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用固相法合成了促δ-波睡眠肽Trp-Ala-Gly-Gly-Asp-Ala-Ser-Glu(DSIP)及其十四种类似物和三个短肽,研究了结构与功能的关系,类似物的设计,主要考虑在分子中引入D-氨基酸以抑制酶的作用和增强稳定性,以及引入疏水侧链氨基酸如Phe和Trp等。位置的修饰主要在1,3,4,5,8和9位,即:D-Trp[1],Tyr[1],Tyr[1]Phe[5],D-Trp[1]Phe[8],Trp[3,4],D-Trp[3,4],D-Trp[1,3,4]Phe[8],D-Glu[9],D-pF-Phe[3,4]Phe[8]D-Glu[9],Phe[5],Glu[5]Asp[9],Tyr[5]Asp[9],Ala[7]和Asp[9]-DSIP以及Trp-Ala-Gly-Gly-Asp,Trp-Ala-Gly-Gly-Glu和Trp-Gly-Glu.合成肽的纯度经氨基酸组成分析、元素分析、薄层层析以及纸电泳鉴定。生物试验表明D-Trp[1],Tyr[1],Tyr[1]Phe[5],Ala[7]-DSIP无促眠活性;而Phe[5]-DSIP的促眠活性与DSIP相接近,其他类似物的生物试验结果将另文发表。 相似文献
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胸腺素α1的C端活性片段环肽类似物的合成与生物活性评价 总被引:1,自引:0,他引:1
用硫酯法合成了一系列Tα1的C端活性片段的环肽类似物, 以提高其活性与稳定性. 用促淋巴细胞增殖法测定了环肽类似物的生物活性, 结果表明, 环肽类似物较好地保留或提高了促淋巴细胞增殖活性. 相似文献
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设计合成了一类侧链带有络合基团的非天然氨基酸, 即侧链带有N,N-二羧甲基氨甲基、N,N-二酰胺甲基氨甲基和N,N-二羟乙基氨甲基的苯丙氨酸衍生物, 并将这类非天然氨基酸用于促性腺激素释放激素(LHRH)类似物的固相合成. 高效液相色谱分析结果表明, 粗肽的纯度较好, 易于纯化; 用电喷雾质谱测定了多肽的分子量. 这些非天然氨基酸可作为其它肽类药物合成的构建单元. 相似文献
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以非经典叶酸拮抗剂2,4-二氨基-6-(4-甲基苯基)乙基吡啶并[3,2-d]嘧啶(wm-5b)及其侧链简化产物2,4-二氨基吡啶并[3,2-d]嘧啶为先导化合物, 选取具有抗肿瘤活性的基团, 通过微波法高效合成了2-位或4-位取代吡啶并嘧啶类非经典叶酸拮抗剂, 研究了2-位及4-位取代基对抗肿瘤活性的影响, 为非经典叶酸拮抗剂的设计合成提供了更多的理论依据. 目标化合物的结构均经核磁共振波谱(NMR)和质谱(MS)确证. 生物活性测定结果表明, 所有目标化合物均具有抗肿瘤活性, 其中, 6-(4-甲基苯基)乙基-4-氨基-2-(3-氯-4-氟苯基)氨基吡啶并[3,2-d]嘧啶(6b)对HL-60细胞的IC50=(4.09±0.48) μmol/L, 对A549细胞的IC50=(17.99±7.20) μmol/L, 而对HCT116细胞的IC50=(14.52±4.74) μmol/L; 部分目标化合物具有二氢叶酸还原酶抑制活性. 此外, 对部分目标化合物和先导物进行了二氢叶酸还原酶晶体结构的分子对接, 对活性结果和构效关系从分子水平上进行解释. 相似文献
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合成了光敏基团位于sn-1脂肪酰基上的光亲和标记磷脂酸(PA)类似物,选用了有较高C-H插入效率的全氟苯基叠氮化合物作为光敏基团.用酶化学方法在PA类似物中引入了同位素标记33P.初步实验表明,合成的PA类似物与天然PA一样对cAMP-磷酸二酯酶有激活作用,提示合成的PA类似物可进一步用于该酶的光亲和标记. 相似文献
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放线菌素D(Actinomycin D,AMD,其结构如Scheme 1所示)是肿瘤的临床治疗药物之一,用于小儿肾母细胞瘤(Wilm’s tumor)、恶性葡萄胎及妊娠绒毛膜上皮癌等一些恶性肿瘤的治疗,但由于毒性太大而限制了其应用范围。 相似文献
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Introduction Actinomycin D (ActD, Figure 1.), containing a planar phenoxazone ring and two cyclic pentapeptides, is one of the most intensely studied anticancer drugs and currently used to treat highly malignant tumors, such as Wilms' tumor and gestational choriocarcinoma. Although ActD possesses high antitumor activities, its clinical usefulness is limited by its extreme cytotoxicity. Thus, if the structure of ActD can be modified to reduce its cytotoxicity while retaining its activity, such an analogue would be a better antitumor drug. On the basis of X-ray crystal structures of the complexes between ActD and DNA[1], and our work [2], we designed and totally synthesized two ActD analogs 8a-b iii which both of the (L)-N-methyl-valine residues of ActD were replaced with LN-MeAla and L-N-MeSer, respectively. The anticancer pharmacology of the two analogs were examined. The result shows that the toxicity of the two analogs are higher than ActD and the antitumoe activity are lower than ActD, too. 相似文献
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Pedro Lois Suarez 《Tetrahedron letters》2004,45(24):4619-4621
Efficient preparation of vitamin D CD ring system synthons with triazole rings in their side chains is based on the formation of the triazole ring from a [3+2]-cycloaddition of a vitamin D side chain terminal azide with a terminal acetylene. 相似文献
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抗癌药物放线菌素D类似物的全合成及生物活性研究 总被引:4,自引:0,他引:4
抗癌药物放线菌素D(ActinomycinD,AMD)与模板DNA相结合,可防止转录反应,能抑制新的RNA形成,临床上被用于治疗恶性肿瘤,但因毒性太大,不能被推广应用[1].为了降低其毒性,研究构效关系[2],我们在AMD-DNA复合物晶体结构研究工... 相似文献
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A series of 2-[1-(2-formylamido-3-phenylpropionyloxy)alkyl]-1,4-dihydroxy-9,10-anthraquinone(2FPADHAQ) derivatives was designed and synthesized.Their antitumor activities were tested against L1210 tumor cells and P388 mouse leukemic tumor cells in vitro and in ICR mice bearing sarcoma 180 cells in vivo.Overall,the introduction of 2-formylamido-3-phenyl-propanoic acid(2-FPPA) into the C-2-alkyl side chain C’-1 hydroxy group in 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinones(2-HDHAQ) enhanced the antitumor activity compared with the starting materials.2-FPADHAQ with alkyl chains longer than the pentyl group had negligible activity,whereas compounds 2b,2c,2d and 2e possessing shorter chains demonstrated moderate cytotoxic activity[50% effective dose(ED 50) of L1210 and P388 are 2.61―4.75 and 5.84―8.74 μg/mL],whereas compound 2l with an aromatic system showed strong cytotoxic activity.T/C(%) values[(average survival days in the test group)/(average survival days in the control group)×100%] also show that the introduction of 2-FPPA into the side chain of 2-HDHAQ enhanced antitumor activity.These data suggest that the introduction of an amino acid into the starting material may increase its affinity for DNA or its selectivity for proliferating cancer cells. 相似文献
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T Hashimoto H Masui Y Uchida N Sakura K Okimura 《Chemical & pharmaceutical bulletin》1991,39(9):2319-2322
To study the structure-activity relationships of neuromedin U-8 (NMU-8) (H-Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2) and to develop a NMU-8 antagonist, twenty-three NMU-8 analogs substituted with Gly or the corresponding D-amino acid(s) at positions 1-8 were synthesized by solid-phase techniques. On isolated chicken crop preparations, the contractile activity of the synthetic NMU-8 analogs was compared with that of NMU-8 and their antagonistic activity was assayed against NMU-8. The replacement of Phe2, Phe4, Arg5, Pro6, Arg7 or Asn8 with Gly brought about a drastic decrease of the agonistic activities. Substitution of the corresponding D-amino acid residue for Phe2, Phe4, Arg5, Pro6 or Asn8 caused a marked decrease of the agonistic activities, while the replacement of Tyr1 with D-form enhanced the activity. It was further revealed that [D-Pro6]-NMU-8 and [D-Leu3, D-Pro6]-NMU-8 exerted a non-competitive antagonistic activity against NMU-8 with x values of 5.22 +/- 0.12 and 5.34 +/- 0.09, respectively. [D-Phe2, D-Pro6]-NMU-8, [D-Arg5, D-Pro6]-NMU-8 and [D-Pro6, D-Asn8]-NMU-8 showed a very weak antagonism. The results indicated that 1) the side chain of each amino acid at positions 2, 4, 5, 6, 7 and 8 of NMU-8 is of relative importance for the expression of the contractile activity, and 2) [D-Pro6]-NMU-8 and its four analogs acted as an antagonist against NMU-8. 相似文献
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Ten Tyr-D-Arg-Phe-betaAla-NH(2) (YRFB) analogs in which specific amino acid side chains are shifted to the N(alpha)-position were synthesized, and the binding to these analogs to the mu receptor and their in vitro biological properties were evaluated. Some analogs in which a N,N-bis(p-hydroxybenzyl)-Gly residue was substituted for Tyr(1) exhibited mu receptor antagonist activities (pA(2)) between 5.3 and 6.1. Of these analogs, [N,N-bis(p-hydroxybenzyl)-Gly(1)]YRFB was found to be the most potent specific antagonist for the mu-opioid receptor. 相似文献
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Naito H Ohsuki S Sugimori M Atsumi R Minami M Nakamura Y Ishii M Hirotani K Kumazawa E Ejima A 《Chemical & pharmaceutical bulletin》2002,50(4):453-462
A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects. 相似文献
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The use of alkyl ammonium cations resulted in four compounds of (A)[FeIII(ox)Cl2] (A = Et3NH+ (1a, 1b), Me4N+ (2), and n-Bu4N+ (3); ox = oxalate), whose structures and magnetic properties were characterized. In all cases, the metal Fe(III) ions are six-coordinated by four oxygen atoms from two bischelating oxalate ligands and the two terminal Cl- ions in the cis position. Thus they form similar anionic 1D [FeIII(ox)Cl2]- chains. The chains are separated by alkyl ammonium cations in the lattice, and the cation size seems to control the interchain separation and packing patterns in the solid. A parallel arrangement of the [FeIII(ox)Cl2]- chains is observed for 1a, 2, and 3, while a crossed one is observed for 1b, which is a polymorph of 1a. Magnetic studies reveal the antiferromagnetic intrachain interactions in all compounds. The last three compounds, 1b, 2, and 3, show spin canting below 14.5, 9.5, and 3.8 K, respectively. The dipolar interaction over the interchain distance is proposed to be the result of 3D magnetic ordering in the materials. 相似文献
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为了探索金属离子对含有不同侧链的多肽气相解离的影响, 采用质谱法研究了碱金属离子Li+, Na+, K+, Rb+和Cs+分别与丝氨酸、 亮氨酸和赖氨酸五肽(分别简写为S5, L5和K5)形成的复合物的裂解反应. 质谱定性结果表明, 5种碱金属离子均可以在气相中与丝氨酸、 亮氨酸和赖氨酸五肽形成配合比为1∶1 和2∶1的非共价复合物; 竞争反应结果表明, 随着碱金属离子半径的增加, 它们与3种五肽的结合能力逐渐减弱. 质谱定量结果表明, K+与丝氨酸、 亮氨酸和赖氨酸五肽复合物的结合常数分别为8.94×104, 2.83×104和2.50×103 L/mol, 表明K+与五肽复合物的结合强度按照丝氨酸、 亮氨酸和赖氨酸的顺序依次减小. 含不同侧链碱金属离子-五肽复合物的碰撞诱导解离结果表明, 复合物的碎裂主要发生在骨架上, 丝氨酸五肽复合物最易碎裂, 亮氨酸五肽复合物其次, 赖氨酸五肽复合物则较难碎裂, 且3种复合物的侧链断裂情况也呈现明显差异. 此外, 研究了Na+与亮氨酸五肽复合物所产生的碎片离子, 分析了不同离子之间的来源关系, 并以Dunbar的复合物理论模型为依据, 推测在碎裂过程中, 碱金属离子可能向五肽的碳端或氮端偏移. 质谱碎片分析结果表明, 在2∶1的非共价复合物中, 第一个碱金属离子与五肽上4个酰胺键的羰基结合, 第二个碱金属离子与五肽的羧基氧原子结合. 相似文献