腺嘌呤衍生物的合成及体外抗疱疹病毒活性

以腺嘌呤为母体,在其9位引入活性基团N-取代缩氨基硫脲(TSC),设计合成了12个6-氨基-9(N^4'-取代乙醛缩氨基硫脲)嘌呤衍生物(4a～1),并进行了体外抗单纯疱疹病毒I型(HSV-1),II型(HSV-2),水痘-带状疱疹病毒(VZV)活性试验及细胞毒性试验。结果表明,除化合物4e及4f对HSV-1及VZV有较高活性外,其余化合物对上述两种病毒的活性均不明显。另外,将4e与4f分别与无环鸟苷(ACV)联合用药,其最小抑制浓度(MIC)及细胞毒性(MCC)均显著下降。     

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。     

N-取代-O-对甲脒苯胺基羰甲基-L-酪氨酸甲酯类化合物的合成及抗血小板聚集活性

目的：根据RGD肽及目前活性较好的非肽类纤维。0蛋白原受体拮抗剂的结构特点,设计、合成一系列有抗血小板聚集活性的化合物。方法：以酪氨酸及对硝基苯甲酸等为主要原料经多步合成,对所得化合物用比浊法测定在1×10^-6 mol.L^-1时对体外血小板聚集的抑制率。结果：合成了18个N-取代-O-对甲脒苯胺基羰甲基-L-酪氨酸甲酯类化合物(Ia～r),均为新化合物。结论：其中10个化合物(Ia,f,g,i～m,q,r)显示一定的活性,活性最高的（Ig）抑制率达64%。     

人工蛹虫草子实体化学成分

目的　研究人工培养蛹虫草（Cordyceps militaris）干燥子实体的化学成分。方法　利用各种色谱技术进行分离纯化,通过理化方法及光谱（UV,IR,HRMS,EIMS,¹HNMR,¹³CNMR,FGCOSY,DEPT,FGHMQC和FGHMBC）分析鉴定其化学结构。结果　从人工培养蛹虫草干燥子实体的乙醇提取物中分离得到7个化合物,分别鉴定为: 3′-脱氧腺苷（3-deoxyadenosine, 1）, 腺苷（adenosine, 2）, N⁶-甲基腺苷（N⁶-methyladenosine, 3）, O^5′-乙酰基虫草素(O^5′-Acetylcordycepin, 4), N⁶-［β-(乙酰胺甲酰)氧乙基］腺苷（N⁶-［β-(acetylcarbamoyloxy) ethyl］ adenosine, 5）,虫草环肽A(cordycepeptide A, 6)和麦角甾醇过氧化物（ergosterol peroxide, 7）。结论　化合物(5）和(6)为两个新化合物,并首次归属这些化合物波谱信号。     

含2-甲基-5-硝基咪唑的吡酮酸类衍生物的合成及其抗菌活性含2-甲基-5-硝基咪唑的吡酮酸类衍生物的合成及其抗菌活性

目的 研究含N-乙基-2-甲基-5-硝基咪唑的诺氟沙星、环丙沙星和依诺沙星衍生物的合成及其抗菌活性。方法 用含2-甲基-5-硝基咪唑的诺氟沙星、环丙沙星和依诺沙星等为原料,通过亲核取代、酯化合成目的物;测定目的物的抗菌活性。结果 设计、合成了9个新化合物(IIa～c,IIIa～f),其结构经MS,¹HNMR和元素分析确证。化合物IIa～c的体内抗菌活性较明显。结论 化合物IIa～c显示了一定的体内抗菌活性,值得进一步研究。     

N-甲基-N-(α-取代萘甲基)取代苄胺类化合物的合成及抗真菌活性

报道25个N-甲基-N-(α-取代萘甲基)取代苄胺类化合物的合成及抗真菌活性。抑菌测试结果表明,目标化合物对于8种试验菌种均有不同程度的抑菌活性,化合物6,7,8,10,11和21等活性为naftifine的4～20倍,化合物8,10,11和21等活性为butenafine的2～10倍,化合物8,9,10,11和21等对Sporotrichum schencki及Aspergilus fumigatus的活性为clotrimazole的8～15倍,化合物7,8,9和21等对Cryptococus neoformans亦表现出较高活性,MIC为0.31～1.25μg·ml^-1。     

