凹脉丁公藤化学成分的研究

自凹脉丁公藤(Erycibe elllptilimba Merr.et Chun)中分得两个香豆素和三个生物碱。经鉴定分别为东莨菪素(scopoletin Ⅰ),东莨菪甙(scopolin Ⅱ),包公藤甲素(Ⅲ),包公藤丙素(Ⅳ)和一新的水溶性生物碱,结构为2β,7β-二羟基去甲茛菪烷,命名为凹脉丁公藤碱(erycibelline,Ⅴ)。包公藤丙素(Ⅳ)是首次分离得到纯品,其O-二乙酰化物(Ⅳa)具有缩瞳活性。     

苦木生物碱的化学研究

苦木(Picrasma quassioides (D.Don)Benn.)总生物碱的各种制剂在临床上证明是有效的抗菌消炎药物。为了阐明其有效成分,对其生物碱进行了研究,自其茎心的乙醇提取物通过硅胶和氧化铝柱层析以及制备性薄层层析,分离得到七个生物碱,根据光谱分析,物理化学常数的测定和衍生物的制备,其中四种鉴别为已知的生物碱:1-甲氧甲酰-β-咔巴啉(Ⅱ),4.5-二甲氧基铁屎米酮(Ⅳ),铁屎米酮(Ⅴ),4-甲氧基-5-羟基铁屎米酮(Ⅵ)。另外三种为新的天然产物,证明其结构为1-乙氧甲酰-β-咔巴啉(Ⅰ),1-甲酰-β-咔巴啉(Ⅲ)和1-乙烯基-4.8-二甲氧基-β-咔巴啉(Ⅶ)。体外抗菌实验表明碱(Ⅱ),(Ⅳ),(Ⅵ)和(Ⅶ)为有效成分。其他生物碱因量少未进行抗菌实验。     

杜衡的抗过敏成分

从马兜铃科植物杜衡(Asarum forbesii Maxin)的醋酸乙酯提取物中分得七个成分,经光谱分析和化学反应鉴定为3 S-苯甲酰氧-2S-羟基-2-异丙基丁酸甲酯(Ⅰ);2R-苯甲酰氧异戊酸甲酯(Ⅱ);2R-肉桂酰氧异戊酸甲酯(Ⅲ);2R-胡椒酰氧异戊酸甲酯(Ⅳ);榄香素(Ⅴ);反式细辛脑(Ⅵ);亚油酸(Ⅶ)。化合物Ⅰ,Ⅱ,Ⅲ和Ⅳ为新化合物,分别命名为杜衡素(asarumin)A,B,C和D。其中Ⅰ,Ⅱ,Ⅲ和Ⅶ对大鼠被动皮肤过敏具有抑制作用。     

新缩瞳剂包公藤甲素人工合成研究

包公藤甲素是从包公藤(Erycibe obtusifolia Benth.)茎中提得的一个新莨菪烷生物碱,具有强烈的缩瞳作用,临床用于治疗青光眼。本文报道用合成的6β-乙酰氧基托品酮为原料,经卤代、水解、还原和N-去甲基化等反应合成包甲素(8)。经光谱测定证实8与天然包甲素的结构完全一致。合成品系外消旋体,其作用机理与天然品相同,而强度则减半。     

手性溶液萃取分离氧氟沙星对映体

目的研究氧氟沙星对映体在手性环境中的萃取分配行为,为外消旋体膜萃取拆分提供理论和设计依据。方法以0.25 mol·L^-1 L-二苯甲酰酒石酸醇溶液为有机相,含0.14 g·L^-1氧氟沙星的0.1 mol·L^-1磷酸氢二钠/磷酸缓冲液为水相,考察了pH对氧氟沙星对映体在水-有机相分配系数(K)和分离因子(α)的影响,研究了不同碳数醇的溶剂化效应,同时运用中空纤维膜对氧氟沙星外消旋体进行初步分离。结果以癸醇为溶剂,pH 6.86时,L-二苯甲酰酒石酸对氧氟沙星外消旋体萃取分配系数大于4.7,α达1.18;用中空纤维支载液膜双有机相逆流分级萃取技术,11个22 cm长膜器串联,产品光学纯度达90%以上。结论L-二苯甲酰酒石酸在醇溶剂中对磷酸氢二钠缓冲液中的RS-氧氟沙星对映体有较强的立体选择性,其中癸醇的效果最好,pH对K和α有较大影响,综合K和α值,取pH 6.86时,手性萃取效果最佳;利用高效中空纤维膜,可使RS氧氟沙星对映体得到不同程度的分离。     

