Synthesis and evaluation of butein derivatives for in vitro and in vivo inflammatory response suppression in lymphedema

• DOI: 10.1016/j.ejmech.2020.112280
• Publication Date: 2020-04-06T15:10:26Z
• Authors: Kangsan Roh; Jung-hun Lee; Hee Kang; Kye Won Park; Youngju Song; Sukchan Lee; Jin-Mo Ku
• Keywords: Lipopolysaccharides; 0303 health sciences; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents; Rats; 3. Good health; Mice; 03 medical and health sciences; Chalcones; Macrophages, Peritoneal; Microsomes, Liver; Animals; Humans; Prodrugs; Lymphedema

Herein, we demonstrate that butein (1) can prevent swelling in a murine lymphedema model by suppressing tumor necrosis factor α (TNF-α) production. Butein derivatives were synthesized and evaluated to identify compounds with in vitro anti-inflammatory activity. Among them, 20 μM of compounds 7j, 7m, and 14a showed 50% suppression of TNF-α production in mouse peritoneal macrophages after lipopolysaccharide stimulation. Compound 14a, exhibited the strongest potency with an in vitro IC50 of 14.6 μM and suppressed limb volume by 70% in a murine lymphedema model. The prodrug strategy enabled a six-fold increase in kinetic solubility of compound 1 and five-fold higher levels of active metabolite in the blood for compound 14a via oral administration in the pharmacokinetics study. We suggest that the compound 14a could be developed as a potential therapeutic agent targeting anti-inflammatory activity to alleviate lymphedema progression.