In Vitro Antioxidant and Pancreatic Anticancer Activity of Novel 5-Fluorouracil-Coumarin Conjugates (original) (raw)
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Synthesis, antioxidant and antitumor activities of new coumarins grafted to 5-fluorouracil
Caspian Journal of Environmental Sciences, 2022
Compounds with chemical systems depend on the coumarin architecture have sparked a lot of interest in the scientific community, not only because of their different morphological characteristics, but also because of their wide range of biological properties. In this study, four 7-halomethylcoumarin-4-acetic acid derivatives tagged as YMa-YMd were synthesized by coupling various 3-halomethyl phenols with 3-oxoglutaric acid that prepared in situ from the interaction of citretten and concentrated H2SO4. The acquired coumarin derived compounds were grafted to 5-fluorouracil through amide bond using dichlorosulfoxide as a coupling reagent. The chemical frames of the final conjugated coumarins, named YM1-YM4, were identified and established by analyzing their spectral data gathered from various analytical spectrophotometers, involving FTIR, 1 HNMR, and 13 CNMR. The potential of the conjugated coumarins to act as antioxidants was investigated by monitoring their ability to trap the free radicals of DPPH. Besides, the chemotherapeutic potential was assessed against two standard tumor-cell lines, named HeLa and MCF 7, using a well-validated technique based on the MTT as a visual indication. The outcomes acquired from these assessments indicated that the synthesized conjugated coumarins have less impact as antioxidizing and cytotoxic agents comparing with the utilized standard drugs. Furthermore, these coumarins showed essentially the same pattern of action against the two cell lines examined, with MCF-7 acquired the most inhibitory effect. Additionally, conjugated coumarin YM1 showed valuable activities as antioxidant and chemotherapeutic agent compared to the other synthesized derivatives. As a result, the authors concluded that the synthesized conjugated coumarins might be used as antioxidant and anticancer agents, with conjugated coumarin YM1 being the most promising. Moreover, the synthesized core might serve as a beneficial framework for developing medicines with potent antioxidant and anticancer properties.
Acta Pharmaceutica, 2009
Synthesis of coumarin heterocyclic derivatives with antioxidant activity andin vitrocytotoxic activity against tumour cellsThe aim of the present work was to synthesise coumarinyl heterocycles and to elucidate the potential role of these compounds as antioxidants and cytotoxic agents against Dalton's lymphoma ascites tumour cells (DLA) and Ehrlich ascites carcinoma cells (EAC). The synthesis of coumarin derivatives containing pyrazole, pyrazolone, thiazolidin-4-one, 5-carboxymethyl-4-thiazolidinone and 3-acetyl-1,3,4-oxadiazole ring is reported. 4-Methylcoumarinyl-7-oxyacetic acid hydrazide (1) reacted with arylazopropanes or hydrazono-3-oxobutyrate derivatives to form pyrazole (3a-c) and pyrazolone derivatives (5a-c). Heterocyclisation of Schiff's bases of 1 with thioglycolic acid, thiomalic acid or acetic anhydride afforded novel heterocyclic derivatives 4-thiazolidinones (7a-c), 5-carboxymethyl-4-thiazolidinones (8a-c) and oxadiazoles (9a-c), respectively. Some of the com...
Molecules (Basel, Switzerland), 2016
Coumarins are naturally occurring oxygen heterocyclic compounds having multifarious medicinal properties, hence used as lead compounds for designing new potent analogs. The chromene butenoic acid 3 and the benzochromene butenoic acid 4 which are derived from the reaction of glyoxalic acid with 3-acetylcoumarin and 3-acetylbenzocoumarin, respectively, were reacted with different nitrogen and carbon nucleophiles to give new heterocyclic compounds. The structures of the prepared compounds were elucidated by IR, ¹H-NMR, and mass spectroscopy. Some of the newly prepared compounds were tested in vitro against a panel of four human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, human prostate cancer PC3, and mammary gland breast MCF-7. Also they were tested as antioxidants. Almost all of the tested compounds showed satisfactory activity.
2018
Coumarin-chalcone hybrids 3a and 3b were utilized as versatile precursor for the synthesis of coumarinyl-pyridine and coumarinyl-pyrimidine hybrids. The reaction of chalcones 3 with malononitrile or ethyl cyanoacetate proceeded in hot glacial acetic acid and ammonium acetate to afford the coumarinyl 2-aminonicotinonitriles 4 and coumarinyl 2-hydroxynicotinonitriles derivatives 5, respectively. Heating of chalcone derivatives 3 with thiourea in refluxing sodium ethoxide furnished the corresponding coumarinyl-pyrimidines 6. Condensation of coumarinyl-acetohydrazide scaffold 7 various aromatic aldehydes afforded the corresponding acrylohydrazides 8 which underwent heterocyclization with malononitrile furnished the coumarinylpyridinone derivatives 9. The constructed coumarin scaffolds were evaluated in vitro for their anticancer activity via the standard MTT method versus Hepatocellular Carcinoma (HepG2) and breast cancer (MCF-7).
