Synthesis and anti-inflammatory activities of methylhesperetin-7-alkyl ether analogues

To investigate the relationship between the structures of methylhesperetin-7-alkyl ether analogues and their anti-inflammatory activities, nine new compounds, methyl-hesperetin (2), methylhesperetin-7-ethyl ether (3), 7-n-butyl ether (4), 7-n-hexyl ether (5), 7-n-octyl ether (6), 7-n-decyl ether (7), 7-n-dodecyl ether (8), 7-n- tetradecyl ether (9) and 7-n-hexadecyl ether (10), were synthesized with the lead compound of methylhesperidin (1).  Their structures were confirmed by UV, ¹H NMR, MS and HR-MS spectral data.  The in vivo anti-inflammatory activities of these compounds were tested on mouse paw edema induced by Freund’s complete adjuvant (FCA) and mouse capillary permeability induced by acetic acid with po dose of 300 mg·kg⁻¹·d⁻¹.  The result indicated that the anti-inflammatory activities of the synthetic compounds increased firstly and then decreased with the elongating of the length of alkyl chain.  After 25-day oral administration of compounds 6, 7 and 8, the inhibitory rates on mouse paw edema of adjuvant arthritis (AA) were 31.9%, 38.5%, 39.1%, respectively.  They showed the concentrations of COX-2 in serum of AA mice respectively were 79.3, 75.4, 73.9 ng·L⁻¹ and the concentrations of PGE₂ were in correspondence with 275.4, 258.9, 242.6 ng·L⁻¹.  The inhibitory rates of compounds 6 and 7 on mouse capillary permeability induced by acetic acid were, respectively, 42.4% and 41.5% after 5-day oral administration.  Compared with the lead compound of methylhesperidin, the anti-inflammatory activities of compounds 6, 7 and 8 were increased and showed an effective inhibition on the symptom of adjuvant arthritis and capillary permeability in mice.