罗通定的合成

盐酸小檗碱在对甲苯磺酸作用下得到去亚甲基小檗碱盐酸盐,再经O-甲基化、还原生成消旋四氢巴马汀,最后经(+)-二对甲基苯甲酰酒石酸拆分得到罗通定,总收率约25％.     

18-甲基炔诺酮中间体的拆分

D-及L-18-甲基炔诺酮是以消旋19-去甲基13β-乙基-3β,17β-双羟基17α-乙炔基-4-雄甾烯(Ⅲ)为原料,经Ⅲ的丁二酸单醋与(+)α-甲基苯乙胺成盐,然后分离,分别水解,氧化即得D-左旋18-甲基炔诺酮(Ⅶa)和L-右旋18-甲基炔诺酮(Ⅶb)。如用(—)α-甲基苯乙胺,首先得L-构型的右旋18-甲基炔诺酮(Ⅶb),而母液中的D-左旋体未进行分离。     

长春胺中间体——1—乙基六氢吲(口朶)喹嗪的合成

本文提出了一条不以色胺为原料合成长春胺的关键中间体——高氯酸Wenkert氏烯胺的新途径。由于1-邻苯二甲酰亚胺基-4,5-辛二酮-4-苯腙(Ⅴ)的吲哚合成这一步收率很高,使这一途径成为合成1-正丙基-3,4-二氢-β-卡波林(Ⅶ)及Wenkert氏烯胺(Ⅹ)的较好方法。本文还利用红外光谱、质谱和核磁共振确定了1-邻羧基苯甲酰胺基-4,5-辛二酮-4-苯腙(Ⅳa)和1-正丙基-3,4-二氢-β-卡波林(Ⅶ)存在互变异构现象.     

毛白杨化学成分的研究

从毛白杨(Populus tomentosa Carr.)的叶中分得一个新的黄酮类化合物,鉴定为洋芹素-7-O-(6″-O-p-羟基肉桂酰)-B-D-吡喃葡萄糖甙(Ⅰ),同时还分得四个已知成分分别鉴定为水杨甙(salicin,Ⅱ)、2″-苯甲酰水杨甙(tremulodin,Ⅲ)、特里杨甙(tremulacin,Ⅳ)和胡萝卜甙(dauvasterol,Ⅴ)。     

山莨菪碱(654-2)异构体的高效液相色谱法分离

本文采用手性流动相用高效液相色谱法对山良菪碱的合成品直接进行分离。所使用的色谱柱为ODS C₁₈柱,手性流动相中的手性物质为d-樟脑磺酸或L-(+)-酒石酸二正丁酯。当在流动相中使用d-樟脑磺酸或将d-樟脑磺酸与L-(+)-酒石酸二正丁酯合用时,样品中的一对差向异构体可得到基线分离,而在流动相中加入β-环糊精对山良菪碱的差向异构体分离没有改善作用。     

Stereoisomers of N-substituted soft anticholinergics and their zwitterionic metabolite based on glycopyrrolate--syntheses and pharmacological evaluations

