The Synthesis And Bioactivities Evaluation Of Derivatives And Prodrugs Of Acacetin

Acacetin is a kind of natural flavone containing in many vascular plants as a pharmaceutical active constituents.Many efforts have been taken in recent years to investigate the bioactivities of acacetin,and many novel potent bioactivities have been found.Acacetin can suppress ultrarapid delayed rectifier K+ current and other cardiac ionic currents,preventing atrial fibrillation in an atrium-selective way.And acacetin can inhibit the xanthine oxidase,which is beneficial to hyperuricemia.Acacetin also shows better spasmolytic and antinociceptive activities than a nonsteroidal anti-inflammatory reference drug diclofenac.However,appropriate chemical modification and prodrug designation are needed to improve its druggability,which is because of its poor water-solubility and low bioavailability.Thus,acacetin can be a lead compound of nature sources.The 4'-OCH3 may be special to the activity of acacetin,which is different from the 4'-OH in apigenin.Therefore,pharmacophore and hydrophilic groups were introduced to enhance the special activities and to improve the water-solubility and bioavailability of acacetin,remaining its special structure of 4'-OCH3 the same.To improve its analgesic effects,pharmacophore(carboxyl groups)and nitrogen-containing groups were induced in 5-OH or 7-OH with a ether linkage,which could also improve the water-solubility after salifycation of carboxyl groups and basic groups.Prodrugs were also formed by ester or carbamate linkage between natural amino acids and acacetin to improve the water-solubility,benefiting from the high hydrophilicity of amino acids.12 acacetin derivatives and 8 prodrugs were designed and synthetized in total,which were identified by 1H-NMR and ESI-MS.And bioactivities of the 20 compounds were evaluated,such as analgesic effect,inhibition of xanthine oxidase and ?-glucosidase,stability in water-solution.Then the structure-activity relationship was discussed.Water-solubility experiment indicated that the water-solubility of carboxyl and nitrogen-containing derivatives and prodrugs was significantly improved,some of which were 5000 times higher than acacetin(beyond 50 mg·mL-1).Stability experiment showed that carboxyl derivatives were stable under pH=7.4 phosphate buffer,however,amino acid prodrugs hydrolyzed to acacetin soon.Every acacetin derivatives had a certain analgesic response in the writhing test in mice(i.p.and p.o.),especially 6 compounds produced an improved analgesic response(i.p.),such as ZBH-ZYY-05,ZBH-ZYY-06,ZBH-ZYY-07,ZBH-ZYY-08,ZBH-ZYY-10 and ZBH-ZYY-11,and the analgesic response of ZBH-ZYY-10 and ZBH-ZYY-11(p.o.)was no less than acacetin.Derivatives showed decreased inhibitory activity in xanthine oxidase inhibitory assay,and the longer the carbon chain of the carboxyl derivatives is,the less inhibitory activity they were.And a-glucosidase experiment showed that all of the derivatives produced a less activity inhibiting a-glucosidase than acacetin.The preliminary SAR indicated that modification in 5-OH or 5,7-OH of acacetin could significantly influence its bioactivities,for instance,improving analgesic response but decreasing inhibition of xanthine oxidase.Especially,disubstituted carboxyl derivatives and nitrogen-containing derivatives notably improved the analgesic response,accompanying with almost no inhibitory activity of xanthine oxidase.Therefore,modification of special sites in acacetin can increase the selectivity of its bioactivities,proving the rationality of this designation.