Synthesis of DPIE [2-(1,2-Diphenyl-1 H -indol-3-yl)ethanamine] Derivatives and Their Regulatory Effects on Pro-Inflammatory Cytokine Production in IL-1β-Stimulated Primary Human Oral Cells

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 3; p. 899
• Main Authors: Lim, Jeongah, Seong, Jihyoun, Jung, Seunggon, Lee, Tae-Hoon, Kim, Eunae, Lee, Sunwoo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.01.2022; MDPI
• Subjects: Affinity; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Autoimmune diseases; Bacterial infections; Binding; Binding sites; Cells, Cultured; Communication; Cytokines; Cytokines - agonists; Cytokines - antagonists & inhibitors; Cytokines - metabolism; Cytotoxicity; DPIE derivative; Drugs; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene expression; Humans; IL-1; IL-1R1; IL-1β; Indoles - chemistry; Indoles - pharmacology; Infections; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation Mediators - agonists; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Interleukin 1; Interleukin 1 receptors; Interleukin 6; Interleukin 8; Interleukin-1beta - agonists; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - metabolism; Ligands; Phenethylamines - chemistry; Phenethylamines - pharmacology; pro-inflammatory cytokine; Proteins; Stimulation; IL-1R1; pro-inflammatory cytokine; IL-1; DPIE derivative
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27030899

Interleukin-1 beta (IL-1β) has diverse physiological functions and plays important roles in health and disease. In this report, we focus on its function in the production of pro-inflammatory cytokines, including IL-6 and IL-8, which are implicated in several autoimmune diseases and host defense against infection. IL-1β activity is markedly dependent on the binding affinity toward IL-1 receptors (IL-1Rs). Several studies have been conducted to identify suitable small molecules that can modulate the interactions between 1L-1β and 1L-1R1. Based on our previous report, where DPIE [2-(1,2-Diphenyl-1 -indol-3-yl)ethanamine] exhibited such modulatory activity, three types of DPIE derivatives were synthesized by introducing various substituents at the 1, 2, and 3 positions of the indole group in DPIE. To predict a possible binding pose in complex with IL-1R1, a docking simulation was performed. The effect of the chemicals was determined in human gingival fibroblasts (GFs) following IL-1β induction. The DPIE derivatives affected different aspects of cytokine production. Further, a group of the derivatives enabled synergistic pro-inflammatory cytokine production, while another group caused diminished cytokine production compared to DPIE stimulation. Some groups displayed no significant difference after stimulation. These findings indicate that the modification of the indole site could modulate IL-1β:IL1R1 binding affinity to reduce or enhance pro-inflammatory cytokine production.