PURPOSE: In this study, isomers of two N-substituted soft anticholinergics based on glycopyrrolate, SGM (PcPOAGP_NA.Me) and SGE (PcPOAGP_NA.Et) [3'-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-alkoxycarbonylpyrrolidinium bromide] and their zwitterionic metabolite, SGa (PcPOAGP_NA.H) [3'-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-carboxymethylpyrrolidinium inner salt] were synthesized and their pharmacological activities were evaluated in vitro and in vivo. METHODS: The isomers of SGM and SGE were synthesized with both optically pure methyl-cyclopentylmandelate and 3-hydroxy-N-methylpyrrolidine. Trans-esterification followed by quarternization with alkyl bromoacetate gave four isomers of SGM or SGE with the nitrogen chiral center unresolved (2R3'S-SGM, 2R3'R-SGM, 2S3'S-SGM, 2S3'R-SGM or 2R3'S-SGE, 2R3'R-SGE, 2S3'S-SGE, 2S3'R-SGE). The hydrolysis of these four isomers followed by HPLC separation resulted in eight fully resolved isomers of SGa (2R3'R1'R, 2R3'S1'R, 2R3'R1'S, 2R3'S1'S, 2S3'R1'R, 2S3'S1'R, 2S3'R1'S, and 2S3'S1'S). Pharmacological activities were assessed by using in vitro receptor-binding assay and guinea pig ileum pA2-assay, and by evaluating the in vivo rabbit mydriatic effects. Results were compared to those obtained with conventional anticholinergic agents, such as glycopyrrolate, N-meythylscopolamine, and tropicamide, as well as those obtained with previously prepared racemic mixtures and 2R isomers. RESULTS: Receptor binding pKi values at cloned human muscarinic receptors (M1-M4 subtypes) were in the 6.0-9.5 range for the newly synthesized SGM and SGE isomers, and in the 5.0-8.6 range for the SGa isomers. In all cases, 2R isomers were significantly more active than 2S isomers (27 to 447 times for SGM isomers, and 6 to 4467 times for SGa isomers). Among the four SGM isomers with unresolved 1' (N) chiral center, the 3'R isomers were more active than the corresponding 3'S isomers (1.5-12.9 times), whereas, among the SGa isomers, the 3'S isomers were not always more active than the corresponding 3'R isomers indicating that activity determined based on configuration at chiral center 3' is significantly affected by the configuration of the other two chiral centers, 2 and 1'. Among the completely resolved eight SGa isomers (all three chiral centers resolved), 1'S isomers were always more active than the corresponding 1'R isomers (1.8-22.4 times). Results also indicate that some isomers showed good M3/M2 muscarinic-receptor subtype-selectivity (about 3-5 times), and 2R and 3'S were the determining configurations for this property. Guinea pig ileum assays and rabbit mydriasis tests on SGa isomers further confirmed the stereospecificity. In rabbit eyes, some 2R-SGa isomers showed mydriatic potencies similar to glycopyrrolate and exceeded tropicamide, but their mydriatic effects lasted considerably shorter, and they did not induce dilation of the pupil in the contralateral, water-treated eye. These results indicate that these compounds are locally active, but safe and have a low potential to cause systemic side effects. The pharmacological potency of the eight SGa isomers was estimated as 2R3'S1'S approximately equal to 2R3'R1'S approximately equal to 2R3'S1'R > 2R3'R1'R > 2S3'R1'S > 2S3'S1'S approximately equal to 2S3'R1'R > 2S3'S1'R (p < 0.05). CONCLUSIONS: The stereospecificity and M3/M2 muscarinic-receptor subtype-selectivity of soft anticholinergics, SGM, SGE, and SGa have been demonstrated. In agreement with previous results, the potential for their effective and safe use has been confirmed.     

