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A series of 17α- (heteroaryl)vinyl estradiols was prepared to evaluate the influence of heteroatom on the affinity and efficacy of estrogenic ligands for the estrogen receptor-alpha ligand binding domain (ERα-LBD). The products demonstrated reduced binding affinity compared to the parent 17α-E-phenylvinyl estradiol, but the binding was relatively independent of the heteroatom. The greatest influence of the heteroatom was evident in the efficacy of the compounds as the thienyl derivatives 2f,g were more potent than either the pyridyl 2b–d or pyrimidinyl 2e analogs. The results suggest that a subtle interplay of interactions between the ligands and the receptor influences the biological response.

As part of our program to develop new probes for the estrogen receptor binding domain, we prepared and evaluated a novel 17α-(rhenium tricarbonyl bipyridyl) vinyl estradiol complex. Preparation of the final compound was achieved using the Stille coupling between the preformed brominated rhenium tricarbonyl bipyridine complex and the tributylstannyl vinyl estradiol. Competitive receptor binding assays and stimulatory assays demonstrated that the final complex retained affinity and efficacy comparable to the corresponding pyridyl vinyl estadiol analog, but lower than that of the phenyl vinyl estradiol analog.

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Synthesis and Evaluation of 17α-E-20-(Heteroaryl)norpregn-1,3,5(10),20-tetraene-3,17β-diols [17α-(Heteroaryl)vinyl Estradiols] as Ligands for the EstrogenReceptor-α Ligand Binding Domain (ERα-LBD). -A series of 17α-(heteroaryl)vinyl estradiols (III) is synthesized to evaluate the influence of heteroatom on the affinity and efficacy of estrogenic ligands for the estrogen receptor-alpha ligand binding domain. The Stille coupling strategy is chosen because Suzuki coupling between 17α-E-iodovinyl estradiol and the corresponding heteroaryl boronic acid gives no satisfying results. The reaction works with both iodo-and bromoheteroarenes. -(OLMSTED, S. L.; TONGCHAROENSIRIKUL, P.; MCCASKILL, E.; GANDIAGA, K.; LABAREE, D.; HOCHBERG, R. B.; HANSON*, R. N.; Bioorg. Med. Chem. Lett. 22 (2012) 2, 977-979, http://dx.