β-(3-吲唑基)-乙胺衍生物的合成及其抗放活性

为了寻找有效的辐射防护药,本文报告了有效防护剂5-甲氧基色胺的吲唑类似物及有关衍生物的合成。经药理试验证明5-甲氧基吲唑乙胺及5-羟吲唑乙胺具有明显的抗放活性。     

5,6-取代-3-吲(口朶)乙胺衍生物的合成

5,6-二甲氧基及5,6-次甲二氧基吲(口朶)用草酰氯法引入乙胺侧链,合成了两类5,6-取代-3-吲(口朶)乙胺衍生物共19个。药理系统筛选结果,表明两类化合物多具有不同程度的安定、抗惊、及镇痛作用。其中以化合物(Ⅱ)_7的作用较显著,详细的药理研究结果,将另文报导。     

5,6-取代-3-吲(口朶)乙胺衍生物的合成

5,6-二甲氧基及5,6-次甲二氧基吲(口朶)用草酰氯法引入乙胺侧链,合成了两类5,6-取代-3-吲(口朶)乙胺衍生物共19个。药理系统筛选结果,表明两类化合物多具有不同程度的安定、抗惊、及镇痛作用。其中以化合物(Ⅱ)₇的作用较显著,详细的药理研究结果,将另文报导。     

2-取代苯基-5-(3′-吲哚基)-唑衍生物的合成及其抗氧化活性

目的合成5-(3′-吲哚基)-唑衍生物并研究其抗氧化活性。方法以色氨酸为原料,与取代的苯甲酸在DCC催化下脱水缩合得到酰胺,再通过DDQ苄位氧化和分子内环合生成5-(3′-吲哚基)-唑。用DPPH体外抗氧化模型测定化合物的抗氧化活性。结果合成了11个2-取代苯基-5-(3′-吲哚基)-唑衍生物,其中化合物21和22的活性比维生素E强约3～4倍;化合物29的活性与维生素E相近。结论合成的目标化合物中有3个化合物有较好的抗氧化活性,有可能开发成为良好的抗氧化剂。     

5-羟基-1-氢-吲唑对SH-SY5Y细胞的保护作用及其机制研究

目的研究5-羟基-1-氢-吲唑对1-甲基-4-苯基-吡啶离子(MPP~+)诱导凋亡的SH-SY5Y神经细胞的保护作用及其可能的作用机制。方法以MPP~+诱导SH-SY5Y细胞凋亡建立体外帕金森病细胞模型,以MTT法筛选药物有效保护浓度;以免疫化学染色以及Hoechst 33258核染研究药物的神经保护作用以及抗凋亡作用;以Western blot法检测与神经元凋亡密切相关的磷酸化tau蛋白及其上游激酶磷酸化糖原合成激酶(P-GSK-3β)和周期依赖性蛋白激酶5(cyclin dependent kinase,CDK5)的表达。结果 MPP+可引起GSK-3β的活化以及CDK5活性升高,诱导tau的异常磷酸化和神经细胞凋亡;而5-羟基-1-氢-吲唑可下调GSK-3β与CDK5的活性,降低磷酸化tau的水平和抑制MPP+导致的SH-SY5Y细胞的凋亡。结论 5-羟基-1-氢-吲唑可抑制MPP+引起的SH-SY5Y神经细胞凋亡,作用机制可能是通过同时抑制GSK-3β和CDK5两条信号传导通路,而降低tau蛋白的磷酸化水平,进一步发挥神经元保护作用。     

5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮的合成

丙酰肼与三光气缩合环化得到5-乙基-1,3,4-噁二唑-2(3H)-酮,继与2-苯氧乙胺反应后在碱性条件下环合得到抗抑郁药奈法唑酮中间体5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮,总收率66.3%.     

1H-吲唑-3-羧酸的合成工艺改进

目的 改进1H-吲唑-3-羧酸的合成工艺.方法 以苯甲醛苯腙与草酰氯为原料得到N-亚苄基氨基-N-苯基-草氨酰氯,后者与三氯化铝反应得到关键中间体N-亚苄基氨基靛红,再经水解得到1H-吲唑-3-羧酸.结果与结论 该方法以55.3%的收率简单方便地制备了1H-吲唑-3-羧酸,所用起始原料及试剂的成本低、反应条件温和、易于操作,适合工业化生产.     

