Phramacological properties of esters of 1-alkyl-2-hydroxyalkylpyrrolidine and their quaternary derivatives

A series of esters of 1-alkyl-2-hydroxyalkylpyrrolidine and their quaternary derivatives have been shown to possess significant anti-acetylcholine activity. The benzilic acid esters were the most active, followed by xanthene-9-carboxylic acid, fluorene-9-carboxylic acid and diphenylacetic acid esters in that order. The quaternary derivatives were more active than their corresponding tertiary compounds both in vivo and in vitro. The most active compound of the series tested in vivo was (1-methylpyrrolid-2-yl)methyl benzilate methiodide and was as potent as atropine. There was a progressive decrease in anti-acetylcholine activity and a proportional increase in local anaesthetic activity as the number of carbon atoms was increased from 1 to 3 in the pyrrolidyl side-chain of the tertiary salts of the benzilic acid ester series. Likewise increasing the size of the group on the nitrogen atom led to a decrease in anti-acetylcholine activity and an increase in local anaesthetic activity. Quaternization of the tertiary salts resulted in a loss of local anaesthetic activity. Most of the compounds tested possessed some antihistamine properties, while papaverine-like activity was confined to the tertiary salts only. No significant neuromuscular blocking activity was evident.     

Pharmacological properties of esters of 1-alkyl-2-hydroxyalkylpyrrolidine and their quaternary derivatives

A series of esters of 1-alkyl-2-hydroxyalkylpyrrolidine and their quaternary derivatives have been shown to possess significant anti-acetylcholine activity. The benzilic acid esters were the most active, followed by xanthene-9-carboxylic acid, fluorene-9-carboxylic acid and diphenylacetic acid esters in that order. The quaternary derivatives were more active than their corresponding tertiary compounds both in vivo and in vitro. The most active compound of the series tested in vivo was (1-methylpyrrolid-2-yl)methyl benzilate methiodide and was as potent as atropine. There was a progressive decrease in anti-acetylcholine activity and a proportional increase in local anaesthetic activity as the number of carbon atoms was increased from 1 to 3 in the pyrrolidyl side-chain of the tertiary salts of the benzilic acid ester series. Likewise increasing the size of the group on the nitrogen atom led to a decrease in anti-acetylcholine activity and an increase in local anaesthetic activity. Quaternization of the tertiary salts resulted in a loss of local anaesthetic activity. Most of the compounds tested possessed some antihistamine properties, while papaverine-like activity was confined to the tertiary salts only. No significant neuromuscular blocking activity was evident.     

Studies on collagenase inhibitors. IV. Inhibitors of bacterial collagenase in Coptidis rhizoma]

A hot aqueous extract of Coptidis Rhizoma had an inhibitory effect on the bacterial collagenase from Clostridium histolyticum. Active principles were isolated by silica gel column chromatography from the CHCl3 extract. Consequently, two inhibitors obtained were identified with the chloride of berberine and coptisine. The concentrations of the berberine and coptisine in the assay mixture to give 50% inhibition (IC50) were 0.73 mM and 0.16 mM, respectively. The type of inhibition by coptisine chloride was shown to be a mixture type from Lineweaver-Burk plots. Tetrahydroberberine, a reduction product of berberine chloride, had no inhibitory effect. This result suggests that the quaternary nitrogen of the alkaloids plays an important role in inhibitory activity.     

Simultaneous determination of baicalin, wogonoside, baicalein, wogonin, berberine, coptisine, palmatine, jateorrhizine and glycyrrhizin in Kampo medicines by ion-pair high-performance liquid chromatography.

An ion-pair high-performance liquid chromatographic method for the simultaneous determination of four flavonoids, namely baicalin, wogonoside, baicalein and wogonin, and four berberine-type alkaloids, namely berberine, coptisine, palmatine and jateorrhizine, and glycyrrhizin in Kampo medicines is described. The analysis can be accomplished within 30 min with a Wakosil-II 5C18 HG column by linear gradient elution using a mobile phase containing aqueous phosphoric acid, sodium dodecyl sulfate and acetonitrile at a flow-rate of 1.0 ml x min(-1), a thermostatic oven at 45 degrees C, and detection at 265 nm. The method was applied to quantifying these components in three Kampo decoctions: Oren-gedoku-to, San'o-shashin-to and Hange-shashin-to. The decoctions were diluted with 65% methanol at the final stage because a large quantity of precipitate, mainly from baicalin and berberine, was formed. The within-day relative standard deviations were less than 2.02% (n=10). The recoveries of these compounds were 90.3-102%. The detection limits of these compounds were 0.02-1.96 microM per injection (5 microl).     