Chiral separation of the enantiomers of metoprolol and its metabolites by high performance liquid chromatography

(1'R, 2R)-, (1'R, 2S)-, (1'S, 2R)- and (1'S, 2S)-alpha-hydroxymetoprolol; (2R)- and (2S)-O-desmethylmetoprolol; and (2R)- and (2S)-metoprolol acid are major metabolites of (2R)-and (2S)-metoprolol, beta-adrenergic antagonist. The focus of most chiral separation methods until now has been on determination of the enantiomeric parent drug. However, it is just as important to be able to follow the metabolism of the enantiomers and their possible chiral metabolites. Therefore, for the study of stereoselective metabolism and pharmacokinetics of metoprolol, the chiral separation of the enantiomers of metoprolol and its metabolites has been investigated using four chiral stationary phases, i.e., Chiralcel OD, Chiral-AGP, Cyclobond I and Sumichiral OA-4900 columns. Metoprolol acid was resolved only by Sumichiral OA-4900. Chiralcel OD provided the highest separation factor and resolution value for metoprolol and O-desmethylmetoprolol and partially resolved the four stereoisomers of alpha-hydroxymetoprolol. Diastereomeric alpha-hydroxymetoprolols were resolved using the coupled column chromatographic system of two chiral stationary phases, Sumichiral OA-4900 column and Chiralcel OD column.     

HPLC和1HNMR分析确定cis-A-和cis-B-羟甲芬太尼的组成和构型

羟甲芬太尼(1)是一个强效的镇痛剂和高亲和、高选择性的阿片μ受体激动剂。通过HPLC和¹HNMR分析,cis-A-l被确定为由等量的cis-(+)-(3R,4S,2'S)-l和:cis-(—)-(3S,4R,2'R)-1组成的外消旋体,cis-B-l被确定为由等量的cis-(—)-(3R,4S,2'R)-1和cis-(+)-(3S/,4R,2'S)-1组成的外消旋体。     

豹皮菌中2-Amino-3-(1,2-dicarboxyethylthio)propanoic acid非对映异构体的绝对构型

Four stereoisomers of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid were prepared by reaction of L- and D-cysteine with fumaric acid. The absolute configuration of the diastereoisomer of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid from Amanita pantherina were assigned as (2R, 1'R) and (2R, 1'S) by analysis of the optical properties. Pharmacological tests showed that all of the four stereoisomers inhibited the depolarization of NMDA on spinal motorneurones in newborn rats, The inhibition intensity of L-A,D-A and D-B were higher than that of L-B.     

Chiral DNA gyrase inhibitors. 1. Synthesis and antimicrobial activity of the enantiomers of 6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid

New quinolone antimicrobial agents (racemic, (1'S,2'R)- and (1'R,2'S)-6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)- 1, 4-dihydro-4-oxoquinoline-3-carboxylic acids) were synthesized, and their in vitro antimicrobial potencies and spectra were determined. As compared to their conceptual parents, these agents retained a considerable amount of the antimicrobial potency and spectra of ciprofloxacin and of 6-fluoro-1-phenyl-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxy lic acid against Gram-positives. Gram-negatives were considerably less sensitive. The (-)-(1'S,2'R) analogue was the more potent of the enantiomers, but the degree of chiral discrimination by most bacteria was only 4-fold. The 4-fold chiral discrimination was observed also using purified DNA gyrase obtained from Micrococcus luteus, whereas the two enantiomers were essentially equiactive against the enzyme derived from Escherichia coli. These results confirm that there is a substantial degree of bulk tolerance available at N-1 of quinolone antimicrobial agents and suggest that electronic factors controlled by substitution at that site are of considerable importance. On the other hand, chiral recognition brought about by attachment of optically active groups to the N-1 position in these derivatives is relatively small.     

三尖杉酯碱衍生物的合成及抗肿瘤活性

目的设计一条适合制备C_3′-N上不同取代的三尖杉酯碱及桥氧三尖杉酯碱的合成路线。方法以光活的中间体I(2′R，3′S)β-苯基缩水甘油酸酯为原料，经过五步反应得到保护侧链酸VI(4′S，5′R)，以2-DPC/DMAP为缩合剂与母核缩合、酸水解，再用不同的酸酐酰化，得到相应的C_3′-N取代的新酯碱。结果合成7个新酯碱化合物，药理筛选结果表明C_3′-N上取代基对抗肿瘤活性有一定影响。结论为进一步结构修饰提供了依据。     

Enantioselective and diastereoselective hydroxylation of bufuralol. Absolute configuration of the 7-(1-hydroxyethyl)-2-[1-hydroxy-2-(tert-butylamino)ethyl]benzofurans, the benzylic hydroxylation metabolites.

