7α-和7β-甲基-10β,17β-二乙酰氧基-△4-雌甾烯-3酮的抗早孕作用

7α-和7β-甲基-10β,17β-二乙酰氧基-△⁴-雌甾烯-3酮(简称7α-和7β-甲-乙氧雌酮)对小鼠抗早孕ED₅₀分别为1.6和5.5 mg/kg。7α-甲-乙氧雌酮在大鼠也有抗早孕作用并使血浆孕酮浓度降低,应用10 μg/ml浓度能抑制离体妊娠大鼠卵巢孕酮合成。7α-和7β-甲-乙氧雌酮与兔子宫胞浆雌二醇受体的相对结合亲和力(RBA)分别为10.8和1.5,与孕酮受体的RBA均<1.7α-和7β-甲-乙氧雌酮都有较弱的雌激素和抗雌激素活性。     

含L-4-氧代赖氨酸和N3-(4-甲氧基富马酰)-L-2,3-二氨基丙酸寡肽类似物的合成及其抗白念珠菌活性

运用“违法传递”概念,根据白念珠菌对寡肽的传送特点,设计并合成了8个含L-4-氧代赖氨酸(以下称I-677)和N³-(4-甲氧基富马酰)-L-2,3-二氨基丙酸(以下称FMDP)的寡肽类似物,均系新化合物。体外抗白念珠菌试验表明:I-677-FMDP-肽(I-677-FMDP,I-677-AA-FMDP,其中AA=Nva,Val,Leu,Phe,Pro,D,L-p-Cl- Phe,D-Pgly)是I-677单体摩尔活性的40～770倍,是FMDP的60～1130倍,其摩尔最低抑菌浓度为6.56×10^-9～3.5×10^-10mol·disk^-1。羧肽酶A存在时化合物I-677-FMDP体外抗菌试验表明,含FMDP的化合物I-677-FMDP能抵抗羧肽酶A的酶解。     

13C核磁共振技术测定鱼肝油中ω-3脂肪酸α(1,3)-酰基和β(2)-酰基的位次分布

目的 应用¹³C核磁共振（¹³C-NMR）光谱测定鱼肝油中ω-3脂肪酸[十八碳四烯酸（C18：4 n-3,moroctic acid,MA）、二十碳五烯酸（C20：5 n-3,eicosapentaenoic acid,EPA）、二十二碳六烯酸（C22：6 n-3,docosahexaenoic acid,DHA）]形成的甘油三脂中α（1,3）-酰基、β（2）-酰基的位次分布。方法 用CDCl₃溶解样品,利用高分辨核磁共振光谱直接测定。结果 鱼肝油中MA、EPA和DHA α（1,3）-酰基、β（2）-酰基在δ 171.5~173.5 ppm的化学位移与文献报道基本一致。2批次鱼肝油未发现上述ω-3脂肪酸特征峰,4批次鱼肝油有特征峰检出,但是β（2）-酰基的位次分布不同。按照β（2）-酰基的比例,4批鱼肝油来源于家养鱼类提取的可能性较大。结论 应用该¹³C核磁共振技术可以鉴别鱼肝油的优劣,方法简单、快捷。     

β-谷甾醇侧链的降解:Δ4-雄甾烯-3,17-二酮的生成

用牝牛分枝杆菌(Mycobacterium vaccae 209-20)切断β-谷甾醇(Ib)的侧链,获得△⁴-雄甾烯-3,17-二酮(Ⅱ)和少量的△^1.4-雄甾烯-3,17-二酮(Ⅲ)。产物Ⅱ的收率为32%。     

血吸虫病化学治疗的研究——ⅩⅩⅩⅣ.α-氯-β-(5-硝基-2-呋喃)丙烯酰胺类及其乙烯噁二唑类衍生物的合成

Synthesis of 35 new compounds of α-chloro-β-(5-nitro-2-furyl) acrylamides and 5-[α-chloro-β-(5-nitro-2-furyl ) vinyl]-oxadiazoles by known methods are reported. In preliminary test in mice 10 compounds were found to possess pronounced activity against Schistosomiasis japonica. Among these Ⅰ₁₂, Ⅰ₁₃, Ⅰ₁₄, Ⅰ₂₀, Ⅱ₁ and Ⅱ₈ were shown to be the most effective.     