(9S)-9-羟基-12-亚甲基红霉素A衍生物的合成

为了合成具有抗菌活性的红霉素衍生物,本文以红霉素A为原料,合成了6-位烯丙基取代中间体12,21-双键-2′-O,4″-O-二苯甲酰基-(9S)-9-O,11-O-异丙基-6-O-烯丙基红霉素A 12,得到(9S)-9-羟基-12-亚甲基衍生物6和6,7-去氢-(9S)-9-羟基-12-亚甲基衍生物11。经¹³C NMR,FAB-MS确证产物结构。所得化合物进行了体外抗菌活性测定。6和11均显示出较弱的抑菌活性。     

抗白血病药物靛玉红以及靛蓝和异靛蓝衍生物的合成

靛玉红是我国用于临床治疗慢性粒细胞白血病的一个药物⁽¹⁾。前报⁽²⁾已报道了N_1′取代靛玉红衍生物的合成。为了研究靛玉红分子内氢键(N₁取代)和两个吲哚环连接位置对于抗肿瘤活性的影响。我们合成了N₁-取代和双取代的靛玉红衍生物(Ⅰ₁,Ⅰ₂,Ⅰ₃)和六个靛蓝、异靛蓝衍生物(Ⅱ_1～3,Ⅲ_1～3)。其中,N-乙基靛蓝和N-甲基或乙基异靛蓝都对Walker癌肉癌256具有抑制作用,而它们的母体化合物则没有抗肿瘤活性。N₁-取代的靛玉红(Ⅰ_1～2)无活性,但N,N′-双甲基靛玉红确又有一定的抗肿瘤活性。     

双分子γ-咔啉衍生物的合成及其对胆碱酯酶的抑制活性研究

目的 合成双分子γ-咔啉衍生物并研究其抑制乙酰胆碱酯酶的活性。方法 以N-乙酰基-3-溴-4-哌啶酮和苯肼为原料,经Fischer法一步合成关键中间体γ-咔啉,γ-咔啉在NaH作用下与二溴代物发生亲核取代反应生成双分子N₅-γ-咔啉系列衍生物,后者进一步在丙酮中经碘甲烷甲基化得到相应的季铵盐。用改良的Ellman法测定化合物的乙酰胆碱酯酶抑制活性。结果 合成了7个新的双分子γ-咔啉衍生物,其化学结构经IR、¹H-NMR、¹³C-NMR、ESI-MS确证。药理实验研究结果表明,所有目标化合物对乙酰胆碱酯酶均具有一定的抑制活性,化合物4g显示出与阳性对照多奈哌齐较为接近的抑制活性。结论 双分子γ-咔啉衍生物对乙酰胆碱酯酶具有抑制活性,连接链的长度对活性有影响,链长为8个碳原子时活性最佳,结构中的叔氮季铵化有利于提高活性。     

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。     

Bioisosterism,enantioselectivity, and molecular modeling of new effective N6‐ and/or N(9)‐substituted 2‐phenyl adenines and 8‐aza analogs: Different binding modes to A1 adenosine receptors

Bioisosterism of the adenine and 8‐azaadenine nuclei was demonstrated by comparison of A₁ adenosine receptor binding affinity of 2‐phenyl N⁶‐substituted adenines and the corresponding 8‐azaadenines. Some of these new compounds are very potent A₁ adenosine receptor antagonists. This work also describes the synthesis and A₁ adenosine receptor binding of the enantiomers of some 2‐phenyladenines substituted with a 1‐phenylethyl chiral group in N⁶ and N(9) positions. Biological results, showing the same stereoselectivity for all the couples of enantiomers, may supply proof for the hypothesis of a possible double arrangement of 2‐phenylsubstituted adenines inside A₁ adenosine receptors. Theoretical studies, based on an improved A₁ adenosine receptor model and consisting of evaluation and comparison of interaction energies in complexes involving some selected chiral ligands, support the above hypothesis. Drug Dev. Res. 54:52–65, 2001. © 2001 Wiley‐Liss, Inc.     

