Synthesis of D-ring annulated pyridosteroids from β-formyl enamides and their biological evaluations.

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Synthesis of D-ring annulated pyridosteroids from β-formyl enamides and their biological evaluations.

ACS Comb Sci. 2018 Dec 21;:

Authors: Nongthombam GS, Borah K, Muinao T, Silla Y, Pal M, Dekaboruah HP, Boruah RC

Abstract
Herein we report the synthesis of a novel class of substituted androst[17,16-b]pyridines (pyridosteroids) from the reaction of β-formyl enamides with alkynes in high yields. The optimized reaction protocol was extended to acyclic and cyclic β-formyl enamides to afford non-steroidal pyridines. Cell survival assay of all compounds were carried against prostate cancer PC-3 cells wherein 3-hydroxy-5-en-2',3'-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',3'-dicarbethoxy-androst[17,16-b]pyridine and abiraterone treated PC-3 cells. The treatment of 3-hydroxy-5-en-2',3'-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',3'-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',3'-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',3'-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.

PMID: 30576125 [PubMed - as supplied by publisher]

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