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Selective Estrogen‐Receptor Modulators (SERMs) in the Cyclopentadienylrhenium Tricarbonyl Series: Synthesis and Biological Behaviour
Author(s) -
Top Siden,
Vessières Anne,
Pigeon Pascal,
Rager MarieNoëlle,
Huché Michel,
Salomon Emmanuel,
Cabestaing Claude,
Vaissermann Jacqueline,
Jaouen Gérard
Publication year - 2004
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200400067
Subject(s) - moiety , chemistry , estrogen receptor , stereochemistry , molecule , nuclear magnetic resonance spectroscopy , selective estrogen receptor modulator , biological activity , tamoxifen , organic chemistry , in vitro , biochemistry , medicine , cancer , breast cancer
A series of organometallic antiestrogens based on the OH‐tamoxifen (OH‐Tam) skeleton and bearing the (η 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 In these molecules the β‐phenyl group of OH‐Tam has been replaced by the (η 5 ‐C 5 H 4 )Re(CO) 3 moiety, and the length of the dimethylamino side chain O(CH 2 ) n N(CH 3 ) 2 was varied ( n =2, 3, 4, 5 and 8).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 (ERα and ERβ). For example, ( Z )‐ 7 b ( n =3) has high relative binding affinity (RBA) values of 31 % for ER α and 16.8 % for ERβ. 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 μ M on two breast‐cancer cell lines, MCF7 (ERα positive) and MDA‐MB231 (ERα 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.