%0 Journal Article
%T Synthesis of D-Ring Annulated Pyridosteroids from ¦Â-Formyl Enamides and Their Biological Evaluations
%J -
%D 2019
%R https://doi.org/10.1021/acscombsci.8b00140
%X Herein, we report the synthesis of a novel class of substituted androst[17,16-b]pyridines (pyridosteroids) from the reaction of ¦Â-formyl enamides with alkynes in high yields. The optimized reaction protocol was extended to acyclic and cyclic ¦Â-formyl enamides to afford nonsteroidal pyridines. Cell survival assay of all compounds were carried against prostate cancer PC-3 cells wherein 3-hydroxy-5-en-2¡ä,3¡ä-dicarbethoxy-androst[17,16-b]pyridine showed the highest cytotoxic activity. Phase contrast microscopy and flow cytometry studies exhibited marked morphological features characteristic of apoptosis in 3-hydroxy-5-en-2¡ä,3¡ä-dicarbethoxy-androst[17,16-b]pyridine and abiraterone treated PC-3 cells. The treatment of 3-hydroxy-5-en-2¡ä,3¡ä-dicarbethoxy-androst[17,16-b]pyridine induces G2/M phase cell cycle arrest in prostate cancer PC-3 cells. Enhancement of apoptotic inductions of PC-3 cells by 3-hydroxy-5-en-2¡ä,3¡ä-dicarbethoxy-androst[17,16-b]pyridine and abiraterone through the activation of caspases-6, -7, and -8 pathways were supported by qRT-PCR. In silico study of the compound 3-hydroxy-5-en-2¡ä,3¡ä-dicarbethoxy-androst[17,16-b]pyridine showed stable and promising interaction with the key caspase proteins. Our studies revealed that the pyridosteroid 3-hydroxy-5-en-2¡ä,3¡ä-dicarbethoxy-androst[17,16-b]pyridine, bearing pyridine-2,3-dicarbethoxy pharmacophore, facilitated initiation of caspase-8 and activates downstream effectors caspase-6 and caspase-7 and thereby triggering apoptosis of PC-3 cancer cells
%U https://pubs.acs.org/doi/10.1021/acscombsci.8b00140