甲基黄酮醇胺盐酸盐对β受体的阻断作用

The β-receptor blocking action of methylflavonolamine hydrochloride(MFA) was studied and compared with those of propranolol. The doseresponse curves of isoproterenol were shifted to the right by MFA on isolated rabbit atrium in this experiment. The pA₂ value and the slope of the regression line of MFA calculated from Schild plot were 5.53 and -0.84 respectively. The effects of MFA and propranolol on duck erythrocyte membranes were studied by the radioligand binding method. Both MFA and propranolol inhibited the binding of [³H] dihydroalprenolol to β-receptors. Their apparent equilibrium dissociation constants were 1.12×10^-5 mol/L and 5.50×10^-9 mol/L respectively. The affinity of propranolol to β-receptors of duck erythrocyte membranes was 2039-fold higher than that of MFA. These results demonstrates that MFA is a weak competitive β-receptor blocking agent.     

VKORC1-3673G>A、CYP2C9*3、CYP4F2 rs2108622和CYP2C19*2基因多态性对中国汉族房颤患者华法林维持剂量的影响

目的 探讨VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2位点基因多态性对中国汉族房颤患者华法林维持剂量的影响。方法 收集107例服用华法林达维持剂量的汉族房颤患者的血样和临床相关资料,应用PCR-RFLP法检测VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2基因型,采用独立样本t检验分析基因型与华法林维持剂量的相关性。多元线性回归建立给药模型,探讨基因多态性对华法林维持剂量的影响。结果 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性和患者年龄、体质量能解释45.2%的华法林维持剂量差异。CYP2C19^*2基因多态性对本研究人群华法林维持剂量无影响。结论 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性显著影响中国汉族房颤患者的华法林维持剂量。     

化学—酶法立体控制合成光学纯L-羟基苯丙氦酸的新方法

Optically pure L-3(2-hydroxyphenyl) alanine(L-o-tyrosine ,Ⅲa,),L-3-(3-hydroxyphenyl) alanine(L-m-tyrosine,Ⅲb )and L-3-(4-hydroxyphenyl )alanine(L-p-tyrosine,Ⅲc )were synthesized by the stereocontrolled amination of corresponding hydroxycinnamic acld(Ⅱ)catalyzed by L-phenylalanine ammonia-lyase(PAL,EC4.3.1.5 )contained in Rhodoterula rubramycelium. The amination of compound Ⅱ was completed in aqueous ammonia solution( 6.4mol·L^-1,pH10.5, 30℃) with the conversion of 74.9%(Ⅱa),21.1%(Ⅱb)and 20.6%(Ⅱc)respectively.The absolute configuration of the products Ⅲa～c were confirmed by circular dichroism(CD),and chiral high-performance ligand exchange chromatography(HPLEC)showed that productsⅢ were optically pure L-isomers.     

3,4-二羟基苯乙酮(DHAP)对离体心肌电活动和机械活动的作用

The effects of DHAP on electrical and mechanical activities were investigated by synchronously recording action potential and isometric tension in isolated myocardium. No influence was demonstrated on action potential (APA, APD₂₀、APD₉₀) by DHAP 10^-5～10^-3M in guinea pig palillary muscle. The inhibition on the force of contraction with the same concentration of DHAP, however, was shown in a concentration-dependent way. The effects of DHAP on the electrical and mechanical activities in cat papillary muscle were similar to those in guinea pig papillary muscle. With the dose of DHAP 10^-5～5×10^-4M, alteration of action potential of pacemaker cells was not observed in the isolated sinus node preparation of the rabbit. When the dosage was increased to 10^-3 M, the electrical activities were inhibited. The experimental results indicate that the effects of a certain dose of DHAP on inhibiting the tension in myocardium are available in clinical application. A warning is given that an increase in dosage may enhance the inhibition on contractile force in myocardium and inhibit the automaticity of sinus node pacemaker cells.     

蝙蝠葛中的新生物碱——N-去甲基蝙蝠葛碱

A new phenolic dauricine-type alkaloid together with the know dauricine, were iso-lated from the rhizoma of Menispermum dauricum DC cultivated in Xianning district, Hubei province.Dauricine was obtained as the major alkaloid and was confirmed by comparison with authentic sample.The new alkaloid is an unstable white powder. Based on spectrometric analysis (UV, IR, FAB--MSand ¹HNMR) and N-methylation which offered clauricine dimethiodide(Ⅴ), the structure was elucidat-ed as RR, N-desmethyldauricine(Ⅱ), which was isolated for the first time from nature.     

