Fluorinated Benzofuran and Dihydrobenzofuran as Anti-Inflammatory and Potential Anticancer Agents
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Multidisciplinary Digital Publishing Institute (MDPI)
Abstract
Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC50 values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E2. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure–activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments. © 2023 by the authors.
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Benzofuran, Cyclooxygenase-2, Hct116 cells, Inflammation, Macrophage, Prostaglandin e2, Acetylsalicylic acid, Antiinflammatory agent, Antineoplastic agent, Arachidonic acid, Benzofuran derivative, Biological marker, Bromine, Carboxyl group, Colony stimulating factor 1, Cxcl2 chemokine, Cyclooxygenase 1 inhibitor, Cyclooxygenase 2, Cyclooxygenase 2 inhibitor, Dihydrobenzofuran derivative, Ester, Fluorinated benzofuran, Fluorine, Hydroxyl group, Ibuprofen, Inducible nitric oxide synthase, Interleukin 1alpha, Interleukin 1beta, Interleukin 6, Lipopolysaccharide, Messenger rna, Mitogen activated protein kinase, Monocyte chemotactic protein 1, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1, Nitric oxide, Prostaglandin e2, Protein bcl 2, Protein kinase b, Unclassified drug, Zymosan, Air pouch, Akt signaling, Animal cell, Animal experiment, Animal model, Animal tissue, Antiinflammatory activity, Antineoplastic activity, Antiproliferative activity, Apoptosis, Apoptotic cell percentage, Article, Biological activity, Bone marrow derived macrophage, Carcinogenesis, Cell proliferation, Dna cleavage, Dna fragmentation, Drug bioavailability, Drug design, Drug synthesis, Enzyme immunoassay, Enzyme linked immunosorbent assay, Female, Flow cytometry, Fluorination, Gene expression, Hct 116 cell line, Hek293 cell line, Human, Human cell, Ic50, In vitro study, Male, Mapk signaling, Molecular model, Monocyte, Mouse, Mrna expression level, Neutrophil, Nonhuman, Nuclear magnetic resonance, Permeability, Protein expression, Reverse transcription polymerase chain reaction, Saponification, Structure activity relation, Synovium, Thp-1 cell line, Toxicity assay, Tumor growth, Tumor microenvironment, Tunel assay, Wst-1 assay