Here, we describe novel series of steroidal anticancer agents. In summary, this study demonstrates that the cyclization of steroidal β-chlorovinyl aldehydes with bis-nucleophilic amidines provides an easy approach to various novel heterosteroids. Natural hormones 1a–c (estrone, 3β-acetoxyandrostene, 3-keto-17β-hydroxyandrostane) were transformed into the corresponding A- and D-modified steroidal pyrimidines and dihydrotriazines in moderate to high yields (29–89%) using a two-step sequence involving the Vilsmeier–Haack reaction and condensation with amidines, such as guanidine and acetimidamide. The new compounds showed remarkable cytotoxic activity against breast and prostate cancer cells. Furthermore, lead compounds demonstrated selectivity toward ERα in MCF-7 breast cancer cells. Compound 4a inhibits 50% of ERα activity at its cytotoxic concentration. Using immunoblotting, partial ERα downregulation was observed in compound 4a-treated MCF-7 cells. Docking approaches confirmed the ability of compound 4a to bind to ERα. Thus, compound 4a may be considered as a candidate for future anticancer drug design, in particular, for ERα-positive breast cancers.