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Carbocyclic steroids D-annulated at 16α and 17α positions with a 5-membered ring E are easily accessible via the interrupted Nazarov cyclization. Three steroid series have been structurally studied: chlorine-containing D-annulated pentacyclic steroids 2, their reduced derivatives 3 and their synthetic precursors – benzylidines of tetracyclic steroids 1. The presence of two conformers for pentacyclic steroids 2 and 3 have been found in crystals, where formation is evidently caused by the conformational flexibility of the ring E. Geometries obtained from X-ray diffraction experiments have been used as the initial ones for semi-empirical and ab initio quantum chemical calculations to confirm the reproducibility of the steroids' geometries by these methods and further used for docking studies against the human androgen receptor ligand-binding domain. The docking results have confirmed that the geometries of the studied D-annulated pentacyclic steroids perfectly match the human androgen receptor active site. Geometry analysis of docking results allowed us to explain the influence of subtle structural differences in series 2 and 3 on the ligand binding energy. Compounds with the highest binding energies have been studied in experiments on AR-positive 22Rv1 prostate cancer cells. Selected steroids revealed antiproliferative potency and inhibited AR pathways in 22Rv1 prostate cancer cells, including downregulation in NKX3.1 and PSA expression. A combination of pentacyclic steroid 2d with non-steroidal antiandrogen bicalutamide exhibited significant antiproliferative effects in 22Rv1 cells. The obtained results for this family of pentacyclic steroids provides insights for further structure–activity relationship studies towards novel drugs targeting nuclear receptors in cancer cells. Pentacyclic steroids are of great interest for the development of innovative therapeutic approaches in the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

The 13C NMR shifts of a variety of organic compounds including pinanes and steroids were predicted using combined molecular mechanics (Pcmod 9.1/MMFF94) and ab initio GIAO (B3LYP/DFT,6-31G(d)) calculations. The accuracy of the ab initio calculations was no different when using the 6-31G(d) basis set than more complex basis sets but the calculations were much faster. The MM calculations for steroids took a few seconds and the Gaussian calculations ca. 45 minutes on a desktop computer. For the data set of alkanes, alkenes and alkynes the 13C shifts were obtained from the GIAO isotropic shieldings (Ciso) by (a) empirically scaled shieldings (δc = A−B·Ciso) and (b) separate references for sp3, sp2 and sp carbons (δc = δref−Ciso). The second method gave better agreement and was used henceforth. For the data set of 34 alkanes, alkenes and aromatics with 96 shifts the mean absolute error (MAE) was excellent (0.90) ppm but the alkyne data set (7 compounds with 27 shifts) did not give as good agreement (MAE 1.7 ppm). For the more complex substituted compounds, pinanes and steroids the MAE ＜ 2 ppm but with large errors mainly from the C–X carbons (X = F, Cl, Br, O, =O). The agreement for fluorocyclohexane (axial and equatorial) was, apart from C1 so good that the fluorine substituent effect is completely explained by this model. The calculations for the pinanes gave good agreement with two exceptions, C6 in the cyclobutane ring and the C=C–CO carbon fragment. In both cases the use of different geometries (MM3 and 6-31G(d) res.) gave good results (apart from the CO carbon) suggesting that the errors are due to the molecular geometries in these strained molecules. In contrast for the seven steroids examined the MAE was 1.4 ppm and the assignments of the calculated and experimental shifts were almost identical. Thus this method could be very useful in assigning the 13C spectra and determining the conformations of relatively large molecules. [ABSTRACT FROM AUTHOR]

A solid support-mediated p-TsOH-catalyzed milder transformative protocol was developed to furnish diverse ring-A and/or ring-B oxo-functionalized steroids. To furnish interesting isomers involving the A/B-ring of biomolecules in a one-pot approach, only solid supports (and not solution!) were found to be effective. p-TsOH/SiO2-oxidation of 4β-hydroxycholesterol, the major oxysterol in human circulation, into a mixture of cholest-4-en-3-one, cholest-4-ene-3,6-dione, and 5α-cholestane-3,6-dione was the starting point for the investigations herein. The reaction protocol was optimized in detail, and efforts were carried out toward gaining an understanding of the mechanistic aspects favoring the solid support, and a possible synergetic catalytic system involving p-TsOH and SiO2 was expected to be a key part. Application of the novel methodology to 4β,7α-dihydroxy steroids resulted in the desired diverse ketosteroids through oxidation/oxidative dehydration, which generalized the process as a facile multi-oxo-functionalization steroidal transformation. [ABSTRACT FROM AUTHOR]