2-去氧-2,3-去氢-N-乙酰基神经氨酸8-硫酸酯、9-硫酸酯衍生物的合成及其生物活性

对2-去氧-2,3-去氢-N-乙酰基神经氨酸(Neu5Ac2en)的8-羟基和9-羟基进行选择性硫酸酯化,以比较不同取代位置的硫酸酯基对唾液酸酶抑制活性的影响.采用三苯甲基氯保护9-羟基后,对8-羟基进行选择性硫酸酯化;在4,7,8-三羟基乙酰化后,酸性条件下水解9-三苯甲基醚,对9-羟基进行选择性硫酸酯化.得到7个结构全新的Neu5Ac2en8-硫酸酯衍生物、9-硫酸酯衍生物.初步生物活性试验表明,这些化合物均具有一定的唾液酸酶抑制活性,9-硫酸酯衍生物的酶抑制活性高于8-硫酸酯衍生物.     

2—去氧—2，3—去氢—N—乙酰基神经氨酸8—硫酸酯、9—硫酸酯衍生物的合成及生物活性

对2－去氧－2,3－去氢－N－乙酰基神经氨酸（Neu5Ac2en)的8－羟基和9－羟基进行选择性硫酸酯化,以比较不同取代位置的硫酸酯基对唾液酸酶抑制活性的影响。采用三苯甲基氯保护9－羟基后,对8－羟基进行选择性硫酸酯化;在4,7,8－三羟基乙酰化后,酸性条件下水解9－三苯甲基醚,对9－羟基进行选择性硫酸酯化。得到7个结构全新的Neu5Ac2en 8-硫酸酯衍生物,9－硫酸酯衍生物。初步生物活性试验表明,这些化合物均具有一定的唾液酸酶抑制活性,9－硫酸酯衍生物的酶抑制活性高于8－硫酸酯衍生物。     

布洛芬糖衍生物的合成

目的为了降低布洛芬的胃肠损伤副作用,提高其抗炎活性,本文合成了若干布洛芬糖衍生物。方法 采用1,2∶3,4-二缩酮-半乳糖,1,3,4,5-四-O-乙酰基-2-去氧-2-氨基-葡萄糖,3,4,6-三-O-乙酰基-2-去氧-2-n-乙酰基-葡糖胺和2,3,6,2′,3′,4′,6′-七-O-乙酰基-乳糖胺作为糖基供体,分别与2-(对异丁基苯基)-丙酰氯1进行偶联,最后脱去糖环上的保护基得到了目标化合物6-(半乳糖基-O)-(±)布洛芬4,2-［2-去氧-2-氨基-葡糖基］-(±)布洛芬7,1-［2-去氧-2-n-乙酰基-β-D-葡糖氨基］-(－)布洛芬12a,1-［2-去氧-2-n-乙酰基-β-D-葡糖氨基］-(+)布洛芬12b和1-(β-乳糖氨基)-(±)布洛芬13。结果共合成了5个新化合物(4,7,12a,12b,13),利用¹HNMR,¹³CNMR,HMQC,COSY,IR和MS对化合物进行了结构确证,并测定了目标化合物的抗炎活性。结论化合物12a的抗炎活性最好且优于布洛芬。     

4-甲氧甲基芬太尼类似物的合成及其镇痛作用

本文报道了某些N-[1-(2-苯乙基)-4-甲氧甲基-4-哌啶基]-N-丙酰苯胺(4-甲氧甲基芬太尼)类似物的合成及其镇痛活性。小白鼠热板试验的结果表明,该类化合物有很强的吗啡样镇痛活性,但活性弱于相应的4-甲氧羰基芬太尼类化合物;4-N-酰基上羰基的存在对产生强效镇痛活性有重要作用。     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

N-[4-(苯并咪唑-2-硫基)苯基]-N'-烷基胍类衍生物的合成和生物活性

为了寻找对诱生型一氧化氮合酶(inducible nitric oxide synthase，iNOS)有抑制活性的新型化合物，设计合成了一系列N-［4-(苯并咪唑-2-硫基)苯基］-N′-烷基胍类衍生物(I₁～I₁₂)。以2-巯基苯并咪唑(1)为原料，经缩合和还原得到2-(4-氨基苯硫基)苯并咪唑(3)，再与异硫氰酸苯甲酰酯反应得双取代硫脲(4)，4经水解和S-烷基化得到关键中间体S-乙基-n-［4-(苯并咪唑-2-硫基)苯基］异硫脲氢碘酸盐(6)，6与伯胺或仲胺反应得目标化合物I₁～I₁₂。这些化合物的结构经IR，¹H NMR，MS和元素分析得到确证。初步的iNOS抑制活性测定结果显示，3个化合物(I₁，I₈和I₁₀)的活性强于阳性对照药氨基胍，其中化合物I₁的活性是氨基胍的5.5倍。     

