| Eucommia ulmoides Oliver is one of the oldest known and used precious tonic herbs in China.Traditionally,the medicinal part of E.ulmoides is its bark.However,the bark of E.ulmoides is a rare crude drug owing to its slow growth speed.Leaves of E.ulmoides are abundant in resources,which have been recorded in the Pharmacopoeia of the People's Republic of China(2005).Leaves of E.ulmoides is proved to possess great therapeutic effect on improving the tone of the liver and kidney,reinforcing muscle and lung,increasing longevity,and anti-tumors.Particularly,it has been reported to possess anti-hypertensive property in vitro and in vivo.However,most of the anti-hypertensive experiments focused on the extract of leaves of E.ulmoides.The main active ingredients of lowering blood pressure have not been clarified to date.In this thesis,the systematic investigation on the chemical constituents of leaves of E.ulmoides was carried out and 170 constituents were isolated.On the basis of chemical evidences and spectral analyses([?],UV,CD,IR,MS,1D-NM.2D-NMR),their structures were elucidated as:eucomegastigsides A(1),eucomegastigsides B(2),eucomegastigsides C(3),eucomegastigsides D(4).eucomegastigsides E(5),eucomegastigsides F(6),eucomegastigsides G(7).eucomegastigsides H(8),eucomegastigmane A(9).eucomegastigmane B(10).eucomegastigmane C(11),eucomegastigmane D(12).(6S,9S)-blumenol C(13),(6R,9R)-blumenol C(14).(6S,9R)-blumenol C(15),(6R,9S)-blumenol C(16),eucomegastigmane E(17),eucomegastigmane F(18),eucomegastigmane G(19),(7S,8S)-alatusol D(20),(7R,8R)-alatusol D(21),(7S,8R)-alatusol D(22),(7R,8S)-alatusol D(23),eucophenolic A(24).eucophenolic B(25),eucophenolic C(26),eucophenolic D(27),erythro-syringylglycerol-8-O-4'-(sinapaldehyde)ether(28),eucophenolic G(29),threo-guaiacylglycerol-?-O-4-guaiacyl aldehyde ether(30),erythro-guaiacylglycerol-?-O-4-guaiacyl aldehyde ether(31),eucophenolic F(32),eucophenolic E(33),dihydroxyl-pedicularis-lactone(34),hematinic acid n-butyl ester(35),dihydro-hematinic acid n-butyl ester A(36),dihydro-hematinic acid n-butyl ester B(37),eucotriterpene A(38),eucotriterpene B(39),2a-(trans-p-coumaroyloxy)-3?,24-dihydroxyurs-12-en-28-oic acid(40),2?-(cis-p-coumaroyloxy)-3?,24-dihydroxyurs-12-en-28-oic acid(41),stigmast-4-en-3-one(42),(6R,7E,9R)-9-hydroxy4,7-megastigmadien-3-one-9-O-[?-L-arabinopyranosyl-(1?6)-?-D-glucopyranoside](43),foliasalacioside B1(44),eleganoside A(45),(6R,9R)-9,10-dihydroxy-4,6megastigmadien-3-one-9-O-[?-D-glucopyranosvl-(1?6)-?-D-glucopyranoside](46),citroside A(47),(6S,9S)-blumenol B(48),(6R,9R)-blumenol B(49),(6S,9S)-vomifoliol(50),(6R,9R)-vomifoliol(51),(6S,9R)-vomifoliol(52).(6R 9S)-vomifoliol(53).(6R.9R)-3-oxo-?-ionol(54),(6S,9S)-3-oxo-?-ionol(55).(6R,9S)-3-oxo-?-ionol(56).(6S,9R)-3-oxo-?-ionol(57),(3S,5R,6R,7E,9R)-megastigman-7-ene-3,5.6.9-tetrol(58).(3S,5R,6R,7E,9S)-megastigman-7-ene-3.5.6.9-tetrol(59).(3R,5R,6R.7E)-3.5.6trihydroxy-7-megastigmen-9-one(60).(3S,5R,6S,7E)-3.5.6-trihydroxy-7-megastigmen-9-one(61),(3S,9R)-3,9-dihydroxv-megastigma-5-ene(62).(3S,9S)-3,9-dihydroxy-megastigma-5-ene(63).(3S,4R)-sonchuionol A(64).(3S,5R,6S,7E.9R)-5,6-epoxy-3.9-dihydroxy-7-megastigmene(65):19-hydroxy-7-butynyl-1,1,5-trimethvl-5-cyclohexen-3-ol(66).(S)-3-hydroxy-8-ionone(67).(6R,9S)-9.10-dihydroxy-4-megastigmen-3-one(68).cucumegastigmane I(69).(-)-phaseic acid(70).trans-(-)-phaseic(71),rel-5-(1R,5S-dimethyl-3R,4R,8S-trihvdroxy-7-oxa-6-oxobicvclo-[3.2,1]oct-8-yl)-3-methyl-2Z.4E-pentadienoic acid(72),grasshopper ketone(73).2,3-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-propan-1-one(74),2,3-dihvdroxv-1(4-hydroxyl-3,5-dimethoxyphenyl)-1-propanone(75),p-coumaric acid(76).erythro-syringoylglycerol(77).(E)-2,3-dihydroxycyclopentyl-3-(3',4'-dihydroxyphenyl)acrylate(78),methyl chlorogenate(79),(8R)-3-(4-hydroxyphenyl)lactic acid n-butyl ester(80),wilfordiol B(81),sphaerophysin A(82).dihydrodehydodiconiferyl alcohol(83).erythro-guaiacyl-glycerol-?-coniferyl aldehyde ether(84),threo-guaiacyl-glycerol-?-coniferyl aldehyde ether(85).erythro-o-guaiacylglycerol-?-O-4'-sinapyl ether(86),threo-guaiacylglycerol-?-O-4'-sinapyl ether(87).