Targeted Isolation And In Vivo Metabolism Of Sesquatrone Sesquiterpene Lactone Analogues

Ixeris sonchifolia Hancewhich belongs to the plant family Compositae, named Kudiezi or mantianxing,is a bitter, perennial herb distributed and cultivated widely in northeastern areas of China. It has been used as a food and folk medicine in invigorating circulation of blood, anti-inflammatory activities, dissipating blood stasis to relieve pain blood stasis, and so on. The major chemical compounds of this plant are phenolic acids, flavonoids, sesquiterpene lactones,and so on.To best understanding the mechanism of action and to promote their availability as well, it is important to study the metabolism of major sesquiterpene lactone in vivo. The main research contents and results were summarized as follows:Part one, reviewThis paper reviewed the chemical constituents and pharmacologic action of Ixeris sonchifolia Hance and 91 references were given. Also we summed up 58 references on metabonomics and metabolite identification by liquid chromatography-mass spectrometry.Part two, target isolation of sesquiterpene lactonesFirstly, we summed up the characteristic feature including UV and MS of sesquiterpene lactone. Secondly, we found the target compound by the the characteristic feature using LC-MS. Finally,23 coupounds (17 were identification) were isolation from Ixeris sonchifolia Hance, in which 3 were new compounds. Also, An HPLC method for the determination of the purities of sesquiterpene lactones separated by HSCCC was established at first.Part three, metabolites of sesquiterpene lactonesThis study is the first to investigate the in vivo metabolism of Ixerin Z (11,13a-dihydroixerin Z) follow-ing intravenously administered of Ixerin Z by HPLC-LTQ-Orbitrap mass spectrometry and multiple massdefect filters (MMDF) technique. A total of 41 (40) metabolites as well as parent drug after using two MMDFfilter templates were unambiguously or tentatively identified based on accurate mass measurements,fragmentation patterns, and chromatographic retention times. Also,12 (21),5 (5),5 (4),8 (10),10 (6),8 (3),10 (9),0 (0) were found in urine, fece, heart, liver, spleem, lung, kindey and brain,respectively.The metabolic pathways of Ixerin Z (11,13 a-dihydroixerin Z) werealso proposed for the first time. The results demonstrated that Ixerin Z underwent extensive metabolicreaction including hydrogenation, hydroxylation, hydrolysis, methylation, cysteine conjugation, glutathione (GSH) conjugation, sulfate conjugation, N-acetylcysteine conjugation, and glucuronidation.Also,18 and 4 metabolites were detected in urine and feceafter intravenously administered of Kudiezi Injection.Part four, metabonomic of sesquiterpene lactonesTo explore the protection mechanism in anti-ischemic cerebral reperfusion damage by the disturbances of endogenous in rats after durgs adminsistrated. The potential biomarkers were chosen based on VIP>1 and p<0.05 by OPLS-DA. Finally 23 metabolites (15 were identification) in plasm,21 metabolites (14 were identification) in hydrophilic partof brain, and 23 metabolites (18 were identification) in lipophilic part of brain were chosen as potential biomarkers. MetPA was used to find the possible metabolic pathways.