β-榄香烯吲哚衍生物的合成及其体外抗K562细胞增殖活性

目的设计合成β-榄香烯吲哚衍生物并进行体外抗癌活性筛选。方法通过合成β-榄香烯氯代物,在其结构中引入3-吲哚乙胺结构片段进而合成β-榄香烯吲哚衍生物。采用MTT法测定目标化合物对K562白血病细胞的增殖抑制作用。结果合成了15个未见文献报道的β-榄香烯吲哚衍生物。目标化合物的结构经1H-NMR、MS谱确证。活性实验结果显示14个目标化合物的活性高于β-榄香烯。结论在β-榄香烯结构中引入3-吲哚乙胺结构片段有利于提高此类化合物的抗癌活性。     

6-羟基-1H-吲唑抑制Tau磷酸化对MPP~+诱导凋亡的SH-SY5Y细胞保护作用的研究

目的研究6-羟基-1H-吲唑通过抑制Tau磷酸化对MPP+诱导凋亡的SH-SY5Y细胞的保护作用。方法体外培养人神经母细胞瘤细胞SH-SY5Y,以MPP+诱导SH-SY5Y细胞凋亡作为帕金森病的细胞模型。MTT分析法检测提前2 h加入6-羟基-1H-吲唑对细胞的保护作用;Hoechst 33258荧光染色法检测神经元凋亡情况;免疫细胞化学方法检测多巴胺能神经元内Tau的磷酸化水平。结果 200μmol·L-1MPP+可以使SH-SY5Y细胞存活率下降至(47.80±0.84)%(P<0.01),并且升高Tau磷酸化水平,出现典型的凋亡。而6-羟基-1H-吲唑抑制MPP+对SH-SY5Y细胞的毒性,并通过抑制Tau蛋白过度磷酸化而减少神经元凋亡,使TH-阳性细胞数目增加。结论 6-羟基-1H-吲唑可以通过抑制Tau磷酸化而对MPP+诱导凋亡的SH-SY5Y细胞发挥保护作用,提示Tau蛋白可能可以作为药物治疗帕金森等神经退行性疾病的新靶点。     

7-硝基吲唑对兔异丙酚麻醉深度调节的研究

目的:研究7-硝基吲唑(7-nitro indazolei,,7-NI)对兔异丙酚麻醉深度的调节作用。方法:20只日本大耳兔,雌雄不限,随机分为2组(n=10):对照组经腹腔注射2 ml花生油;7-硝基吲唑组经腹腔注射50 mg·kg-17-硝基吲唑。20 min后经颈外静脉连接Graseby 3 500注射泵进行靶控输注(TCI),以咀嚼反射消失作为浅麻醉标志,测定达浅麻醉状态所需异丙酚TCI血药浓度、双频指数(BIS)值及心率变异指数(HRVI)值。对照组达浅麻醉状态后再次经腹腔注射50 mg·kg-17-硝基吲唑,观察BIS值、HR-VI值变化。结果:50 mg·kg-17-硝基吲唑显著降低兔达浅麻醉状态时所需TCI浓度。对照组达浅麻醉状态后再次注射50 mg·kg-17-硝基吲唑麻醉深度表现加深趋势,但无显著的统计学意义(P>0.05)。结论:7-硝基吲唑通过选择性抑制中枢nNOS活性增强异丙酚麻醉效能,提示中枢NO／cGMP信号转导途径在异丙酚全麻作用机制中发挥作用。异丙酚可能通过抑制中枢nNOS活性影响NO／cGMP信号转导系统。     

An efficient and practical EPC synthesis of β-amino acids from L-asparagine

The synthesis of enantiomerically pure β-arnino acids (1a-c) via an O-activated equivalent of β-homoserine is discussed. The chiral synthon 2 was planned to be represented by (S)-3-N,N-dibenzylamino-4-mesyloxybutanoic acid methyl ester (3) or by (S)-3-N,N-dibenzylamino-4-mesyloxybutanenitrile (6). Both intermediates should be approached from L-aspartic acid 4 or L-asparagine 5 through selective reduction of the α-carboxyl group. It turned out that only nitrile 6 was suitable for the envisioned β-amino acid synthesis, since alcohol 14 - the synthetic precursor of 3 - was unstable towards intramolecular nucleophilic attack to accomplish the chiral building block 15. Reaction of mesylate 6 with different ‘Gilman cuprates’ afforded the 3-N,N-dibenzylamino nitrile derivatives 22a-c, which could be readily deprotected to give the target compounds 1a-c in 23-36% overall yield from asparagine. In contrast Me₂Cu(CN)Li₂ as an example for higher order ‘Lipshutz cuprates’ did not afford the desired substitution product 22a. The optical integrity of the synthesis was established by coupling of the methyl ester 24 with chiral 1-phenylethyl isocyanate followed by appropriate NMR studies of carbamate 25.     

