In fulvestrant, the alkylsulfinyl moiety is attached to the endogenous estrogen receptor ligand, 17β-estradiol, at the 7-position, providing a structure similar to that of natural hormones but showing reverse biological activity. Recently, we have demonstrated that the modification of 17β-estradiol with imidazo[1,2-a]pyridine pendant at the 17α-position has the same effect (Rassokhina et al., 2016). 17α-Imidazopyridine-17β-methoxyestradiol showed remarkable effects as a selective ERα receptor modulator. In this study, we turned to an investigation of the structure—ERα-modulator activity relationship for two novel classes of heterosteroids possessing an N-heterocycle attached at the 16-position and fused to the A/D ring of the steroid core. We report the unique derivatives of the androstene and estrane series containing A/D-ring annulated pyrimidine or linked dihydrotriazine moieties. The antiproliferative potential of all synthesized compounds was evaluated in the MCF-7 and MDA-MB-231 breast cancer cell lines. The compounds were also tested toward two prostate cancer cell lines PC3 and 22Rv1. Taking into account activities of the compounds against hormone-dependent breast cancer ERα was analyzed as possible target for this series. Four compounds proved to be active as ERα antagonists. Steroidal dihydrotriazine 4a was selected as the lead compound and analyzed by the ERα-reporter assay, immunoblotting, and docking simulation. Finally, the binding of compound 4a to the estrogen receptor pocket was discussed using different docking models.