Synthesis of D-Ring Annulated Pyridosteroids from β-Formyl Enamides and Their Biological Evaluations
| Autor: | Kasmika Borah, Geetmani Singh Nongthombam, Thingreila Muinao, Romesh C. Boruah, Mintu Pal, Yumnam Silla, Hari Prasanna Deka Boruah |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cell Survival
Pyridines Stereochemistry Alkyne Antineoplastic Agents Apoptosis Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Flow cytometry Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Pyridine medicine Humans Cytotoxic T cell Caspase chemistry.chemical_classification Molecular Structure biology medicine.diagnostic_test 010405 organic chemistry General Chemistry General Medicine Caspase Inhibitors 0104 chemical sciences Molecular Docking Simulation chemistry Alkynes Azasteroids Caspases Cancer cell biology.protein Thermodynamics Androstenes Steroids Drug Screening Assays Antitumor Pharmacophore |
| Zdroj: | ACS Combinatorial Science. 21:11-27 |
| ISSN: | 2156-8944 2156-8952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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