1-(2,6-Dichloro-4-hydroxyphenyl)-2-phenylethanes – New Biological Response Modifiers for the Therapy of Breast Cancer. Synthesis and Evaluation of Estrogenic/Antiestrogenic Properties ✩ Sabine Schertl a) , Rolf W. Hartmann b) , Christine Batzl-Hartmann b) , Richard Schlemmer a) , Thilo Spruß a) , Günther Bernhardt a) , Ronald Gust c) , and Helmut Schönenberger a) a) Lehrstuhl für Pharmazeutische Chemie II, Institut für Pharmazie, Universität Regensburg, D-93040 Regensburg, Germany b) Pharmazeutische und Medizinische Chemie, Universität des Saarlandes, D-66041 Saarbrücken, Germany c) Institut für Pharmazie der FU Berlin, D-14195 Berlin (Dahlem), Germany Key Words: 1-(2,6-Dichloro-4-hydroxyphenyl)-2-phenylethanes; biological response modifiers; synthesis; estrogen receptor affinity; estrogenic/antiestrogenic activity Summary Introduction 1) In preceding publications [1–6] we have shown that the marked effect of the [meso-1,2-bis(2,6-dichloro-4-hydroxy- phenyl)ethylenediamine]platinum(II) complexes (meso-1- PtLL′; Chart 1) on ER + rodent breast cancers is not due to an impairment of the DNA function in the tumor cells as de- scribed for the therapeutically established platinum complex cisplatin (cDDP), but rather to a modification of the immune response. It became apparent that the estrogenic activities of the meso-1-PtLL′ complexes are responsible for their antitu- mor effect, since their diamine ligand meso-1; (formula see Chart 1), which is endowed with hormonal but not with cytotoxic properties, also inhibited the growth of the ER + breast cancer, if only to a lower degree. The capability of meso-1-PtLL′ and of meso-1 to trigger an ER-mediated process which interrupts the tumor growth stimulation by cells of the phagocytic system and restores the natural im- mune defense, appears to be responsible for their anti-breast cancer activities [3–6] . In the search for well tolerated biological response modifi- ers for the therapy of breast cancer, we synthesized 1,2- bis(2,6-dichloro-4-hydroxyphenyl)ethane (23H: pharmaco- phor of meso-1-PtLL′; formula see Chart 1) and performed an extensive structure-activity study on this lead structure. Arch. Pharm. Pharm. Med. Chem. © WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 0365-6233/01/0404/0125 $17.50 +.50/0 ——— Correspondence: Ronald Gust, Institut für Pharmazie der FU Berlin, D-14195 Berlin (Dahlem), Germany. E-Mail: rgust@zedat.fu-berlin.de [meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes ( meso-1-PtLL′; L,L′= Cl or L = H2O and L′ = OSO3) are highly effective towards hormone-sensitive, rodent breast cancers due to their significant estrogenic potencies. Their antitumor activities are caused by modification of the immune response. The pharmacophor of these compounds, the 1,2-bis(2,6-dichloro-4-hydroxy- phenyl)ethane (23H), was used as the lead structure in a structure-activity study with the goal of finding new biological response modifiers for the therapy of breast cancer. As intermediates for the synthesis of the 23H derivatives, the CH3O-substituted stilbenes 12E/12Z– 16E/16Z were prepared by reaction of the related benzyltriphenylphosphonium halides with 2,6-dichloro-4-methoxybenzaldehyde by the method of Wittig/Campbell and Donald, respectively. Separation of the E/Z-mixtures was performed by fractional crystallization and/or column chromatography. The E-1,2-bis(2,6-dichloro-4-methoxyphenyl)ethene (17E) was obtained by reductive coupling of 2,6-dichloro- 4-methoxybenzaldehyde with TiCl4/Zn according to the method of Mukaiyama. Illumination of the solution of 17E in benzene with UV light resulted in an E/Z-isomerization. Compound 17Z could be isolated from this mixture. The CH3O-substituted stilbenes were transformed into their 1,2-diphenylethanes (12H–17H) by catalytic hydrogenation of the C1=C2 double bond. Ether cleavage of the compounds was performed with BBr3. In the estrogen receptor binding assay all OH-substituted 1,2-diphenylethanes showed affinity to the estrogen receptor, which was about two orders of magnitude lower than that of 17 β-estradiol. In the uterus weight test on the immature mouse 1,2-diphenylethanes with 4-substituted OH groups proved to be “true” estrogens (19H: 2-F/4-OH; 20H: 2-Cl/4-OH; 23H: 2,6-Cl2/4-OH), while those with a 3-substituted OH group in the 2-phenyl ring showed the properties of a “partial” estrogen (18H: 3-OH) or of an “impeded” estrogen (21H: 2-Cl/3-OH; 22H: 2-Cl/5-OH). The latter also showed significant additional antiestrogenic activity. The related E-stilbenes mostly exhibit similar hormonal activities. As a rule, the replacement of the OH groups by the CH3O groups and the change from the E- to the Z-configuration led to a reduction of the estrogenic potencies. Several of the 1-(2,6-dichloro-4-methoxyphenyl)- 2-phenylethenes (12E: 3-OCH3; 12Z: 3-OCH3; 15E: 2-Cl/3-OCH3; 15Z: 2-Cl/3-OCH3; 16E: 2-Cl/5-OCH3) produced antiestrogenic effects in the uterus weight test. It is supposed that those new 1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethanes endowed with marked estrogenic properties are also active as biological response modifiers in animals bearing hormone-sensitive breast cancer. The antiestrogenic derivatives presumably inhibit the breast cancer development by competing with tumor growth stimulating endogenous estrogens for the binding to the receptor. This is to be confirmed in a further study. ——— 1) The abbreviations used are: ER, estrogen receptor; ER + and ER – indicate the presence or the absence of the ER; cDDP, cisplatin; Tam, tamoxifen; DES, diethylstilbestrol; metastilbestrol, DES with 3, 3′-standing OH groups; HES, hexestrol; metahexestrol, HES with 3, 3′-standing OH groups; but- estrol, meso-2,3-bis(4-hydroxyphenyl)butane; E1, estrone; E2, 17β-estradiol; E3, estriol. 1-(2,6-Dichloro-4-hydroxyphenyl)-2-phenylethanes 125