Most breast and prostate
tumors are
hormone-dependent, making it possible to use
hormone therapy in patients with these
tumors. The design of effective endocrine drugs that block the growth of
tumors and have no severe side effects is a challenge. Thereupon, synthetic
steroids are promising therapeutic drugs for the treatment of diseases such as
hormone-dependent breast and
prostate cancers. Here, we describe novel series of steroidal
pyrimidines and dihydrotriazines with anticancer activities. A flexible approach to unknown
pyrimidine and dihydrotriazine derivatives of
steroids with selective control of the heterocyclization pattern is disclosed. A number of 18-nor-5α-androsta-2,13-diene[3,2-d]
pyrimidine, androsta-2-ene[3,2-d]
pyrimidine, Δ1, 3, 5(10)-estratrieno[16,17-d]
pyrimidine, and 17-chloro-16-dihydrotriazine
steroids were synthesized by condensations of
amidines with β-chlorovinyl
aldehydes derived from natural
hormones. The synthesized compounds were screened for cytotoxicity against
breast cancer cells and showed IC50 values of 7.4 μM and higher. Compounds were tested against
prostate cancer cells and exhibited antiproliferative activity with IC50 values of 9.4 μM and higher comparable to that of
cisplatin. Lead compound 4a displayed selectivity in ERα-positive
breast cancer cells.
At 10 μM concentration, this heterosteroid inhibited 50% of the E2-mediated ERα activity and led to partial ERα down-regulation. The ERα reporter assay and immunoblotting were supported by the docking study, which showed the probable binding mode of compound 4a to the
estrogen receptor pocket. Thus, heterosteroid 4a proved to be a selective ERα modulator with the highest antiproliferative activity against
hormone-dependent
breast cancer and can be considered as a candidate for further anticancer drug development. In total, the synthesized heterosteroids may be considered as new promising classes of active
anticancer agents.