天然产物黄连碱的合成工艺改进

目的改进天然产物黄连碱的合成工艺。方法以2,3-二羟基苯甲醛为起始原料,经环合、缩合和闭环3步反应得到目标化合物黄连碱。其中,主要针对第二步缩合反应的纯化步骤以及第三步闭环反应的溶剂选择和纯化过程做了有效的改进工作。结果中间体和目标产物结构经1H-NMR、13C-NMR图谱数据确证,总收率可达43.0%,目标化合物经HPLC检测纯度高达98.5%。结论改进后的合成方法反应步骤少、操作简单、条件温和、产物收率及纯度较高,有利于工业化生产。     

Conformations, DNA binding parameters, and antileukemic activity of certain cytotoxic protoberberine alkaloids.

The tetrahydroprotoberberine alkaloids 5 and 7 possessing a trans-quinolizidine conformation display in vitro KB cytotoxicities in contrast to their corresponding diastereomers 4 and 6 which exist in the cis-quinolizidine conformation and are much less toxic. The DNA-binding parameters of these compounds as well as the protoberberine salts 1, 8, and 9 have been examined by equilibrium dialysis. Only the quaternary salts bind to DNA. The alcohol 5 showed low in vivo activity against leukemia P388 systems, while the quaternary salts 8 and 9 proved to be toxic to the host.     

灯盏乙素苷元4’-N-取代氨甲基苯甲酸酯的合成与活性研究

目的合成具有较强神经细胞氧化损伤保护作用的灯盏乙素苷元4’-N-取代氨甲基苯甲酸酯衍生物。方法灯盏乙素苷元与N-取代氨甲基苯甲酸在偶联剂N,N’-二环己基碳酰亚胺(DCC)/二甲基吡啶(DMAP)的作用下缩合后者经过酰氯/甲醇体系脱保护基,获得目标化合物(6a～6c)。并对受试化合物进行了神经细胞氧化损伤保护活性研究。结果合成的化合物及中间体均经过1H-NMR,ESI-MS进行了结构表征,确证结构与目标产物一致,受试化合物均具有较好的抗氧化活性,其中化合物6c活性明显好于维生素E、灯盏乙素。结论 4’-N-取代氨甲基苯甲酸酯前药设计方法能用于灯盏乙素苷元结构修饰,所采用的合成方法具有较好的实用性,能用于灯盏乙素苷元4’-N-取代氨甲基苯甲酸酯的制备。     

黄连中小蘖碱的含量测定

測定黄連中小蘗碱含量的方法很多,这里就常見的一些方法略予評述。中国药典1953年版第一增补本(1957)和日本药局方的方法相同,都是在含黃連生物碱的水溶液中加碘化鉀溶液,使小蘗碱成碘氫酸盐沉淀而析出,然后将沉淀悬浮在水中,加入丙酮,使小蘗碱成为丙酮小蘗碱沉淀,过滤,干燥,而后称重。但是根据文献可知,不但小蘗碱能与碘化鉀形成沉淀,并且結构与小蘗碱类似的生物碱(如黄連中的palmatine,jatrorrhizine 和columbamine等)以及甚至結构不同的其他季胺化合物也能发生沉淀。再者,与小蘗碱     

Alkaloids of papaveraceous plants

From the whole plants of CORYDALIS TASHIROI M AKINO a new quaternary protoberberinium base dehydrodiscretamine chloride was isolated along with four known quaternary alkaloids by the application of droplet countercurrent chromatography (DCCC). The structure of the new base was established by spectral and chemical evidence. Eight known tertiary alkaloids were also isolated from the same plant.     

Triclisia sacleuxii (Pierre) Diels (Menispermaceae), a potential source of acetylcholinesterase inhibitors

Objectives To search for compounds possibly useful for the treatment of Alzheimer's disease. Methods Alkaloid fractions from the roots, stems and leaves of Triclisia sacleuxii (Menispermaceae) and pure bisbenzylisoquinoline alkaloids isolated from the roots (phaeanthine, N‐methylapateline, 1,2‐dehydroapateline and gasabiimine) were assessed for acetylcholin‐esterase inhibitory activity. Key findings All extracts and compounds tested inhibited acetylcholinesterase to varying degrees; the leaf tertiary alkaloid fractions and the root quaternary alkaloid fractions exhibited the strongest inhibitory potential (90% at 0.1 mg/ml). The leaf tertiary alkaloid fraction was selected for further analysis (the quaternary alkaloids, which are too polar for absorption and brain distribution, were presumed to be clinically uninteresting). TLC bioautography using Ellman's reagent allowed the detection of acetylcholinesterase inhibitors and the isolation of the major active constituent, which was identified as lindoldhamine, a one‐bridged bisbenzylisoquinoline alkaloid. Lindoldhamine displayed high acetylcholinesterase inhibitory activity with a 50% inhibition concentration in the micromolar range. Conclusions All T. sacleuxii alkaloid fractions tested exhibited anti‐acetylcholinesterase activity; isolated bisbenzylisoquinoline alkaloids showed weak‐to‐high inhibition depending on their structural features. Structure modification could provide interesting derivatives with enhanced anti‐acetylcholinesterase activity.     

