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.

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

“…Natural and synthetic coumarins (2H-chromen-2-one) demonstrate diverse biological activities, and are often considered as a privileged scaffold [1][2][3][4][5][6]. In particular, a large number of coumarin derivatives with high antitumor activity have been found in recent years [7][8][9][10][11][12][13][14][15][16][17][18]. Natural derivatives of 7-hydroxycoumarin containing terpene fragments have also attracted the attention of the medicinal chemistry community [19][20][21].…”

1,2,3‐Triazole hybrids as anticancer agents: A review

“…[45] 1,2,3-Triazole containing coumarin ring 29 (IC 50 value of 2.97 μM) was found to be more potent than cisplatin (IC 50 value of 24.15 μM) and induced sub-G1 phase arrest, increased apoptosis, and promoted the production of reactive oxygen species (ROS). [46] Incorporation of isatin into the 1,2,3-triazole-tethered coumarin hybrid (30) showed cytotoxicity, with an IC 50 value of 18.67 μM against A549 cells. [47,48] 1,2,3-Triazole-incorporated asiatic acid derivative 31 was found to be active, with IC 50 values in the range 2.67-4.84 μM against the three tested lung cancer cells.…”

Synthesis and Biological Properties of Coumarin Derivatives. A Review

“…Phadtare et al [77] . developed one‐pot synthesis of fluorescent cyanocoumarin‐based dye using deep eutectic solvent (DES) ChCl:urea from 4‐(diethylamino)‐2‐hydroxybenzaldehyde and ethyl acetoacetate leading to 3‐acetyl‐7‐(diethylamino)‐2 H ‐chromen‐2‐one as intermediate before addition of different aromatic aldehydes, Scheme 50.…”