PLOS ONE
Despite substantial research on cancer therapeutics, systemic toxicity and drug-resistance limits the clinical application of many drugs like cisplatin. Therefore, new chemotherapeutic strategies against different malignancies are needed. Targeted cancer therapy is a new paradigm for cancer therapeutics which targets pathways or chemical entities specific to cancer cells than normal ones. Unlike normal cells, cancer cells contain elevated copper which plays an integral role in angiogenesis. Copper is an important metal ion associated with chromatin DNA, particularly with guanine. Thus, targeting copper via copper-specific chelators in cancer cells can serve as an effective anticancer strategy. New pharmacophore di(2picolyl)amine (DPA)-3(bromoacetyl) coumarin (ligand-L) was synthesized and characterized by IR, ESI-MS, 1 Hand 13 C-NMR. Binding ability of ligand-L to DNA/Cu(II) was evaluated using a plethora of biophysical techniques which revealed ligand-L-DNA and ligand-L-Cu(II) interaction. Competitive displacement assay and docking confirmed non-intercalative binding mode of ligand-L with ctDNA. Cyclic voltammetry confirmed ligand-L causes quasi reversible Cu(II)/Cu(I) conversion. Further, acute toxicity studies revealed no toxic effects of ligand-L on mice. To evaluate the chemotherapeutic potential and anticancer mechanism of ligand-L, DNA damage via pBR322 cleavage assay and reactive oxygen species (ROS) generation were studied. Results demonstrate that ligand-L causes DNA cleavage involving ROS generation in the presence of Cu(II). In conclusion, ligand-L causes redox cycling of Cu(II) to generate ROS which leads to oxidative DNA damage and pro-oxidant cancer cell death. These findings will establish ligand-L as a lead molecule to synthesize new molecules with better copper chelating and pro-oxidant properties against different malignancies.
Synthesis and Evaluation of New Coumarins as Antitumor and Antioxidant Applicants
Journal of Medicinal and Chemical Sciences, 2022
This work involves the synthesis of eight novel fused coumarin compounds, which were confirmed by various spectrophotometers and then, assessed for their apoptotic-inducing and free radical-quenching activities. The pharmacokinetic parameters were evaluated in silico using pre-ADMET, a free online program. The apoptotic-inducing activity was tested against six tumorigenic cell lines. Also, their safety against normal cells was examined. The free radical-quenching activity was assessed by checking these compounds' ability to eliminate DDPT and hydroxyl moieties. Pharmacokinetic investigations showed that the synthesized fused coumarin compounds have excellent penetration across the GIT mucosa and most of them have poor penetration across the blood-brain barrier. These findings suggest good oral bioavailability along with low neurological toxicity profiles. The evaluation of the apoptotic-inducing activity revealed that all of the compounds have weaker activity as compared to the reference. Among these compounds, SA4 was the most potent one. Nevertheless, all of these new compounds had an excellent safety profile against normal cells. On the other hand, the assessment of the free radical-quenching activity of these synthesized compounds also indicated that all of them were less active than the reference. In this field, SA0 was the strongest free radical-quenching compound. From these realizations, along with the apparent safety and good pharmacokinetic characteristics in accordance with the in silico study, compounds SA4 and SA0 are considered the most promising agents. The authors hope that these new fused coumarin compounds can be utilized in the coming years for the production of new powerful drugs with apoptoticinducing and free radical-quenching potentials which can help in the battle against many diseases.
Design, synthesis and discovery potent of novel anticancer agents based on the coumarin scaffold
2015
Several effective anticancer therapeutic drugs containing coumarin nucleus targeting carbonic anhydrase enzyme. Thus, some coumarin derivatives 1-22 were prepared. The structures of these compounds established on the basis of IR, 1 HNMR, 13 CNMR and MS data. Moreover, the optimization geometries for compounds 1-22 were discussed using DFT theory with B3LYP\6-311G base set. The molecular docking simulations into the active site of COX-2 were performed, and showed that, some compounds (7,8, 11,13,19b and 20) suitable inhibitor against CAII, and can used as anti-cancer drugs. These compounds (7,8, 11,13,19b and 20) were evaluated against Ehrlich solid carcinoma (EAC) tumor model in Swiss albino mice on dose 50µg. The activity was assessed using survival time and average increase in body weight, which showed that, administration of derivatives (7,8, 11,13,19b and 20) were effective in reducing solid tumor mass EAC cells. In silico, The ADMET profiles showed that, these compounds are goo...
Synthesis and biological evaluation of coumarin-quinone hybrids as multifunctional bioactive agents
ADMET and DMPK
We report the synthesis, structural characterization and pharmaceutical activity of four coumarin-quinone hybrids. The compounds were significantly active against Staphylococcus aureus, Pseudomonas aeoginosa and Candida albicans. Promising antioxidant activity was observed when compared to ascorbic acid. Two compounds, DTBSB and DTBSN, also showed commendable in vitro antiproliferative activities against the cells of human cancer cell lines MCF-7, MDA-MB-231, COLO-205, HT-29 and A549 along with appreciable tumor selectivity with distinct selectivity index. Molecular docking studies using cyclooxygenase-2 (PDB ID: 6COX) revealed strong binding affinities for the COX-2 active site. Moreover, ADMET properties of the synthesized compounds were determined using the pKCSM and SwissADME online tools and all the compounds had accurate pharmacokinetic profiles. Hence, the new coumarin-quinone hybrids DTBSB and DTBSN can be considered for optimization and lead development.
Synthesis and in vitro evaluation of novel coumarin–chalcone hybrids as potential anticancer agents
Bioorganic & Medicinal Chemistry Letters, 2010
A series of coumarin-chalcone hybrids have been synthesized and evaluated for their in vitro cytotoxicity against a panel of four human cancer cell lines and normal fibroblasts (NIH3T3). Among 21 compounds screened, three compounds (23, 25 & 26) showed IC 50 range in between 3.59 to 17.97 µM. The most promising compound 26 showed around 30 fold more selectivity towards C33A (cervical carcinoma) cells over normal fibroblast NIH3T3 cells with an IC 50 value of 3.59 µM.
Molecules
A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a–4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 μM). In the DCF-DA assay, the 4′-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3′-fluoro-substituted coumarins 3e ...