Synthesis and antimicrobial and antifungal activities of quaternary salts of adamantane-containing alkoxydialkylaminopropanols

A series of quaternary salts of adamantane-containing alkoxydialkylaminopropanols was synthesized. The structures of the reaction products were confirmed by IR and PMR spectroscopy. Some compounds were found to have high levels of antimicrobial activity.     

Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids

The alkaloids from Chelidonium majus L. which had a significant inhibitory effect in mitochondrial respiration were those which contain a positive charge due to a quaternary nitrogen atom, i.e., chelerythrine, sanguinarine, berberine and coptisine, both with malate+glutamate or with succinate as substrates. When malate+glutamate was used as substrate, chelerythrine and berberine, which contain methoxy groups, were particularly more active, since they had a strong effect even at low concentrations. In submitochondrial particles, berberine and coptisine had a marked inhibitory effect on NADH dehydrogenase activity but practically no effect on succinate dehydrogenase activity, whereas chelerythrine and sanguinarine inhibited more strongly succinate dehydrogenase than NADH dehydrogenase, which is in agreement with the results found for mitochondrial respiration. Protopine and allocryptopine, which did not inhibit mitochondrial respiration, strongly inhibited NADH dehydrogenase in submitochondrial particles, but had no effect on succinate dehydrogenase activity.     

交泰丸中4种生物碱与人血浆蛋白结合率的测定

目的：研究交泰丸中表小檗碱,盐酸黄连碱,盐酸巴马汀,盐酸小檗碱与人血浆蛋白的结合率。方法：采用平衡透析法测定交泰丸中4种生物碱与人血浆蛋白的结合率,用高效液相色谱（HPLC）法测定透析内、外液中4种成分的质量浓度,计算血浆蛋白结合率。结果：表小檗碱,盐酸黄连碱,盐酸巴马汀和盐酸小檗碱的线性关系、精密度、提取回收率和稳定性均符合方法学要求;交泰丸低、中、高（0.5,1,1.5 mg·mL^-1）浓度中,表小檗碱与人血浆蛋白结合率分别为40.28%±3.02%,42.41%±2.61%,33.76%±2.19%,盐酸黄连碱与人血浆蛋白结合率分别为46.60%±3.47%,58.49%±6.47%,47.00%±1.3%,盐酸巴马汀与人血浆蛋白结合率分别为40.17%±3.26%,33.71%±3.74%,24.05%±1.81%,盐酸小檗碱与人血浆蛋白的结合率分别为29.41%±4.99%,25.35%±1.37%,18.07%±1.61%。结论：交泰丸中表小檗碱,盐酸巴马汀和盐酸小檗碱属于低等结合型成分,盐酸黄连碱属于中等结合型成分。     

Acetylcholinesterase inhibitors from Stephania venosa tuber

Acetylcholinesterase (AChE) inhibitors have lately gained interest as potential drugs in the treatment of Alzheimer's disease. Three AChE inhibitors were isolated from tubers of a Thai medicinal plant, Stephania venosa (Bl) Spreng. They were identified as quaternary protoberberine alkaloids, stepharanine, cyclanoline and N-methyl stepholidine. They expressed inhibitory activity on AChE with IC50 values (concentration that caused 50% inhibition of activity) of 14.10 +/- 0.81, 9.23 +/- 3.47 and 31.30 +/- 3.67 microM, respectively. The AChE inhibitory activity of these compounds was compared with those of the related compounds, palmatine, jatrorrhizine and berberine, as well as tertiary protoberberine alkaloids isolated from the same plant, stepholidine and corydalmine. The results suggest that the positive charge at the nitrogen of the tetrahydroisoquinoline portion, steric substitution at the nitrogen, planarity of the molecule or substitutions at C-2, -3, -9, and -10 affect the AChE inhibitory activity of protoberberine alkaloids.     

Synthesis of new antirusty disinfectants. I]

New quaternary ammonium salts [N-alkyl-N-2-hydroxyethyl-N,N-dimethylammonium ethyl phosphate (21, 22), isopropyl phosphate (23), n-butyl phosphate (24) and N-alkyl-N-2-hydroxy-3-phenoxypropyl-N,N-dimethylammonium ethyl phosphate (25, 26), isopropyl phosphate (27), n-butyl phosphate (28) and bis(N-alkyl-N-2-hydroxy-3-phenoxypropyl-N,N-dimethylammonium) malate (29), fumarate (30), succinate (31), adipate (32) and N-alkyl-N-2-hydroxy-3-phenoxypropyl-N,N-dimethylammonium tartrate (33)] were synthesized by alkylation of the corresponding trialkylammonium salts with various epoxy compounds. The new quaternary ammonium salts showed much greater bactericidal activities and antirusting effects than those of benzalkonium chloride. They had also good compatibilities since no precipitate was observed if the solution of any anionic surface active agents were added to the solution of these new quaternary ammonium salts. This property is the same as that of amphoteric surface active agents.     

