Novel steroidal 1,3,4-thiadiazines: Synthesis and biological evaluation in androgen receptor-positive prostate cancer 22Rv1 cells.

A flexible approach to previously unknown spirofused and linked 1,3,4-thiadiazine derivatives of steroids with selective control of heterocyclization patterns is disclosed. (N-Arylcarbamoyl)spiroandrostene-17,6' [1,3,4]thiadiazines and (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes, novel types of heterosteroids, were prepared from 16ß,17ß-epoxypregnenolone and 21-bromopregna-5,16-dien-20-one in good to high yields by the treatment with oxamic acid thiohydrazides. The synthesized compounds were screened for antiproliferative activity against the human androgen receptor-positive prostate cancer cell line 22Rv1. Most of (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes exhibit better antiproliferative potency (IC50 = 2.1-6.6 µM) than the antiandrogen bicalutamide. Compounds 7d with IC50 = 3.0 µM and 7j with IC50 = 2.1 µM proved to be the most active in the series under study. Lead synthesized compound 7j downregulates AR expression and activity in 22Rv1 cells. NF-κB activity is also blocked in 7j-treated 22Rv1 cells. Apoptosis is considered as a possible mechanism of 7j-induced cell death.

Steroidal Pyrimidines and Dihydrotriazines as Novel Classes of Anticancer Agents against Hormone-Dependent Breast Cancer Cells.

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 ß-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.

A Straightforward Approach toward Multifunctionalized Pyridazines via Imination/Electrocyclization.

A facile synthesis of functionalized 3-carbamide pyridazines starting from readily available chlorovinyl aldehydes and oxamic acid thiohydrazides via cascade imination/electrocyclization is reported. In the presence of p-toluenesulfuric acid, various ketones have been efficiently incorporated into the pyridazine derivatives through a two-step sequence involving a Vilsmeier-Haack reaction and imination. The synthetic value of this method has been demonstrated by efficient synthesis of steroidal pyridazines.