Design, Synthesis and Biological Evaluation of Novel 4-Substituted Coumarin Derivatives as Antitumor Agents

Abstract

Herein, fifteen new compounds containing coumarin, 1,2,3-triazole and benzoyl- substituted arylamine moieties were designed, synthesized and tested in vitro for their anticancer activity. The results showed that all tested compounds had moderate antiproliferative activity against MDA-MB-231, a human breast cancer cell line, under both normoxic and hypoxic conditions. Furthermore, the 4-substituted coumarin linked with benzoyl 3,4-dimethoxyaniline through 1,2,3-triazole (compound 5e) displayed the most prominent antiproliferative activities with an IC50 value of 0.03 μM, about 5000 times stronger than 4-hydroxycoumarin (IC50 > 100 μM) and 20 times stronger than doxorubicin (IC50 = 0.60 μM). Meanwhile, almost all compounds revealed general enhancement of proliferation-inhibiting activity under hypoxia, contrasted with normoxia. A docking analysis showed that compound 5e had potential to inhibit carbonic anhydrase IX (CA IX).

Synthesis, computational studies and assessment of in vitro inhibitory activity of umbelliferon-based compounds against tumour-associated carbonic anhydrase isoforms IX and XII

“…The existence of an extensive library of coumarins from (semi)synthetic source has been triggered by the high versatility of benzo-a-pyrone system to be an excellent scaffold to perform structural modifications [3][4][5][6] . Moreover, the chemical diversity of the coumarin system implies that they might play an important role in medicinal chemistry for drug discovery processes, so that many coumarins are used currently in drug development as vitamin K antagonists, choleretic and antibacterial and antiviral agents [7][8][9][10][11] . It has been suggested that the benzopyrone structure enables its derivatives to readily interact with biological molecular targets through a network of non-covalent interactions such as hydrophobic, p-p stacking, and cation-p interactions as well as hydrogen and coordination bond interactions.…”

Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

“…isohaichulactone [ 10 ], matairesinol [ 11 ], 7-hydroxymatairesinol [ 12 ], mammalian lignan enterolactone [ 13 ]. Numerous structural analogs of these bioactive molecules, in some cases exhibiting comparable or higher activity than their parent compounds, have also been designed and synthesized, such as novel derivatives of coumarins: dihydropyrazole thio-ethanone derivatives [ 14 ], α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton [ 15 ], series of 4-substituted coumarins [ 16 ] or coumarin/2-cyanoacryloyl hybrids [ 17 ]. Various antitumor analogs of isohaichulactone [ 18 ], homocampthotecin [ 19 ] and styryl lactones i.a.…”

Fluorogenic Polyfunctional Coumarin-Based Chemosensors for Multianalyte Detection

“…Coumarins (derivatives of 2H-chromene-2-one) constitute a comprehensive group of extensively studied heterocyclic compounds in organic, physical, and medical chemistry [9,10]. Some coumarins have been selected as privileged scaffolds for drug design [11][12][13], and a number of antitumor, antiproliferative, antioxidant, antifungal, anti-inflammatory, and antiviral agents have been obtained on their basis [14][15][16][17][18][19]. As a rule, substituted coumarins possess fluorescence in the visible part of the spectrum, as well as other useful photophysical properties.…”