz, CH 2 ), 0.77 (t, J = 7.5 Hz, CH 3 ); 13 C NMR (75 MHz, CDCl 3 , 25°C): d 156.9, 156.8 (C ipso , C-OMe), 137.8, 136.1 (C para , C 6 H 4 OMe), 136.6, 132.9 (C@C), 135.6 (C ipso , C 4 Ph 4 ), 129. 9,129.2,112.7,112.4 (CH,C 7 H 7 O),127.8,126.9,125.1 (CH,Ph 4 H 5.80. Found: C,81.88;H,5.86%.…”

“…Thus, tamoxifen-type systems containing such metals as titanium and manganese [7], iron [8], rhenium [9], ruthenium [10], or platinum [11] have been reported. At present, the most promising candidates are the ferrocifens [8] in which a b-phenyl ring in tamoxifen has been replaced by a ferrocenyl moiety (Chart 1).…”

The particular role of radiopharmacy within bioorganometallic chemistry

“…Metal-based reactivity such as Fenton chemistry is occasionally suspected but usually not directly observed. Other substitution inert organometallic complexes such as [CpRe(CO) 3 ] can sometimes substitute ferrocene while keeping the biological activity of the lead compound intact [20,21]. Similarly, carbonyl complexes can be used as probes due to the high sensitivity of the CO stretching frequency in infrared spectroscopy.…”