A Facile Synthesis of C 2 -Symmetric 17-Estradiol Dimers Daniel Rabouin, a Vale´rie Perron, a Blaise N’Zemba, a Rene´ C.-Gaudreault b and Gervais Be´rube´ a, * a De ´partement de Chimie-Biologie, Universite ´ du Que ´bec a ` Trois-Rivie `res, C.P. 500, Trois-Rivie `res, Que ´bec, Canada G9A 5H7 b Unite ´ de Biotechnologie, Institut des Biomate ´riaux de Que ´bec, C.H.U.Q., Ho ˆpital Saint-Franc ¸ois d’Assise, 10 Rue de l’Espinay, Que ´bec, Canada G1L 3L5 Received 29 May 2002; accepted 1 October 2002 Abstract—A rapid and efficient synthesis of a series of C 2 -symmetric 17b-estradiol dimers is described. The new molecules are linked at position 17a of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER + and ER  ) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER + cell line. # 2002 Elsevier Science Ltd. All rights reserved. Introduction The design of C 2 -symmetric ligands (bivalent ligands) as bioactive molecules have attracted considerable attention over the years because of their promising therapeutic value in treating a number of diseases. For example, bivalent ligands were designed as antagonist of the mus- carinic receptor and of the k opiod receptor. 1,2 A variety of dimeric enzyme inhibitors were also studied such as HIV-1 protease inhibitors as well as the glycosidases inhibitors. 3,4 Some bivalent ligands were used as prodrugs with androgenic and myotrophic activities and a dimer of a naturally occurring monomeric naphthylisoquinoline alkaloid was prepared yielding an analogue with high antimalarial activity. 5,6 Recently, we have reported the synthesis of spermidine and norspermidine dimers as high affinity polyamine transport inhibitors. 7 It is generally believed that a bivalent ligand would be expect to show enhanced receptor affinity (or biological activity) relative to the monovalent ligand. 8 Hence, we can understand the great interest in making such dimeric compounds. Furthermore, some attempts have been made to design estrogenic bivalent ligands in order to interfere with the process of estrogen receptor dimerization. 9,10 These dimeric molecules were constructed from non-steroidal estrogenic moieties analogues of hexestrol or triphenyl- ethylene. It was demonstrated that some of the hexestrol bivalent ligands possess antiestrogenic activity. 9 In some cases, a biphasic interaction with the estrogen receptor was observed. 9 On the other hand, it was demonstrated that a symmetrical triphenylethylene dimer bearing six hydroxy functions, possesses a cytotoxic activity similar to that of tamoxifen. However, this type of molecule did not present selectivity towards ER + breast cancer cells. 10 Recently, we have reported the synthesis of estrone dimers linked at position 16 of the steroid nucleus. 11 These dimers were linked via two ester groups with an alkyl chain or a polyethylene glycol (PEG) chain. It was shown that the estrone dimers were non-toxic towards ER + (MCF-7) and ER  (MDA-MB-231) human breast cancer cell lines. In order to obtain dimers with a stron- ger linkage than the ester bonds found in the previously described molecules, we planned the synthesis of estra- diol dimers which are linked together via ether bonds. The ether connection should increase the stability of the dimeric molecules while improving its solubility. We believed that the used of the natural steroid nucleus in the design of such dimeric molecule could increase the chance of interactions with the estrogen receptor. Therefore, by increasing its interaction with the ER, one would theoretically enhance its biological activity as compared to the non-steroidal dimers. It is also believed that this type of molecules synthesized from the natural 0960-894X/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(02)00987-3 Bioorganic & Medicinal Chemistry Letters 13 (2003) 557–560 *Corresponding author. Fax: +1-819-376-5084; e-mail: gervais_ berube@uqtr.ca