1-Allyl and 1-(3,3-dimethylallyl) analogues of pethidine and its reversd ester

The preparation of some 1-allyl and 1-(3, 3-dimethylallyl)-4-phenylpiperidines related to pethidine and its reversed ester is described and the hot-plate activities in mice of these compounds reported. All six derivatives displayed morphine-like properties in mice, four being more potent (1·5–6 times) than morphine, but failed to act as analgesic antagonists in rats. The results are contrasted with the properties of similarly N-substituted fused-ring analgesics and differences discussed in terms of drug-receptor interaction modes.     

The influence of 3-ester side chain variation on the cardiovascular profile of nitrendipine in porcine isolated trabeculae and coronary arteries

Summary It has been reported that the lipophilicity of dihydropyridine-type calcium entry blockers may influence both their negative inotropic and their vasodilator activities. The action of nitrendipine and six related 3-ester side-chain derivatives with increasing alkyl and aryl substituents have been investigated in isolated porcine trabecular muscles and coronary artery rings. The lipophilicity of the drugs was determined by high-pressure liquid chromatography. In addition, some sterical parameters of the ester derivatives were considered. For the drugs tested, an increase in 3-ester side chain volume correlated well with increasing lipophilicity. Compared to nitrendipine, vascular selectivity of the ester side-chain derivatives, as expressed by the ratio of their negative inotropic and vasodilator activities, was much reduced. Neither vasodilator nor negative inotropic activity was directly related to the corresponding lipophilicity. Based on these results, earlier suggestions about the influence of the ester side-chain in dihydropyridines on their cardiovascular profile are extended. Send offprint requests to U. Fricke at the above address     

Synthesis of 2-methyl and 2-carboxymethyl derivatives of ornithine and arginine

Synthesis and characterization of a dozen derivatives of ornithine and arginine bearing 2-methyl or 2-carboxymethyl substituents are described. These substituents were introduced by dilithiation of 3-(4-methoxybenzylidineamino)-2-piperidinone with lithium diisopropylamide followed by regiospecific alkylation at C-3 with iodomethane or ethyl bromoacetate. 2-Methyl-d,l -ornithine was obtained in three steps from 3-amino-2-piperidinone in 68% overall yield, and 2-carboxymethyl-d,l -ornithine was isolated in 56% overall yield. 2-Methyl-and 2-carboxymethyl-d,l -arginine were obtained by mild acid hydrolysis to remove the 4-methoxybenzylidine group, N -acylation with 4-toluenesulfonyl chloride, mild alkaline hydrolysis of the lactam ring and the ester group, guanidination of the 5-amino group with O -methylisourea, and strong acid hydrolysis to remove the 4-tolunenesulfonyl group. Several of these compounds are inhibitors of carboxypeptidase B.     

Synthesis of 3-(3-pyridyl)- and 3-(3-benzo[b]thienyl)-D-alanine

The DL-arylamino acid ethyl ester derivatives of β-(3-pyridyl)-DL-alanine, and β-(3-benzo[b]thienyl)-DL-alanine were synthesized by diethyl acetamidomalonate condensation with the respective arylmethyl halides followed by partial hydrolysis to the monoethyl ester and decarboxylation. Each derivative was enzymatically resolved to a separable mixture of the corresponding N-acetyl-L-amino acid and the unchanged D amino acid derivative. Acidic hydrolysis of the latter gave the corresponding D-amino acid, the optical purity of which was established by HPLC analysis of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (GITC) derivative. The free D amino acids were converted to D-BOC derivatives by reaction with di-tert-butyldicarbonate in tert-butyl alcohol, water and sodium hydroxide.     

