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Antiproliferative activity and toxicity evaluation of 1,2,3-triazole and 4-methyl coumarin hybrids in the MCF7 breast cancer cell line.

ABSTRACT: Four coumarin-triazole hybrids were selected from our in house library and screened for cytotoxic activity on A549 (lung cancer), HepG2 (liver cancer), J774A1 (mouse sarcoma macrophage), MCF7 (breast cancer), OVACAR (ovarian cancer), RAW (murine leukaemia macrophage), and SiHa (uterus carcinoma) and their in vitro toxicity was assessed on 3T3 (healthy fibroblasts) cell lines. SwissADME pharmacokinetic prediction was performed. Effects on ROS production, mitochondrial membrane potential, apoptosis/necrosis and DNA damage were evaluated. All of the hybrids have good pharmacokinetic predictions. Each of them showed cytotoxic activity against the MCF7 breast cancer cell line, with IC₅₀ between 2.66 and 10.08 μM, lower than cisplatin (45.33 μM) for the same test. One can observe an order of reactivity from the most potent: LaSOM 186 > LaSOM 190 > LaSOM 185 > LaSOM 180, with a better selectivity index than the reference drug cisplatin and the precursor hymecromone, and caused cell death by apoptosis induction. Two compounds showed antioxidant activity in vitro and three disrupted the mitochondrial membrane potential. None of the hybrids caused genotoxic damage to healthy 3T3 cells. All hybrids showed potential for further optimization, mechanism elucidation, in vivo activity and toxicity tests.

SUBMITTER: Augsten LV

PROVIDER: S-EPMC10211326 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Antiproliferative activity and toxicity evaluation of 1,2,3-triazole and 4-methyl coumarin hybrids in the MCF7 breast cancer cell line.

Augsten Lucas Volnei LV Göethel Gabriela G Gauer Bruna B Feiffer Charão Mariele M von Poser Gilsane G Canto Romulo F S RFS Arbo Marcelo Dutra MD Eifler-Lima Vera Lucia VL Garcia Solange Cristina SC

RSC medicinal chemistry 20230302 5

Four coumarin-triazole hybrids were selected from our in house library and screened for cytotoxic activity on A549 (lung cancer), HepG2 (liver cancer), J774A1 (mouse sarcoma macrophage), MCF7 (breast cancer), OVACAR (ovarian cancer), RAW (murine leukaemia macrophage), and SiHa (uterus carcinoma) and their <i>in vitro</i> toxicity was assessed on 3T3 (healthy fibroblasts) cell lines. SwissADME pharmacokinetic prediction was performed. Effects on ROS production, mitochondrial membrane potential, a ...[more]

PMID: 37252094

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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

Antiproliferative activity and toxicity evaluation of 1,2,3-triazole and 4-methyl coumarin hybrids in the MCF7 breast cancer cell line.

Publications

Antiproliferative activity and toxicity evaluation of 1,2,3-triazole and 4-methyl coumarin hybrids in the MCF7 breast cancer cell line.

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