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Design, Synthesis, and Antiproliferative Evaluation of Novel Coumarin/2-Cyanoacryloyl Hybrids as Apoptosis Inducing Agents by Activation of Caspase-Dependent Pathway.

ABSTRACT: A series of novel coumarin/2-cyanoacryloyl hybrids were prepared and evaluated for their in vitro anticancer activity. Among them, two analogs 5p and 5q showed promising antiproliferative activity against a panel of cancer cell lines, including A549, H157, HepG2, MCF7, MG63, and U2OS. Particularly, 5q showed the most potent activity towards MG63 cells with an IC₅₀ value of 5.06 ± 0.25 ?M. Morphological observation and 4,6-diamidino-2-phenylindole (DAPI) staining assay showed that 5q-treated MG63 cells displayed significant apoptosis characteristics. Moreover, flow cytometric detection of phosphatidylserine externalization revealed that 5q induced MG63 apoptosis in a dose-dependent manner. Real-time PCR and western blot assay further confirmed that 5q had strong effects to induce MG63 cell apoptosis, suggesting that the action was associated with down-regulation of the anti-apoptotic protein Bcl-2, upregulation of pro-apoptotic protein Bax, and induced activation of caspase-3, 8, and 9. The present results provide a new chemotype for anticancer drug development and continuing investigation into candidates with coumarin/2-cyanoacryloyl scaffold is warranted.

SUBMITTER: Zhang YY

PROVIDER: S-EPMC6222758 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Antiproliferative Evaluation of Novel Coumarin/2-Cyanoacryloyl Hybrids as Apoptosis Inducing Agents by Activation of Caspase-Dependent Pathway.

Zhang Yu-Ying YY Zhang Qian-Qian QQ Song Jia-Li JL Zhang Liang L Jiang Cheng-Shi CS Zhang Hua H

Molecules (Basel, Switzerland) 20180807 8

A series of novel coumarin/2-cyanoacryloyl hybrids were prepared and evaluated for their in vitro anticancer activity. Among them, two analogs 5p and 5q showed promising antiproliferative activity against a panel of cancer cell lines, including A549, H157, HepG2, MCF7, MG63, and U2OS. Particularly, 5q showed the most potent activity towards MG63 cells with an IC50 value of 5.06 ± 0.25 μM. Morphological observation and 4,6-diamidino-2-phenylindole (DAPI) staining a ...[more]

PMID: 30087276

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Project description:BackgroundNitrogen heterocyclic rings and sulfonamides have attracted attention of several researchers.ResultsA series of regioselective imidazole-based mono- and bis-1,4-disubstituted-1,2,3-triazole-sulfonamide conjugates 4a-f and 6a-f were designed and synthesized. The first step in the synthesis was a regioselective propargylation in the presence of the appropriate basic catalyst (Et3N and/or K2CO3) to afford the corresponding mono-2 and bis-propargylated imidazoles 5. Second, the ligation of the terminal C≡C bond of mono-2 and/or bis alkynes 5 to the azide building blocks of sulfa drugs 3a-f using optimized conditions for a Huisgen copper (I)-catalysed 1,3-dipolar cycloaddition reaction yielded targeted 1,2,3-triazole hybrids 4a-f and 6a-f. The newly synthesized compounds were screened for their in vitro antimicrobial and antiproliferative activities. Among the synthesized compounds, compound 6a emerged as the most potent antimicrobial agent with MIC values ranging between 32 and 64 µg/mL. All synthesized molecules were evaluated against three aggressive human cancer cell lines, PC-3, HepG2, and HEK293, and revealed sufficient antiproliferative activities with IC50 values in the micromolar range (55-106 μM). Furthermore, we conducted a receptor-based electrostatic analysis of their electronic, steric and hydrophobic properties, and the results were in good agreement with the experimental results. In silico ADMET prediction studies also supported the experimental biological results and indicated that all compounds are nonmutagenic and noncarcinogenic.ConclusionIn summary, we have successfully synthesized novel targeted benzimidazole-1,2,3-triazole-sulfonamide hybrids through 1,3-dipolar cycloaddition reactions between the mono- or bis-alkynes based on imidazole and the appropriate sulfonamide azide under the optimized Cu(I) click conditions. The structures of newly synthesized sulfonamide hybrids were confirmed by means of spectroscopic analysis. All newly synthesized compounds were evaluated for their antimicrobial and antiproliferative activities. Our results showed that the benzimidazole-1,2,3-triazole-sulfonamide hybrids inhibited microbial and fungal strains within MIC values from 32 to 64 μg/mL. The antiproliferative evaluation of the synthesized compounds showed sufficient antiproliferative activities with IC50 values in the micromolar range (55-106 μM). In conclusion, compound 6a has remarkable antimicrobial activity. Pharmacophore elucidation of the compounds was performed based on in silico ADMET evaluation of the tested compounds. Screening results of drug-likeness rules showed that all compounds follow the accepted rules, meet the criteria of drug-likeness and follow Lipinski's rule of five. In addition, the toxicity results showed that all compounds are nonmutagenic and noncarcinogenic.

Dataset Information

Design, Synthesis, and Antiproliferative Evaluation of Novel Coumarin/2-Cyanoacryloyl Hybrids as Apoptosis Inducing Agents by Activation of Caspase-Dependent Pathway.

Publications

Design, Synthesis, and Antiproliferative Evaluation of Novel Coumarin/2-Cyanoacryloyl Hybrids as Apoptosis Inducing Agents by Activation of Caspase-Dependent Pathway.

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