Asymmetric synthesis of the diastereomeric 7-(1-hydroxyethyl)-2-[1-hydroxy-2-(tert-butylamino)ethyl]benzofurans (2), the benzylic hydroxylation metabolites of bufuralol (1), is described, and the absolute configurations of these diastereomers are assigned. 1"-Oxobufuralol (3) was reduced with a complex of (2S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol and borane, yielding 2, which had a 95:5 ratio of the possible 1"R and 1"S isomers as determined by HPLC. Separation of the resulting diastereomers was facilitated by derivatization with the enantiomers of 1-phenethyl isocyanate (PEIC). The absolute configurations 1'S,1"R and 1'R,1"R were assigned to the diastereomers formed in excess, 2c and 2b, on the basis of the known stereochemistry of reduction of closely related alkyl phenyl ketones to R alcohols by using this chiral borane reagent. The circular dichroism spectra of the four isomeric benzylic alcohols were in agreement with these assignments. In the presence of the rat liver microsomal fraction, benzylic hydroxylation of bufuralol was significantly product stereoselective favoring formation of diastereomers with the 1"R absolute stereochemistry at the new chiral center in products from (1'R)-1 by a ratio of 4.5:1 [(1'R,1"R)-2:(1'R,1"S)-2] and by nearly 8:1 [(1'S,1"R)-2:(1'S,1"S)-2] from (1'S)-1. (1'R)-Bufuralol was more rapidly hydroxylated than was (1'S)-1, by about 3-fold. In the presence of human liver microsomes, (1'R)-bufuralol was also more rapidly hydroxylated than was (1'S)-1, by ca. 2.5-fold. However, product stereoselectivity from the 1'R enantiomer was reversed from that observed in the rat liver microsomal oxidation, with more (1"S)-carbinol being formed than 1"R isomer by nearly 4-fold. From (1'S)-1, about equal amounts of the two possible hydroxybufuralol diastereomers were formed. The results from the human liver microsomal studies are consistent with observed enantioselectivity of hydroxylation of bufuralol in vivo in humans.     

Synthesis and analgesic activity of stereoisomers of cis-fluoro-ohmefentanyl

Four stereoisomers 1a-d of cis-fluoro-ohmefentanyl have been synthesized. Their absolute configurations were determined by X-ray analysis of (3S,4R,2'S)-(-)-cis-I d. The analgesic activity (mice, sc, hot plate) revealed extreme stereodifferences. The ED50 value of (3R,4S,2'S)-(+)-cis-I (1a) was 0.000774 mg/kg (17958 times more potent than that of morphine), while the corresponding antipode 1c was almost inactive.     

Stereoselectivity in the N'-oxidation of nicotine isomers by flavin-containing monooxygenase

N'-Oxidation of nicotine isomers by porcine liver flavin-containing monooxygenase shows a clear stereoselectivity in the formation of the diastereomeric N'-oxides. (S)-(-)-Nicotine exhibited no stereoselectivity in the formation of cis-1'R,2'S- and trans-1'S,2'S-products, whereas with (R)-(+)-nicotine, only the trans-1'R,2'R-N'-oxide was formed. The concentration of each isomer required for half maximal activity differs significantly, and access of (S)-(-)-nicotine to the active site appears to be more restricted than for (R)-(+)-nicotine as judged from the observed Km values (Km = 181 and 70 microM, respectively, for the (S)-(-)- and (R)-(+)-isomers). These results indicate that a region adjacent to the active site may sterically prohibit binding of (R)-(+)-nicotine when the N'-methyl and pyridyl groups are in a cis-orientation. N-Methylnicotinium ion (both R- and S-isomers) is not a substrate for either porcine flavin monooxygenase, guinea pig liver microsomes, or ram seminal vesicular microsomes.