11-酮基-△9-炔诺酮的合成

We have introduced a carbonyl group at the 11-position and a double bond at the 9-position of norethisterone in order to increase its antifertility potency. The starting material for the preparation of 11-keto-Δ⁹-noret-histerone(9) was 19-hydroxy-Δ⁴-androstene-3,17-dione(1), which was converted to the title compound by partial synthesis through the sequence of reactions:(1)→(9).11-Keto-Δ⁹-norethisterone was found to possess very potent antifertility effect by preliminary screening tests.     

4(3H)-喹唑啉酮衍生物的合成及体外抗肿瘤活性

将6-溴甲基-2-甲基-4(3H)-喹唑啉酮在无水磷酸钾存在下与二硫化碳以及不同的胺反应，合成了一系列具有二硫代氨基甲酸酯侧链的4(3H)-喹唑啉酮衍生物，其结构经ESI-MS，¹H NMR，元素分析或HRMS所证实。采用MTT法测定了目标化合物8a~8q对人慢性髓性白血病K562细胞和人宫颈癌Hela细胞的体外抗肿瘤活性，结果表明化合物8q对K562和Hela细胞的体外生长具有显著的抑制作用，IC₅₀值分别为0.5和12.0 μmol·L^-1，因而可作为抗肿瘤药物研究的先导化合物。     

β-受体阻断剂对异丙肾上腺素提高心肌耗氧量作用的影响

The blockade effect of β-receptor blockers bupranolol and ACC9089 on the increase of heart muscle oxygen consumption by isoprenaline was studied according to Castellucci's method with Warburg's apparatus on thin slices of swine heart muscle instead of the rabbit heart muscle. The results showed that Bupranolol was about 2.5 times more stronger than practolol and about 2 times more stronger than ACC-9089 to block the increase of effects of isoprenaline for swine heart muscle oxygen consumptions on equal molar concentration levels. The results showed also that only the secondary higher concentration of 4 different concentrations of ACC-9089 could block the β-receptor to decrease the heart muscle oxygen consumption in comparison with the control. It was suggested that the highest molar cone. (1.72×10^-3M) of ACC-9089 would probably show an intrinsic sympathomimetic effect which could overlay its blockade effect to β-receptors. That the β-receptor blockers would act as the competitions with isoprenaline to the β-receptors according to their similarity of the side chain chemical structures has been discussed.     

7α和7β-甲基-10β,17β-二乙酰氧基-4-雌甾烯-3-酮的合成

由于7α-甲基或10β-乙酰氧基4(5)烯-3-酮雌(雄)甾化合物具有显著的抗着床或抗蜕膜活性,我们合成了既具有7α-甲基或7β-甲基又具有10β-乙酰氧基的两个新甾族化合物(1_a)和(1_b)。经药理试验表明(1_a)和(1_b)对孕鼠均有抗早孕作用。     

氚标记强效镇痛剂N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺的制备以及与阿片受体的结合试验

本文报道以N-[1-(对-溴苯甲酰甲基)-3-甲基-4-哌啶基]-N-丙酰苯胺(Ⅲ)为前体,以PdO/BaSO₄作催化剂,用氚气进行卤—氚置换,氚化还原羰基的反应。反应产物经硅胶纸层析纯化后,用甲基橙比色法定量测定,得到N-{1-[β-羟基-β-氚-β-(对-氚苯基)乙基]-3-甲基-4-哌啶基}-N-丙酰苯胺(Ⅳ,[³H]F-7302),其比放射性为59 Ci/mM,放化纯度为98%。[³H]F-7302与小鼠脑内阿片受体的特异性结合在浓度为4.5×10^-9M时达到饱和,解离常数Kd=1.25×10^-9M,最大结合量B_max=93.08×10¹²M/g蛋白,其特异性结合与非特异性结合比值达10～15。     

