Synthesis of new steroidal imidazo [1,2-a] pyridines: DNA binding studies, cleavage activity and in vitro cytotoxicity.

Abstract

A one-pot strategy for the catalytic synthesis of series of new 5α-cholestan-6-spiro-5'-phenylamino-2H-imidazo [1',2'-a] pyridines (4-14) has been investigated. The synthesized products were obtained in good yields (85-90%) and the protocol uses Multi-component Reaction (MCR) involving steroidal ketones, 2-aminopyridines, isocyanides and propylphosphonic anhydride (®T3P) as a catalyst. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were studied by UV-vis, fluorescence spectroscopy, gel electrophoresis and molecular docking. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.35×10(4), 3.71×10(4) and 3.24×10(4) M(-1), respectively, indicating the higher binding affinity of compound 5 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compounds 4-6 with DNA. Molecular docking studies suggested that compounds bind through minor groove to DNA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay depicted promising anti-proliferative activity of compound 4-9 against different given cancer cells. In Western blotting, the expressions of relevant apoptotic markers depicted an apoptosis by steroidal imidazopyridines in A549 cells. Annexin V-FITC/PI staining data indicated that compounds could effectively induce apoptosis in A549 cells in a dose-dependent manner. FACS analysis shows that the compound 6 bring about cell cycle arrest at 2.62 μM concentration.

• Authors: Ayaz Mahmood Dar, Shamsuzzaman, Manzoor Ahmad Gatoo
• Journal: Steroids (Steroids) Vol. 104 Pg. 163-75 (Dec 2015) ISSN: 1878-5867 [Electronic] United States
• PMID: 26433147 (Publication Type: Journal Article)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents
• Pyridines
• Steroids
• DNA
• calf thymus DNA
• imidazo(1,2-a)pyridine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Cattle
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA (chemistry)
• DNA Cleavage (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Molecular Docking Simulation
• Molecular Structure
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Steroids (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured