Fluorinated Benzofuran and Dihydrobenzofuran as Anti-Inflammatory and Potential Anticancer Agents.
Abeer J AyoubGhewa A El-AchkarSandra E GhayadLayal HarissRazan H HaidarLeen M AntarZahraa I MallahBassam BadranRené GréeAli HachemEva HamadeAida HabibPublished in: International journal of molecular sciences (2023)
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 IC 50 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 E 2 . 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.
Keyphrases
- oxidative stress
- nitric oxide synthase
- anti inflammatory
- nitric oxide
- structure activity relationship
- signaling pathway
- diabetic rats
- poor prognosis
- dna damage
- binding protein
- endothelial cells
- papillary thyroid
- emergency department
- cell cycle arrest
- cancer therapy
- squamous cell carcinoma
- drug induced
- bone marrow
- inflammatory response
- endoplasmic reticulum stress
- mass spectrometry
- long non coding rna
- transcription factor
- high resolution
- protein protein
- small molecule
- climate change
- radiation therapy
- stress induced
- mesenchymal stem cells
- risk assessment
- circulating tumor
- toll like receptor
- human health
- high speed
- induced pluripotent stem cells
- combination therapy
- pet imaging