1-ARYL-2-PYRIDYL-3,4-DIHYDRONAPHTHALENES - PHOTOFLUOROGENIC LIGANDS FOR THE ESTROGEN-RECEPTOR

Three 1,2-substituted-3,4-dihydronaphthalenes that are pyridine analog s of the antiestrogen desmethylnafoxidine were prepared and evaluated as fluorescent ligands for the estrogen receptor. These compounds repr esent a class of fluorescent probes that we term ''photofluorogenic'', denoting their ability to exist initially as a high affinity though w eakly fluorescent stilbazole form which can be photocyclized-oxidized to a highly fluorescent though low affinity azaphenanthrenoid form. Th ese probes also contain an aziridine function that provides a means fo r their permanent, covalent attachment to the receptor. The three dihy dronaphthalene systems were prepared by efficient routes from alpha-(2 -, 3-, and 4-pyridyl)acetophenone precursors. They demonstrate high ap parent affinity for the estrogen receptor and show time-dependent irre versible inactivation, consistent with their covalent attachment to th e receptor via the aziridine function. Each system is converted into a n azaphenanthrene by photocyclization-oxidation of the cis-stilbazole unit. The absorbance and fluorescence emission spectra of the dihydron aphthalene precursors and azaphenanthrene products have been character ized, and they display marked sensitivity to both solvent polarity and pH. The azaphenanthrenoids derived from the 2- and 4-pyridyl isomers exhibit intense emission at wavelengths that exceed 500 nn under certa in conditions and appear to be well suited as fluorescent probes for t he estrogen receptor.