Synthesis and antimalarial activity of substituted pyrazole derivatives

The development of new antimalarial drugs is an urgent priority considering the increasing prevalence of drug-resistant Plasmodium falciparum parasites. A series of pyrazoles are described as part of efforts directed toward the synthesis of some potent antimalarial agents. The replacement of the ester group as a substituent in the pyrazole ring by nitrile group caused a precipitous loss of activity as antimalarial due to the lack of hydrogen-bond formation. Further modification of the heterocyclic ring to give substituted aryl derivatives afforded potent antimalarial derivatives: methyl 5-amino-3-anisidinepyrazole-4-carboxylic acid 3a (IC50: 0.149 mumol/l) and methyl 5-amino-3-(m anisidin)pyrazole-4-carboxylic acid 3c (IC50: 0.15 mumol/l). The synthesis, structure-activity relationships (SAR), X-ray crystallography and pharmacological activity associated with these series of compounds are discussed.     

Synthesis of 1,4-dihydropyridine derivatives with vasodilating activities (I)

□Asymmetric 2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylate with [N-(3,4-methylenedioxybenzyl)-N-methyl] aminoethyl group as the ester moiety and related 1,4-dihydropyridine derivatives were prepared and tested for the effects on vascular smooth muscles. 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[N-(3′, 4′-methylenedioxybenzyl)-N-methyl] aminoethyl ester 5-methyl ester (11) and 2,6-dimethyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[N-2′,3′-methylenedioxybenzyl)-N-methyl] aminoethyl ester 5-ethyl ester (15) showed potent vasodilating activities. IC₅₀ (10⁻⁸ M) was 2.6 and 2.7 for11 and15, compared with 3.5 for nicardipine.     

Synthesis and tuberculostatic activity of some derivatives of imidazo [4, 5-b]pyridine-1-carboxylic acid

Imidazo [4,5-b] pyridine-2-carboxylic acid 2, its methyl ester 5, amide 7, hydrazide 12, hydrazone 14, nitrile 16, thioamide 18, and amidoxime 20 were synthesized. By methylation of acid 2 with diazomethane N3-CH3 derivatives of the above mentioned compounds were obtained. The resulting compounds displayed low tuberculostatic activity.     

Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid‐ and Multidrug‐resistant Escherichia coli

As a part of our drug discovery program, ursolic acid was chemically transformed into six semi‐synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid‐sensitive and nalidixic acid‐resistant strains of Escherichia coli. Although ursolic acid and its all semi‐synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3‐O‐acetyl‐urs‐12‐en‐28‐isopropyl ester (UA‐4) and 3‐O‐acetyl‐urs‐12‐en‐28‐n‐butyl ester (UA‐5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid‐resistant and four and eightfold against nalidixic acid‐sensitive, respectively. The UA‐4 and UA‐5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug‐resistant clinical isolate of Escherichia coli‐KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration‐dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA‐4 and UA‐5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug‐resistant Gram‐negative infections.     

Stereoselective syntheses of 3-mercaptoproline derivatives protected for solid phase peptide synthesis

The incorporation of cis- and trans-3-mercaptoproline (3-MPc and 3-MPt) into analogs of biologically active peptides has been shown to be an effective means for reducing the conformational mobility of the peptide backbone. We report herein a novel stereoselective synthetic route to l -1 and l -2, derivatives of 3-MPt and 3-MPc suitably protected for solid phase peptide synthesis. The optically active starting material was the previously reported cis-3-hydroxyprolinol derivative l -3. Oxidation of the C1 alcohol to the carboxylic acid, formation of the methyl ester and deprotection of the C3 alcohol yielded l -6 in an overall yield of 68%. Reaction of the secondary alcohol with thiolacetic acid under Mitsunobu conditions gave the thiolacetate l -7 in 77% yield with clean inversion of configuration. Conversion of l -7 to l -1 was accomplished in a one-pot sequence consisting of three steps: hydrolysis of the thiolacetate, formation of the thioether and hydrolysis of the methyl ester. The overall yield of l -1 from l -3 was 38%. Synthesis of l -2 required an epimerization of l -6, which was accomplished using a standard Mitsunobu inversion to give the trans-3-hydroxyproline derivative l -8. Transformation of l -8 to l -2 followed that described for l -1, except that removal of the methyl ester from l -10 required acidolysis in refluxing 4_N HCl. The overall yield of l -2 from l -3 was 18%. The availability of pure enantiomers of 3-MPt and 3-MPc protected for SPPS will greatly facilitate their use as conformational constraints for studying peptide-receptor interactions. © Munksgaard 1996.