α-青心酮对损伤的脑线粒体Na+,K+-ATPase活性和脑细胞耗氧的作用

目的研究α-青心酮对抗坏血酸和硫酸亚铁诱导脑线粒体Na⁺，K⁺-ATPase活性和脑细胞耗氧的作用。方法采用无机磷法测定Na⁺，K⁺-ATPase活性,分光光度法检测脑线粒体膨胀和脂质过氧化物，氧电极法测定脑细胞耗氧量。结果在抗坏血酸和硫酸亚铁的作用下，鼠脑线粒体Na⁺，K⁺-ATPase活性降低，线粒体膨胀和脑细胞脂质过氧化物升高。α-青心酮抑制其抗坏血酸和硫酸亚铁诱导脑线粒体和细胞的损伤,增加Na⁺，K⁺-ATPase活性，降低脑线粒体膨胀和脑细胞脂质过氧化物生成。α-青心酮还具有减少ADP刺激的脑细胞耗氧的作用。结论α-青心酮通过清除自由基和抗氧化作用保护脑细胞结构和功能的完整。     

1-氨基-6-氟-1,4-二氢-4-氧代-7-(取代)哌嗪基-3-喹啉羧酸及其衍生物的合成与抗菌活性

The title compounds 6～24 were obtained by the reaction of 5 with corresponding benzaldehydes. 5 wes prepared with ethyl 7-chloro-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate by hydrolysis, amination and condensation with piperazine. Anti—bacterical activities of 5～24 were tested in vitro.     

北京鸭红细胞膜β肾上腺素受体放射配基结合测定法

本文以[³H]dihydroalprenolol([³H]DHA)为放射配基。对北京鸭红细胞(RBC)膜β受体进行了系统研究。结果表明,[³H]DHA与北京鸭RBC结合具有饱和性,肾上腺素能激动剂与[³H]DHA竞争结合的强弱顺序与它们的生物活性一致,提示结合有结构特异性和立体特异性,[³H]DHA与鸭RBC结合迅速、可逆。可见北京鸭RBC膜存在β受体,用于放射配基结合测定有取材方便,受体较丰富,膜蛋白得率高,[³H]DHA非特异结合低和易于保存等优点,可以代替火鸡RBC。     

20(R)-人参皂苷Rg3人体药代动力学研究

目的　研究20(R)-人参皂苷Rg3(GRg3)人体药代动力学。方法高效液相色谱－紫外检测法。结果　8名健康志愿者单剂量口服3.2mg.kg^-1GRg3,其药时曲线符合口服吸收有滞后时间的二房室模型,T_max为(0.66±0.10)h,C_max为(16±6)ng.mL^-1,T_1/2α为(0.46±0.12)h,T_1/2β为(4.9±1.1)h,T_1/2(Ka)为(0.28±0.04)h,AUC_0-∞为(77±26)ng.mL^-1.h;6名健康志愿者单剂量口服0.8mg.kg^-1GRg3,由于血药浓度低,可测数据点少,未进行模型模拟;两组给药剂量与相应C_max实测值比较,二者成正比关系。结论　本品口服吸收快,消除也较快,但血药浓度很低。在所试剂量范围内,GRg3属一级动力学吸收、消除过程。     

新的高强度高选择性阿片μ受体激动剂[11C]-羟甲芬太尼的合成

羟甲芬太尼(I)是一个新的高强度高选择性阿片μ受体激动剂。本文用cis-A-N-[1-(2-羟基-2-苯乙基)-3-甲基-4-哌啶基]-苯胺(II)或cis-N-[1-(苯甲酰甲基)-3-甲基-4-哌啶基]-苯胺(III)作为前体合成了[¹¹C]-羟甲芬太尼,以便用正电子发射断层扫描(PET)来观察μ受体。通过水解cis-A-羟甲芬太尼(I)和cis-N-[1-(苯甲酰甲基)-3-甲基-4-哌啶]-N-苯基丙酰胺(cis-IV)的4-N-丙酰基分别获得II和III。溴乙烷的格氏试剂与回旋加速器产生的[¹¹C]-二氧化碳反应后继而直接加入邻苯二甲酸二酰氯和2,6-二叔丁基吡啶生成同位素标记中间体[¹¹C]-丙酰氯。[¹¹C]-丙酰氯与OH-前体(II)反应后再经HPLC分离纯化直接得[¹¹C]-羟甲芬太尼;[¹¹C]-丙酰氯与酮-前体(III)反应后,再用硼氢化钠甲醇溶液处理,然后进行HPLC分离纯化得[¹¹C]-羟甲芬太尼。两种方法均可获得ll.1～14.8GBq/μmol的特异性放射化学纯[¹¹C]-羟甲芬太尼。总共耗时为40～50min(EOB)。