Synthesis of D-Ring Annulated Pyridosteroids from β-Formyl Enamides and Their Biological Evaluations

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 nonsteroidal 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.

Potential Therapeutic Agents on Alzheimer's Disease through Molecular Docking and Molecular Dynamics Simulation Study of Plant‐Based Compounds

“…At a constant temperature (300 k) and constant pressure (1 atm), the conformational sampling was started after the equilibration. Then the MD simulation trajectory time frame was collected every 2 ps time [7,86] …”

Green Fischer Indole Synthesis Using a Steroidal Ketone in a Conductively Heated Sealed-Vessel Reactor for the Advanced Undergraduate Laboratory

“…Finally, the instructor describes what is a pharmacophore in medicinal chemistry and provides a description of the steroidal inhibitors of liver CYP-450 enzymes used in cancer treatments for hormone-dependent tumors; for example, the CYP17A1 inhibitor and antiandrogen pro-drug abiraterone acetate − (Figure ). The instructor can also describe structures of select indole alkaloids, for example, the diterpene paspaline (Figure ), which has been of considerable interest because of its potential anticancer properties .…”

α,β‐Unsaturated Aldehydes as C‐Building Blocks in the Synthesis of Pyridines, 1,4‐Dihydropyridines and 1,2‐Dihydropyridines

“…The synthesis of tetrasubstituted pyridines 47 by the reaction of alicyclic β‐formyl enamides 45 with alkynes 46 have been developed by Boruah et al. in 2018 (Scheme ) . As shown in Scheme , the mechanism involves the initial generation of intermediate A by nucleophilic attack of the proton from NH‐group (initiated by K 2 CO 3 ) on alkynes activated by catalytic system CuI/1,10‐phenanthroline ( 48 ).…”