4-甲氧羰基芬太尼非芳基类似物的合成及镇痛作用

报道了某些4-N-苯基或4-N-苯基与1-β苯基同时被某些非芳香基团替代的4-甲氧羰基芬太尼衍生物的合成及其镇痛活性。结果表明,4-N-苯基和1-β-苯基被某些适宜非芳香基团替代可保持强效镇痛活性。分子中不含苯(或芳)基的化合物4和6的镇痛活性分别是吗啡活性的695倍和818倍。讨论了结构与镇痛活性之间的关系。     

2-芳亚胺基-4-噻唑烷酮类化合物的合成及生物活性

目的设计、合成新的2-芳亚胺基-4-噻唑烷酮类化合物并研究其对一氧化氮合酶(NOS)的抑制活性。方法运用N-氯乙酰-1,2,3,4-四氢异喹啉或N-氯乙酰邻苯二甲酰亚胺与取代硫脲反应，简便地合成了15个新的2-芳亚胺基-4-噻唑烷酮类化合物，测试新合成的目标化合物的NOS抑制活性。结果和结论合成了15个新的2-芳亚胺基-4-噻唑烷酮类化合物，大部分反应收率大于65%。所有化合物的结构用¹H NMR，IR，MS及元素分析进行了表征。初步药理筛选结果表明，部分化合物具有NOS抑制活性。     

N-（氨基吡啶）苯甲酰胺类组蛋白去乙酰化酶抑制剂的合成及其抗肿瘤活性研究

目的 寻找新型组蛋白去乙酰化酶（HDACs）抑制剂,探讨其初步构效关系。方法 在前期研究发现活性结构 Ａ和Ｂ的基础上,参考恩替司他（MS-275）的结构特点,设计合成系列N-（氨基吡啶）苯甲酰胺类新化合物。采用苯并三氮唑-N,N,N',N’-四甲基脲六氟磷酸盐(HBTU)为缩合剂,以取代羧酸与2,3-二氨基吡啶或3, 4-二氨基吡啶反应生成系列含N-（氨基吡啶）结构的目标化合物;采用CCK-8 法并进行体外组蛋白去乙酰化酶抑制活性及抗肿瘤细胞增殖活性测试。 结果 共合成 18 个未见文献报道的新化合物,其结构经质谱、核磁共振氢谱确认。体外抗肿瘤初步研究表明：所有目标化合物均具有组蛋白去乙酰化酶抑制活性及抗肿瘤细胞增殖活性,Ⅴ-12、Ⅴ-13 和Ⅴ-16等化合物体外抑酶活性和抗肿瘤活性与阳性对照药MS-275相当,值得进一步深入研究。结论 初步构效关系研究发现,含有活性结构B的化合物具有更好的体外抗肿瘤活性;适当增加化合物酶表面识别区基团（R基团）的空间位阻或在R基团上引入供电子取代基将会增强化合物的抗肿瘤活性。     

S-9-(2,3-二羟丙基)腺嘌呤类似物的合成及其对S-腺苷-L-高半胱氨酸水解酶的抑制活性

为了寻找高效、低毒的抗病毒剂,本文通过用腺嘌呤及嘧啶碱基与3-氯-2-甲基丙烯缩合合成6个DHPA类似物的中间体5a,5b,6～8a和8b。应用OsO₄催化,在N-甲基吗琳-N-氧化物氧化下对烯键进行邻位双羟化,合成了5个DHPA类似物1～4a,b。对化合物5a,5b,6～8a,8b的¹HNMR数据进行了初步总结。对4个DHPA类似物测定了它们对S-腺苷-L-高半胱氨酸水解酶(SAH)的抑制活性,其中化合物1的IC₅₀为1.1mmol·L^-1,其余化合物均无抑制活性。     

