Substituted Stilbenes and 1,2-Diaryl-1,2-diazidoethanes as Potential Anticancer Agents (2006)

In this work, a series of novel hydroxylated stilbene derivatives and 1,2-diaryl-1,2-diazido-ethanes as potential anticancer agents were synthesized and investigated for their estrogenic / antiestrogenic effects in the MCF-7-2a cell line with luciferase assays. The (di)hydroxylated stilbene derivatives, which were synthesized either by the crossed reductive coupling of the corresponding bezaldehydes with low-valent titanium or by the Wittig reaction using the corresponding aryl aldehyde and benzyltriphenylphosphonium chloride followed by demethylation with boron tribromide, showed agonist activities in MCF-7-2a cells. One para-phenolic hydroxy group in stilbenes was necessary for a full activation of the gene expression. An other para-phenolic hydroxy or a methoxy group in combination with appropriate halo-substituents enhanced the estrogenic potency. The most active hydroxylated stilbene was 2'-chloro-4,4'-dihydroxystilbene 43 (EC50 = 40 nM). In contrast to the above- described agonists , several 2-alkyl-1,1,2-triarylethenes were antagonistically active in MCF-7-2a cells without agonist activity. The antagonist activity of 4,8-dibromo-1,1,2-tris(4-hydroxyphenyl)oct-1-ene 79 (IC50 = 99 nM) was even higher than that of tamoxifen (IC50 = 500 nM). Synthesis of the novel hydroxylated erythro- and threo-1,2-diaryl-1,2-diazidoethanes as well as two 2-alkyl-1,1,2-tris(4-methoxyphenyl)-1,2-diazidoethanes 96 and 97 was performed by treatment of the corresponding stilbene derivatives with ICl / NaN3 in acetonitrile. Most of the erythro- and threo-1,2-diaryl-1,2-diazidoethanes were capable of activating transcription in MCF-7-2a cells and some of them were full-agonists, e. g. 93 (2,2',6'-Cl3, EC50 = 65 nM) and 95 (2,2',6,6'-Cl4, EC50 = 56 nM). The agonist activities of these compounds had obvious relevance to the phenolic hydroxy and halo-substituents as well as the configuration. The dihydroxylated compounds were estrogenically more active than the monohydroxylated compounds bearing a further methoxy group; The compounds bearing more halo-substituents on aromatic rings possessed greater estrogenic potencies; The erythro-isomers were estrogenically more active than their diastereomers. Only the dihydroxylated compound 86 showed a significant antagonist activity (IC50 = 626 nM). Without the phenolic hydroxy group, 1,2-diazido-1,1,2-tris(4-methoxyphenyl)propane 96 exhibited also a significant antiestrogenic effect in MCF-7-2a cells. Several compounds containing the stilbene structure, the olefin bond of which was integrated to a ring skeleton, were synthesized in an attempt to gain evidence concerning the pharmacologically active skeleton structure. So reductive coupling of the isomerically pure 1,2,4,5-tetraaryl-1,5-pentandione with low-valent titanium afforded the isomerically pure 1,2,3,5-tetraarylcyclopent-1-ene. An other type was triarylfuran derivative containing a diarylimidazole unit prepared by condensation of a side-formylated triarylfuran with a commercially available benzil and ammonium acetate. 1,2,3,5-Tetraarylcyclopent-1-ene showed neither agonist nor antagonist activities in the luciferase assay. The modification of triarylfuran by combination with a diarylimidazole unit resulted in the loss of agonist activity. The compound 117 activated slightly the luciferase expression (EC50 = 1450 nM), while the hydroxylated compound 120 antagonized completely the E2 effect (IC50 = 2750 nM).