RESUMEN
Synthesis of 21,22-cyclosteroids has been achieved starting from pregnenolone acetate. The key transformation was the Kulinkovich reaction of 17-vinyl steroids with esters. The resulting cyclopropanols were further subjected to three-membered ring-opening under various conditions including to base-, palladium or visible light-promoted isomerization and cross-coupling reaction. A number of steroidal Δ2-6-ketones and 3ß-hydroxy-Δ5-enes with functional groups at C-21 - C-23 have been synthesized via the 21,22-cyclosteroids. The antiproliferative and antihormonal activity of the obtained compounds on the cell lines of prostate (22Rv1) and breast (MCF-7) cancer was studied. The androgen receptor activity was assessed by reporter assay when the expression of signalling proteins was evaluated by immunoblotting. (20S,22R)-22-Acetoxy-21,22-cyclo-5α-cholest-5-ene with the moderate antiandrogenic potency revealed IC50 values of 18.4 ± 1.2 and 14.6 ± 1.4 µM against MCF-7 and 22Rv1 cells, respectively, and its effects on the expression of AR-V7, cyclin D1 and BCL2 were explored.
Asunto(s)
Antineoplásicos , Cicloesteroides , Humanos , Masculino , Línea Celular Tumoral , Proliferación Celular , Cicloesteroides/química , Cicloesteroides/farmacología , Imidazoles , Pregnenolona , Receptores Androgénicos/metabolismo , Esteroides , Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
A photochemical approach to 18-nor-17ß-hydroxymethyl-17α-methylandrost-13-ene unit of the long-term metabolites of 17-methylated androgenic anabolic steroids (AAS) is reported. It is based on a visible light-promoted radical decarboxylative alkynylation of steroidal redox-active ester. The developed method was used in synthesis of the long-term metabolite of AAS oxymesterone.
Asunto(s)
Anabolizantes/síntesis química , Androstenos/síntesis química , Esteroides/síntesis química , Anabolizantes/química , Anabolizantes/metabolismo , Androstenos/química , Androstenos/metabolismo , Luz , Conformación Molecular , Procesos Fotoquímicos , Estereoisomerismo , Esteroides/química , Esteroides/metabolismoRESUMEN
Palladium-catalyzed C-H acetoxylation has been proposed as a key transformation in the first chemical synthesis of steroids bearing a unique 17ß-hydroxymethyl-17α-methyl-18-nor-13-ene D-fragment. This C-H functionalization step was crucial for inverting the configuration at the quaternary stereocenter of a readily available synthetic intermediate. The developed approach was applied to prepare the metandienone metabolite needed as a reference substance in anti-doping analysis to control the abuse of this androgenic anabolic steroid.
