Synthesis and biological evaluation of morpholines linked coumarin-triazole hybrids as anticancer agents.

Abstract

A series of novel morpholines linked coumarin-triazole hybrids (6a-6v) has been synthesized and evaluated for their anti-proliferative potential on a panel of five human cancer cell lines, namely bone (MG-63), lung (A549), breast (MDA-MB-231), colon (HCT-15) and liver (HepG2), using MTT assay. Among all, the compound 6n {7-((1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl) methoxy)-4-((2,6-dimethylmorpholino) methyl)-2H-chromen-2-one} showed significant growth inhibition against MG-63 cells with an IC50 value of 0.80 ± 0.22 μM. Further, induction of apoptosis by 6n of MG-63 cells confirmed as a result of morphological changes, the sub-G1 phase arrest, increased percentage of apoptotic cells, and decrease in mitochondrial membrane potential and increase in reactive oxygen species levels. The in vitro Gal-1 expression in cell culture supernatant of MG-63 cells treated with compound 6n showed dose-dependent reduction. The binding constant (Ka ) of 6n with Gal-1 was calculated from the intercept value which was observed as 3.0 × 105  M-1 by fluorescence spectroscopy. Surface plasmon resonance showed that 6n binds to Gal-1 with binding constant (Ka ) of 1.29E+04 1/Ms and equilibrium constant KD value of 7.54E-07 M, respectively. Molecular docking studies revealed the binding interactions of 6n with Gal-1.

• Authors: Nerella Sridhar Goud, Venkatesh Pooladanda, Ghouse S Mahammad, Pranay Jakkula, Santhosh Gatreddi, Insaf A Qureshi, Ravi Alvala, Chandraiah Godugu, Mallika Alvala
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 94 Issue 5 Pg. 1919-1929 (09 2019) ISSN: 1747-0285 [Electronic] England
• PMID: 31169963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons A/S.

Chemical References

• Antineoplastic Agents
• Coumarins
• Galectin 1
• Morpholines
• Reactive Oxygen Species
• Triazoles

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Coumarins (chemistry)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Galectin 1 (chemistry)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Docking Simulation
• Molecular Structure
• Morpholines (chemical synthesis, pharmacology)
• Protein Binding
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship
• Triazoles (chemistry)