Determination of the adenosine A1 agonist N-cyclopentyladenosine in rat blood by solid-phase extraction and HPLC

A solid-phase extraction procedure has been developed for the isolation of the adenosine A1 receptor agonist N⁶-cyclopentyladenosine from rat blood. The biological samples were spiked with N⁶-cyclopentyladenosine and the analogue N⁶-cyclohexladenosine (internal standard), diluted with sodium hydroxide, loaded onto disposable cartridges with subsequent desorption with methanol and analysis by HPLC. The performance of columns pre-packed with different C18-bonded silica phases or with a polymeric reversed-phase sorbent (Oasis HLB) was assessed. The highest extraction efficiencies (recovery rates>83.3%) for the two N6-alkyl substituted adenosines were achieved by the Oasis HLB cartridges. In addition, the polymeric sorbent provided reproducible recoveries (relative standard deviation<4.8%), whereas large variations (relative standard deviation values, 9–16.3%) in the extraction yields were observed using the conventional silica-based C18 cartridges. The described sample preparation method is rapid, simple, selective and it is suitable for pharmacokinetic studies.     

Phenyl‐substituted N6‐phenyladenosines and N6‐phenyl‐5′‐N‐ethylcarboxamidoadenosines with high activity at human adenosine A2B receptors

A series of phenyl‐substituted N⁶‐phenyladenosines and N⁶‐phenyl‐5′‐N‐ethylcarboxamidoadenosines were synthesized and tested at adenosine receptor subtypes. EC₅₀ values were determined for cyclic AMP production in CHO cells expressing human A_2B receptors. Binding affinities were determined for rat A₁ and A_2A receptors and human A₃ receptors. N⁶‐phenyladenosine displayed an EC₅₀ value at A_2B receptors of 6.3 μM. Several N⁶‐phenyladenosine derivatives were more active than N⁶‐phenyladenosine, while two analogs were also more potent than 5′‐N‐ethylcarboxamidoadenosine (NECA, 0.76 μM), i.e., the 4‐iodophenyl ( 10 , 0.37 μM) and the 4‐aminosulfonylphenyl ( 20 , 0.44 μM) derivatives. N⁶‐phenyl‐NECA derivatives were as active as their analogous adenosine derivatives. Drug Dev. Res. 49:85–93, 2000. © 2000 Wiley‐Liss, Inc.     

Synthesis of [15N4] purine labeled cytokinin glycosides derived from zeatins and topolins with 9‐β‐d, 7‐β‐d‐glucopyranosyl,or 9‐β‐d‐ribofuranosyl group

Synthesis of [¹⁵N₄] purine labeled cytokinine glycosides derived from zeatins and topolins containing a 9‐β‐d , 7‐β‐d ‐glucopyranosyl, or 9‐β‐d ‐ribofuranosyl group is described. These N⁶‐substituted adenine derivatives are intended as internal analytic standards for phytohormone analysis. All labeled compounds were prepared from 6‐chloro[¹⁵N₄]purine ( 1 ). The equilibrium reaction of 1 with acetobromo‐α‐d ‐glucose gave isomeric 7‐β‐d ( 3 ) and 9‐β‐d ( 4 ) chloro glucosyl precursors, which were treated with the corresponding amines to get desired labeled cytokinin 7‐β‐d ( 6 ) and 9‐β‐d ( 5 ) glucopyranosides. Cytokinins containing 9‐β‐d ‐ribofuranosyl group ( 8 ) were obtained by direct enzymatic transglycosylation reaction of cytokinins ( 7 ) prepared from 6‐chloro[¹⁵N₄] purine ( 1 ).     

