Studies On The Antitumor Constituents From The Fruits Of Euodia Ruteacarpa And Synthesis Of Evodiamine Derivatives

Euodia rutaecarpa(Juss.)Benth.,a plant belonging to the family of Rutaceae,is a small tree and its dried and nearly ripe fruits are used as a traditional Chinese medicine.It has been used for treatment of headache accompanied by retching and cold limbs,abdominal colic,dysmenorrhea,diarrhea occurring before dawn daily,and hyperbaropathy.Pharmacological studies showed that Euodia rutaecarpa exhibited promising anti-inflammatory,antibacterial,antitumor and myocardial protection activities.By means of various chromatographic methods such as silica gel,Sephadex LH-20,opening ODS column chromatography,and semi-preparative HPLC,61 compounds were isolated from the 75%ethanol extract of the fruits of Euodia rutaecarpa.Their structures were elucidated on the basis of spectroscopic data and physico-chemical methods.The compounds were comprised by 37 alkaloids,7 limonins and 7 flavonoids,5 phenylpropanoids,5 others,and identified as 1-methyl-2-[6-carbonyl-(E)-4-undecenyl]-4(1H)-quinolone(1),1-methy l-2-[6-carbonyl-(E)-7-tridecenyl]-4(1H)-quinolone(2),1-methyl-2-(15-hydroxyl-pentadecenyl)-4(1H)-quinolone(3),1-methyl-2-(13-hydroxyl-tridecenyl)-4(1H)-quinolone(4),1-methyl-2-[(Z)-5-undecenyl]-4(1H)-quinolone(5),1-methyl-2-[(Z)-6-undecenyl]-4(1H)-quinolone,(6)1-methyl-2-[(Z)-7-tridecenyl]-4(1H)-quinolone(7),evocarpine(8),1-methyl-2-[7-carbonyl-(E)-8-tridecenyl]-4(1H)-quinolone(9),euocarpine D(10),1-methyl-2-[(4Z,72)-4,7-tridecadienyl]-4(1H)-quinolone(11),1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone(12),1-methyl-2-octyl-4(1H)-quinolone(13),1-methyl-2-nonyl-4(1H)-quinolone(14),1-methyl-2-decyl-4(1H)-quinolone(15),1-methyl-2-undecyl-4(1H)-quinolone(16),dihydroevocarpine(17),1-methyl-2-pentadecyl-4(1H)-quinolone(18),evodiamine(19),13b-hydroxymethylevodiamine(20),wuzhuyurutine C(21),wuzhuyurutine D(22),wuzhuyurutine B(23),bouchardatine(24),rutaecarpine(25),1-hydroxyrutaecarpine(26),3-hydroxyrutaecarpine(27),7?-hydroxyrutaecarpine(28),hortiacine(29),7,8-dehydrorutaecarpine(30),dehydroevodiamine(31),goshuyuamide-?(32),goshuyuamide-?(33),N-(2-methylaminobenzoyl)tryptamine(34),evodiamide(35),wuchuyuamide-?(36),1,2,3,4-tetrahydro-1-oxo-?-carboline(37),limonin(38),6?-acetoxy-5-epilimonin(39),rutaevine(40),rutaevine acetate(41),evodol(42),jangomolide(43),shihulinmonin A(44),tricin 7-O-?-D-glucopyranoside(45),epimedoside C(46),phellodensin F(47),isorhamnetin-3-O-?-D-galactoside(48),quercetin(49),catechin(50),cinchonain(51),sinapyl alcohol 9-O-feruloyl-4-O-?-D-glucopyanoside(52),3-O-feruloylquinic acid methyl ester(53),caffeic acid(54),ferulic acid(55),p-hydroxycinnamic acid(56),4-methoxyphenyl-methanol(57),3,4-dihydroxy-benzoic acid(58),salsoline A(59),1?,4?-dihydroxyeudesman-11-ene(60),7-hydroxy coumarin(61),respectively.Among them,compounds 1-4,20-22,and 52 were new,and compounds 45,47,50,51,53,54,and 56-60 were obtained from Euodia rutaecarpa for the first time.The cytotoxic activities of all the isolated alkaloids were tested against the human leukaemic HL-60 and human prostate cancer PC-3 cell lines.Evodiamine(19)displayed the strongest activity against the two cell lines,with IC50 values of 0.51 and 14.35,?M,which was more cytotoxic than 5-Fu.In the quinolone alkaloids,compounds 4,8 and 17 exhibited significant activities against HL-60,with IC50 values of 12.07,10.44 and 16.02 ?M,respectively.By the conjugation strategy for NO donor,a series of novel NO-donating evodiamine derivatives were designed and synthesized by changing the substitution on N13.The inhibitory activities of synthesized analogues against Bel-7402,A549,BGC-823 and L-O2 cell lines in vitro were tested by the standard MTT assay.The results showed that the inhibition rates of tested compounds were bigger than 50%at concentration of 10 ?M.In addition,the derivatives were tested for NO-releasing activity in vitro.The results suggested that all compounds could release high concentration NO and the amount was increased time-dependently.