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.

• Authors: Geetmani Singh Nongthombam, Kasmika Borah, Thingreila Muinao, Yumnam Silla, Mintu Pal, Hari Prasanna Deka Boruah, Romesh Chandra Boruah
• Journal: ACS combinatorial science (ACS Comb Sci) Vol. 21 Issue 1 Pg. 11-27 (01 14 2019) ISSN: 2156-8944 [Electronic] United States
• PMID: 30576125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Androstenes
• Antineoplastic Agents
• Azasteroids
• Caspase Inhibitors
• Pyridines
• Steroids
• Caspases
• abiraterone

Topics

• Alkynes (chemistry)
• Androstenes (pharmacology)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Azasteroids (chemistry)
• Caspase Inhibitors (chemical synthesis, pharmacology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Molecular Structure
• Pyridines (chemical synthesis, pharmacology)
• Steroids (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Thermodynamics