Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents.

A series of new steroidal pyridines have been synthesized through the based-promoted three-component reaction and preliminarily evaluated for their antiproliferative activity against different types of cancer cell lines. SARs studies showed that the heterocyclic rings attached to the 4-position of the pyridine ring were preferred over the phenyl rings for the activity. Among these compounds, the most potent compound exhibited good growth inhibition against all the tested cancer cells, especially for PC-3 cells with an IC50 value of 1.55 µM. Further mechanistic studies revealed that the most potent compound inhibited colony formation, migration and evasion of PC-3 cells in a concentration-dependent manner as well as induced apoptosis of PC-3 cells possibly through the mitochondria-related apoptotic pathways. Caspase-3/-9 and PARP were activated, finally leading to the apoptosis of PC-3 cells. For the androgen-sensitive (AR+) prostate cancer cell line LNCaP, the most potent compound was less potent than abiraterone with the IC50 value of 8.48 and 3.29 µM, respectively. The most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity. The synthesized steroidal pyridines contain the functional -OEt and CN groups, which could be used for further modifications for the construction of the steroid library.

Solvent-free synthesis of novel steroidal 2-aminopyridines.

The synthesis of novel steroidal 3-cyano-2-aminopyridines using enaminonitrile and various primary amines was established under solvent-free condition. Structures of the new compounds were characterized by MS, 1H and 13C NMR data and the structure of 2-aminopyridine of the product 5b was further confirmed by X-ray analysis. The reaction mechanism was proposed on the basis of the key intermediate obtained. The adjacent amine and nitrile groups existed in the final products have the potential for late stage functionalization, which would provide efficient access to steroidal compound collections with structural diversity and complexity.

Multicomponent assembly of novel antiproliferative steroidal dihydropyridinyl spirooxindoles.

Multicomponent assembly of steroidal dihydropyridinyl spirooxindoles from pregnenolone, isatins, malononitrile, and ammonium acetate is described, which involves the formation of two C-C bonds, two C-N bonds, and an all-carbon quaternary stereogenic center in a single operation. MTT assays showed that some of these compounds had moderate to excellent cytotoxicity against the tested cancer cell lines and were more potent than 5-FU. Particularly, compound 5o represented excellent inhibitory effect toward EC-109 (IC50=0.3 µM), being about 33-fold more potent than 5-FU.

Efficient three-component one-pot synthesis of steroidal polysubstituted anilines.

An efficient and practical base-promoted cascade reaction has been developed to access steroidal polysubstituted anilines from simple precursors. The protocol reported herein achieved the formation of a benzene ring as well as three continuous C-C bonds in a single operation. The reaction mechanism was proposed on the basis of the key intermediate obtained. Besides, this method could be potentially employed for the synthesis of biphenyl compounds. The adjacent amine and nitrile groups existed in the final products have the potential for late stage functionalization, which would provide efficient access to steroidal compound collections with structural diversity and complexity.