4-烃基脲取代Neu5Ac2en衍生物的合成筛选

目的合成若干4-烃基脲Neu5Ac2en衍生物并检测其抗病毒活性。方法以5-乙酰氨基-4β-氨基-7，8，9-三-O-乙酰基-2，3，4，5-四脱氧-D-甘油-D-半乳糖-壬-2-烯吡喃糖酸甲酯为起始原料，经过2步反应得到目标化合物，并对目标化合物进行抗病毒活性测定。结果目标化合物的结构均经过核磁共振、质谱确证。结论Neu5Ac2en的4-位被烃基脲替代后失去抗病毒活性。     

唾液酸衍生物的合成及生物活性研究 Ⅰ 2-去氧-2,3-去氢-N-乙酰基神经氨酸的合成

提供了２－去氧－２，３－去氢－Ｎ－乙酰基神经氨酸甲酯及４位差向异构体的立体选择性合成方法．考察了反应条件对异构体生成的影响，结果表明，提高反应温度或提高酸的浓度有利于４位差向异构体的生成．此反应机理可能包括中间体４位碳正离子或一个口恶唑啉衍生物的形成．     

2,3-苯并吡喃酮类化合物的合成及药理活性

２，３苯并吡喃酮类化合物的合成及药理活性季小慎梁晓天（中国医学科学院、中国协和医科大学药物研究所，北京１０００５０）在研究番荔枝酰胺全合成的过程中［１］，曾将乙酰化高丁香酸甲酯和香草醛在Ａｃ２Ｏ／ＺｎＣｌ２条件下作用，以期获得如下Ｋｎｏｅｖｅｎａ...     

New prenylated benzoic acid derivatives of Piper hispidum

Three new 4-hydroxy-benzoic acid derivatives, 4-methoxy-3,5-bis-(3-hydroxy-3-methyl-1-butenyl)benzoate, 3-hydroxy-2-(1-hydroxy-1-methylethyl)-2,3-dihydrobenzofuran-5-carboxylic acid, and 3-hydroxy-2-(1-hydroxy-1-methylethyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester together with eight known compounds, have been isolated from the stems of Piper hispidum. Their structures were elucidated by a detailed spectroscopic analysis. In addition, the cytotoxicity of seven isolated compounds has been evaluated, revealing a moderate activity for three derivatives of dillapiole.     

金刚烷胺衍生物的设计、合成及其抗禽流感病毒活性

目的 设计合成金刚烷胺衍生物并对其进行抗禽流感病毒活性测试。方法 以金刚烷甲酰氯和氨基酸甲酯盐酸盐为起始原料经酰胺化、水解、成盐等反应依次得到3个系列金刚烷胺衍生物。以金刚烷胺为阳性对照,采用幼犬肾（MDCK）细胞系噬斑形成实验测定目标化合物的抗禽流感病毒活性。结果与结论 共合成了20 个未见报道的新化合物,目标化合物的结构均经¹H-NMR、IR、MS 谱确证;仅有化合物 A₅ 显示出较好的抗禽流感病毒活性。     

Synthesis, cytotoxicity, and antiviral activity of certain 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine nucleosides related to toyocamycin and sangivamycin

A number of 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine (1) with (2-acetoxyethoxy)methyl bromide (2) afforded a mixture of 4-amino-6-bromo-5-cyano-7-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d] pyrimidine (3) and the corresponding N1 isomer. Debromination of this mixture gave the corresponding 4-amino-5-cyano-7-[(2-acetoxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidi ne (4) and 4-amino-5-cyano-1-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidin e (5). Deacetylation of 4 and 5 furnished 4-amino-5-cyano-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (6) and the corresponding N1 isomer (7), respectively. The sites of attachment for the acyclic moiety for 6 and 7 were assigned on the basis of UV spectral studies as well as 13C NMR spectroscopy. Conventional functional group transformation of 6 provided a number of novel 5-substituted derivatives (8-10), including the sangivamycin derivative 8. The methyl formimidate derivative 10 was converted to the thioamide derivative 11 and the carbohydrazide derivative 12. Compounds 6 and 8-12 were tested for cytotoxicity to L1210 murine leukemic cells in vitro. None of these compounds caused significant inhibition of cell growth. Evaluation of compounds 4 and 6-12 for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the thioamide (11) was active. It inhibited HCMV but not HSV-1 at concentrations producing only slight cytotoxicity in human foreskin fibroblasts (HFF cells) and KB cells.     