9-(2-膦酰甲氧乙基)腺嘌呤及其位置异构体3-(2-膦酰甲氧乙基)腺嘌呤的合成和抗病毒活性研究

Phosphonylmethoxyethyl)adenine (1),PMEA,an acyclic nucleotide withbroad-spectrum antiviral activity was synthesized with some modifications of Holy's procedure.Simutaneously,an N-3 regioisomer(2)of PMEA and a by-preduct, formaldehyde di-[2-(9-adenyl)ethyl] acetal(7)were seperated by silica gel chromatography in the ratio of 50:10:1.Compound(2)and(7) are new compounds that we have not yet found in literatures. The structure of them weredetermined with ¹HNMR,2DNMR, MS and Spot test.Antiviral test showed that N-3 isomer(2)completely lost activity against both HIV-1 and HSV-1 in vitro. It seems that regiospecificity of theacyclic nucleotide structure is important for antiviral activity.     

Influence of the molecular structure of N6-(ω-aminoalkyl)adenosines on adenosine receptor affinity and intrinsic activity

The affinities of a series of N⁶-(ω-aminoalkyl)adenosines as probes for A₁ and A₂ adenosine receptors were determined in various radioligand binding assays and the intrinsic activities were measured in adenylate cyclase assays. Clear species differences were noticed for A₁ receptor affinity of these adenosine receptor agonists, the compounds being more active in calf than in rat brain tissue. The affinity profile within the series was, however, rather similar in both membrane preparations, with N⁶-9-aminononyladenosine displaying highest affinity. The A₂ receptor affinities were comparable to values measured for the A₁ receptor in its low affinity state, as assessed with a radiolabelled antagonist in the presence of 1 mM GTP. Calculation of the intrinsic activities of the adenosine analogues from their modulating action on adenylate cyclase showed almost all the compounds to be equally effective to (−)-N⁶-(R-phenylisopropyl) adenosine, on either A₁ or A₂ adenosine receptors. N⁶-3-Aminopropyl- and N⁶-12-aminododecyladenosine, however, proved to be partial agonists, the first on A₁ and the second on A₂ adenosine receptors. The data are used as the basis for a discussion of adenosine receptor subtype selectivity and intrinsic activity in general.     

苯甲酰胺类抗精神病药物的研究:6β-羟基,乙酰氧基和苯甲酰氧基-3α及β-托品烷衍生物的合成

合成了15个3α和β-取代苯申酰氨基-6β-羟基,乙酰氧基和苯甲酰氧基-托品烷类化合物。其中化合物5d,12c和12d对D-1和D-2受体都有一定的亲和作用。     

含有替加氟的卵磷脂类似物设计、合成及抗癌活性

目的合成含有替加氟的以卵磷脂类似物作载体的缀合物,并测定其生物活性。方法将替加氟转化为羟烷基衍生物,六乙基亚磷酰三胺作磷酰化试剂,与羟烷基替加氟、1-十六烷基甘油及硫作用,经一锅法合成得到环甘油硫代磷脂羟烷基替加氟缀合物,通过三乙胺对环甘油硫代磷脂替加氟缀合物开环得到标题产物。结果得到新化合物9个(2a～c,3a～c,4a～c),其结构经IR,NMR和元素分析确证。结论体外活性测定表明,化合物4a对人体膀胱癌细胞的抑制效果比替加氟好。     

疟疾防治药物的研究——Ⅹ.2,4-二氨基-6-N1,N2-二取代肼基-喹唑啉类衍生物的合成及其抗疟作用

本文报道了2,4-二氨基-6-N¹,N²-二取代肼基-喹唑啉类衍生物的合成及其抗疟活性的研究。这类化合物的合成是以2,4-二氨基6-取代苄基氨基-喹唑啉为原料经亚硝化、还原成为2,4-二氨基6-(N¹-取代苄基)—肼基喹唑啉,再与相应的醛缩合而成。此类化合物经伯氏鼠疟原虫抑制性治疗初筛表明有少数具有一定的效果。有11个化合物经约氏鼠疟原虫—斯氏按蚊系统病因性初筛有效。其中化合物Ⅱ_1,7,8,11,15和Ⅲ₁口服2.5mg/kg,连续3天,可使受试小鼠全部得到保护。