Ion exchange interactions on silica gel layers. II. Halogen salts of compounds containing organic tertiary and quaternary nitrogen

Primary and secondary ion exchanges--of hydrochloric acid and hydrobromic acid salts of well hydrolyzing organic bases as well as quaternary ammonium bromide which are important drug substance--taking place on silica gel using methanol as mobile phase have been investigated by thin-layer chromatographic and spectrophotometric methods. In case of tertiary ammonium salts (hydrolyzing salts) basis linked to silanate ion and halogen acid have been formed by primary ion exchange. During secondary ion exchange halogen acid has exchanged metal ions linked to silanate ions on the layer. In case of non hydrolyzing salts, the quaternary ammonium bromide salts it could not surely be proved by the applied methods whether primary ion exchange had been followed by secondary ion exchange or only primary ion exchange had occurred.     

N-quaternary derivatives of tilorone

Tilorone (free base) reacts with alkyl halides forming quaternary ammonium salts. Bis- as well as mono quaternary compounds (2 resp. 3) were synthesized. The tilorone-bis-methoiodide (2a) was converted to several carbonyl derivatives (4 and 5). All produced compounds did not show any cytostatic activity against the murine leukemias L 1210 and P 388 in vivo. Especially the bis-quaternary derivatives 2 were highly toxic in the mouse.     

有机磷酸酯解毒剂嘧啶甲醛肟季铵盐及其衍生物的合成

解磷定(I,2-PAM)对有机磷农药中毒的解毒机理,系由其分子中的肟基阴离子向中毒的磷酰化乙酰胆碱酯酶(AcChE)的磷原子作亲核进攻,致使磷酰基断裂而使AcChE复能。因此,醛肟基的pKa可能与AcChE的复能活性之间存在一定联系。Childs曾报道嘧啶-2-异羟肟酸(Ⅱ)和Ashani等报道4-嘧啶甲醛肟碘甲烷季铵盐(Ⅲ_b),分别对沙林(sarin)和异氟磷(DFP)有一定复能作用。为此,作者合成了一些不同位置的嘧啶甲醛     

硫胺素二硫化物类脑靶向药物载体的设计与合成

目的设计并合成一系列硫胺素二硫化物类脑靶向药物载体。方法 2-(4-甲基噻唑-5-基)乙醇(Ⅰ)在不同溴代物的作用下,氮烷基化制成季铵盐(Ⅱ),该中间体经碱性开环后与烷基硫代硫酸钠(Ⅳ)反应即得到目标产物Ⅴ。结果与结论成功制备了9个含有不同取代基的硫胺素二硫化物;目标化合物经1HNMR和MS确证。     

3-(4-甲磺酰氨基/乙酰氨基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物的设计、合成及α-糖苷酶抑制活性

目的: 在研究非糖类α-糖苷酶抑制剂的过程中,发现3-(4-苯磺酰氨基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物具有显著的α-糖苷酶抑制活性。为进一步探讨该类化合物的构效关系,将4-位的苯磺酰氨基替换为甲磺酰氨基和乙酰氨基,合成3-(4-甲磺酰胺基/乙酰基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物,并评价其α-糖苷酶抑制活性。 方法: 以4-硝基苯甲酸为原料,经氯代、酰化、水解、还原反应制得4-氨基-β-氧代苯丙酸乙酯,与甲磺酰氯/乙酰氯经酰化反应得4-甲磺酰氨基/乙酰氨基-β-氧代苯丙酸乙酯,再与取代水杨醛经Knoevernagel缩合,同时环合得到目标化合物。采用酵母α-葡萄糖苷酶对所合成的目标化合物进行α-糖苷酶抑制活性评价。 结果: 合成了22个目标化合物,结构经1H-NMR和IR确证。大部分3-(4-甲磺酰氨基/乙酰氨基)苯甲酰基-2H-1-苯并吡喃-2-酮类化合物未表现出α-糖苷酶抑制活性,只有化合物3-(4-甲磺酰氨基)苯甲酰基-6,8-二叔丁基-2H-1-苯并吡喃-2-酮(10f)表现出良好的α-糖苷酶抑制活性,IC50值为10.16 μmol﹒L-1。 结论: 对于3-苯甲酰基-2H-1-苯并吡喃-2-酮类化合物,其苯甲酰基以4-位甲磺酰氨基/乙酰氨基取代对该类化合物的α-糖苷酶抑制活性不利,该类化合物的构效关系值得进一步研究。