22,23-Epoxy-2-aza-2,3-dihydrosqualene derivatives: potent new inhibitors of squalene 2,3-oxide-lanosterol cyclase

Two new azasqualenoid derivatives, bearing a 22,23 epoxidic function, were synthesized, to obtain more efficient, competitive inhibitors of the enzyme squalene 2,3-oxide-lanosterol cyclase (EC 5.4.99.7). The activities of 22,23-epoxy-2-aza-2,3-dihydrosqualene 4 and of its N-oxide derivative 5 were studied using rat and pig liver microsomal preparations and compared with a pig liver partially purified squalene 2,3-oxide-lanosterol cyclase. The activities of compounds 4 and 5 were compared in the different enzymatic preparations with the activities of 2-aza-2,3-dihydrosqualene 2 and of 2-aza-2,3-dihydrosqualene N-oxide 3 previously studied only with rat liver microsomes. Using a solubilized, partially purified squalene 2,3-oxide cyclase, all the compounds exhibited a non-competitive type of inhibition. As the previously suggested mechanism of inhibition does not account for this kinetic behaviour, a new hypothesis is suggested.     

Nitrite-induced nitration pathways of retinoic acid, 5,6-epoxyretinoic acid,and their esters under mildly acidic conditions: toward a reappraisal of retinoids as scavengers of reactive nitrogen species

All trans retinoic acid (1), a cancer chemopreventive agent and a pluripotent morphogen, was found to react efficiently with nitrite ions in a biphasic system consisting of CH(2)Cl(2)/0.1 M phosphate buffer (pH 3) 1:1 v/v to give a complex mixture of nitration products. Repeated TLC fractionation of the reaction mixtures after methylation allowed isolation of the main products, which could be identified as the 12-nitro derivatives 3a,b and the decarboxylated 12,14-dinitro and 5,6-epoxy-14-nitro derivatives 4 and 5a by spectral analysis. Use of (15)NO(2)(-) followed by extensive 2D NMR analysis, including (1)H,(15)N heteronuclear multiple bond correlation experiments, allowed identification of nitronitrate derivatives as additional constituents of the mixture. Under similar conditions, 1 methyl ester gave mainly 3a,b. 5,6-Epoxyretinoic acid (2) reacted smoothly with acidic nitrite to give mainly 5a and its isomer 5b whereas its methyl ester afforded 14-nitro derivatives 9a,b as chief products. The observed patterns of reactivity along with mechanistic experiments would suggest that nitrite-induced nitration of 1 proceeds through complex reaction pathways set in motion by attack of NO(2) to the 12- and 14-positions. Separate experiments showed that 1 can inhibit nitrite-induced N-nitrosation of 2,3-diaminonaphthalene at pH values of 4 and 5.5, as well as decomposition of caffeic acid under similar conditions. Overall, these results provide the first detailed insight into the reaction behavior of a retinoid toward reactive nitrogen species and shed light on previously overlooked nitrite scavenging properties of 1 of potential relevance to the mechanism of its antiinflammatory, antimutagenic, and cancer chemopreventive action.     

Adriamycin analogues. Preparation and biological evaluation of some N-(trifluoroacetyl)-14-O-[(N-acetylamino)acyl]adriamycin derivatives

In connection with structure-activity studies related to the novel DNA-nonbinding adriamycin analogues N-(trifluoroacetyl)adriamycin 14-valerate (AD 32) and N-(trifluoroacetyl)adriamycin 14-O-hemiadipate (AD 143), we have now prepared a series of N-(trifluoroacetyl)adriamycin derivatives with N-acylamino acid esters at the 14-carbinol position. Target compounds were made by reaction of N-(trifluoroacetyl)-14-iododaunorubicin with the sodium salts of N-acylamino acids generally in dimethylformamide-ethylene glycol solvent. Products were evaluated for in vitro growth-inhibitory activity and, to a limited extent, in vivo antitumor activity in the murine P388 leukemia system. ID50 values for the target compounds vs. cultured CCRF-CEM cells were generally in the same range as those for the above-mentioned DNA nonbinding adriamycin analogues. Of the four compounds tested for in vivo activity, although none was as effective as N-(trifluoroacetyl)adriamycin 14-valerate, all showed significant activity in the P388 assay system, with three of the compounds, at the doses used, being essentially equiactive with an optimal dose of adriamycin. Studies on the rate of esterase-mediated deacylation of the products, in a defined system containing unfractionated mouse serum as the source of enzyme, showed no relationship between the in vitro and in vivo activities of these compounds and the relative ease at which the side-chain ester substituents were hydrolyzed.