(7'S,8S,8'R)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one(88).wikstrone(89),cycloolivil(90).olivil(91).pinoresinol(92).syringaresinol(93).8-methoxy-medioresinol(94),(+)-(7R,7'R,7"S,7"'5,8S,8'S,8"S,8"'S)-4",4"'-dihydroxy-3,3',3",3"',5,5'-hexamethoxy-7,9':7'.9-diepoxv-4,8";4',8"'-bisoxv-8,8'-dineolignan-7",7"',9",9"'-tetraol(95),ficusesquilignan A(96).eucommiol(97),1-deoxyeucommiol(98),3-acetyl eucommiol(99).asperulogenin(100),pedicularis-lactone(101),n-butyl-dihydroxyl-eucommiol(102),cyclopentenol(103),hematinic acid(104),hematinic acid methyl ester(105),hematinic(106),heliolactam(107),quercetin(108),kaempferol(109),apigenin(110),2S-eriodictyol(111),naringenin(112),quercetin-3-O-?-glucopyranoside(113),quercetin-3-O-?-L-rhamnoside(114),kaempferol-3-O-?-L-rhamnoside(115),kaempferol-3-O-?-D-6'-glucopyranoside(116),kaempferol-3-O-?-D-6'-acetylglucopyranoside(117).kaempferol-3-O-?-L-arapyranoside(118),puerarin(119),daidzin(120).quercetin-3-O-?-D-glucopyranosyl-?-D-xylopyranoside(121),quercetin-3-O-?-rhamnopyranosyl(1?6)-?-glucopyranosvl-(1?3)-?-glucopyranoside(122),siebolside B(123),ulmoidol(124),ilelatifol B(125),2?,3?-dihydroxy-23-norolean-4(24).12(13)-dien-28-oic acid(126).ilekudinols A(127),ursolic acid(128),uvaol(129).euscaphic acid(130),tormentic acid(131).24-methylenecycloartanol(132).a-amyrin(133),?-amyrin(134).maslinic acid(135).asiatic acid(136).2a-hydroursolic acid(137),neoilexonol(138).betulinic acid(139),cycoartenol(140).3?.24-dihydroxy ursolic acid(141),3?-(cis-p-coumaroyloxy)-2?,23-dihydroxyurs-12-en-28-oic acid(142),3?-(trans-p-coumaroyloxy)-2?,23-dihydroxyurs-12-en-28-oic acid(143).3?-(cis-p-coumaroyloxy)-2?-hydroxy-urs-12-en-28-oic acid(144).3?)-(trans-p-coumaroyloxy)-2?-hydroxyurs-12-en-28-oic acid(145).3-O-cis-p-coumaroyl maslinic acid(146).3-O-trans-?-coumaroyl maslinic acid(147).3-O-trans-p-coumaroy loxyltormentic(148),caesalpiniaphenol D(149),p-hydroxybenzoic acid(150),3,4-dihydroxyphenacyl alcohol(151),1.2.4-benzenetriol(152).methyl gallate(153),protocatechuic acid methyl ester(154).(E)-but-2-enedioic acid monomethyl ester(155),fumaric acid(156),3-hydroxyphenylacetic acid(157),p-hydroxyphenylacetic acid methyl ester(158),n-butyl-p-hydroxybenzoate(159).chakvunglupulin A(160).icariside F2(161),succinic acid(162),2S,3S,4S-trihydroxypentanoic acid(163),2,3,4-trihydroxyl isovaleric acid(164),2-hydroxy-butandioic acid 1-methylester(165),13-hydroxy-9Z.11E.15Z-octadecatrienoic acid(166).13-hydroxy-9Z.11E,15E-octadecatrienoic acid(167).phytyl-1-hexanoate(168).trans-phytyl palmitate(169).ergosta-4.6.8(14).22-tetraen-3-one(170).Among them,thirty one compounds were new compounds;three compounds were new natural products:four compounds were first isolated by chiral resolution.The above research provides information which enrich the phytochemical constituents of the plant.The phytochemical constituents lay the material foundation for further biological activities.ACE and AT1R are the key enzymes and receptors,respectively,which regulate the renin-angiotensin system(RAS)involved in the regulation of the plasma sodium concentration and arterial blood pressure.ACE inhibitors(ACEI)and AT1R blockers(ARBs)are the first-line therapies for hypertension.In this study,docking-based virtual screening was carried out using CDOCKER protocol in BIOVIA Discovery Studio 4.5 software.All compounds were used to dock with ACE and AT1R.The results showed that flavonoids have strong intermolecular interactions with the binding site residues of ACE and AT1R.Based on the docking,53 compounds with high scores were tested for their inhibitory activities against ACE in vitro.Favonoids(108,109,110,113,114),phenylpropanoids(26,27).and megastigmanes(50,51)were found to inhibit ACE potently which has good fit with the above virtual screening experiments.These results suggested that favonoids and phenylpropanoids might be active constituents which showed anti-hypertensive activity in the leaves of E.ulmoides.Furthermore,37 phenylpropanoids were tested for their inhibitory activities against HepG2 cells through MTT assay.Compounds 27,84,85 were found to inhibit HepG2 cells production. |
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