RESUMEN
Steroid anticancer drugs are the focus of numerous scientific research efforts. Due to their high cytotoxic effects against tumor cells, some natural or synthetic steroid compounds seem to be promising for the treatment of different classes of cancer. In the present study, fourteen novel O-alkylated oxyimino androst-4-ene derivatives were synthesized from isomerically pure 3E-oximes, using different alkylaminoethyl chlorides. Their in vitro cytotoxic activity was evaluated against eight human cancer cell lines, as well as against normal fetal lung (MRC-5) and human foreskin (BJ) fibroblasts, to test the efficiency and selectivity of the compounds. Most derivatives displayed strong activity against malignant melanoma (G-361), lung adenocarcinoma (A549) and colon adenocarcinoma (HT-29) cell lines. Angiogenesis was assessed in vitro using migration scratch and tube formation assays on HUVEC cells, where partial inhibition of endothelial cell migration was observed for the 17α-(pyridin-2-yl)methyl 2-(morpholin-4-yl)ethyl derivative. Among the compounds that most impaired the growth of lung cancer A549 cells, the (17E)-(pyridin-2-yl)methylidene derivative bearing a 2-(pyrrolidin-1-yl)ethyl substituent induced significant apoptosis in these cells. In combination with low cytotoxicity toward normal MRC-5 cells, this molecule stands out as a good candidate for further anticancer studies. In addition, in vitro investigations against cytochrome P450 enzymes revealed that certain compounds can bind selectively in the active sites of human steroid hydroxylases CYP7, CYP17A1, CYP19A1 or CYP21A2, which could be important for the development of novel activity modulators of these enzymes and identification of possible side effects.
RESUMEN
An efficient and practical method has been developed for the synthesis of steroidal imidazoheterocycles via cost-effective and environmentally benign FeCl3-catalyzed oxidative amination. A library of steroidal imidazo[1,2-a]pyridines was directly synthesized from readily available 2-aminopyridines and steroidal ketones in aerobic conditions. The synthesized compounds were screened for activity on human microsomal cytochrome P450s CYP7, CYP17 and CYP21. Antiproliferative activity of two lead compounds 3ia and 3la was additionally evaluated against the human MCF-7 (breast cancer), SKOV3 (ovarian cancer), and 22Rv1 (prostate cancer) cell lines. Steroidal imidazo[1,2-a]pyridine 3la which is a substrate molecule for CYP17A1 with IC50 = 1.7 µM (MCF-7), 3.0 (SKOV3), and 6.0 µM (22Rv1) has proved to be more active than reference drug cisplatin.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Férricos/química , Compuestos Heterocíclicos/farmacología , Imidazoles/farmacología , Esteroides/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Conformación Molecular , Estereoisomerismo , Esteroides/síntesis química , Esteroides/químicaRESUMEN
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 (IC50â¯=â¯2.1-6.6⯵M) than the antiandrogen bicalutamide. Compounds 7d with IC50â¯=â¯3.0⯵M and 7j with IC50â¯=â¯2.1⯵M 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.