马蔺子甲素全合成工艺的研究

以邻丁香酚为原料，经苄基保护酚羟基、臭氧制备醛、缩合、加氢还原并脱苄基保护基、硅烷保护酚羟基、缩合、脱保护基、催化氧化八步反应合成了马蔺子甲素。使反应的成本比原路线有了很大的降低。总收率也有了一定的提高。     

阿司匹林维生素C酯的合成

以丙酮缩酮化反应保护维生素Ｃ５，６位羟基，再与乙酰水杨酸氯反应，经酸水解去保护基，制备阿司匹林维生素Ｃ－２一羟基酯，以维生素Ｃ计算总收率达７７．３％。     

去铁酮的合成

以3-羟基-2-甲基-4-吡啶酮为原料，经羟基保护、N-甲基化和脱保护基反应得到去铁剂去铁酮，总收率49％。     

青霉烯类抗生素Men-10700的合成

目的：合成新型青霉烯类抗生素Men-10700。方法：以4-乙酰氧基氮杂环丁-2-酮为起始原料，经取代、关环、生成目标侧链、脱保护基等8步合成目标化合物。结果与讨论：经。H—NMR，MS证明得到了Men-10700；其中改用对硝基苄基保护羧基，简化了后处理过程，对引入侧链和脱硅氧保护基2个步骤作了改进。     

他唑巴坦的合成

以2β－氯甲基青霉烷酸二苯甲酯为起始原料，经叠氮化、氧化后，用乙炔成三唑环，再用间甲苯酚脱羧基保护基制得新型β－内酰胺酶抑制剂他唑巴坦，总收率28％。     

阿斯巴甜的内酯法制备

以L－天冬氨酸为原料，采用内酯法并通过先脱羟甲基再去保护基的方法，以避免原酸酐工艺中β－阿斯巴甜副产物的生成，提高阿斯巴甜成品的质量。     

海洋天然产物brevianamide K的全合成

摘 要：目的 对海洋曲霉菌的次级代谢产物brevianamide K进行全合成研究，旨在解决其天然来源有限的问题，进而为其生物活性、作用机制的进一步研究以及同家族其他化合物的合成奠定基础。方法 以N-Pht-甘氨酸为起始原料，通过酰化、去保护、胺酯交换、乙酰基保护反应得到羟醛缩合反应的1个片段。以吲哚为起始原料，通过氯代、取代、Vilsmeier-Haack反应、保护基保护得到另1个片段。2个片段发生羟醛缩合反应后脱除保护基完成目标分子的全合成。结果 从商业可得化合物出发，通过最长线性7步反应，以9%的总收率完成brevianamide K的首次全合成，为后续活性研究和同家族其他化合物的合成奠定了基础。 关键词：brevianamide K；吲哚二酮哌嗪生物碱；羟醛缩合     

盐酸西曲酸酯的合成方法研究

以４－羟基苯丙酸２和反式４－氨甲环己烷羧酸４为起始原料，以丙酮基为保护基团，合成盐酸曲酸酯１，总收率为４０％左右，质量达到ＪＰⅩⅢ要求。     

选择性脱乙酰保护基的方法

以甲醇为溶剂，采用催化剂量的乙酰氯在温和的酸性条件下，高效地脱除伯醇、仲醇、芳香醇以及各种糖醇的乙酰保护基。在其它常用的酯基存在下。可选择性脱除乙酰基。反应条件温和，产物易纯化。22例收率73％～98％。     

马蔺子乙素的合成

以3-甲氧基水杨醛为原料,经羟基保护、缩合、还原,脱保护基和催化氧化五步反应合成马蔺子乙素。     

New 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs: synthesis and anti-HIV evaluation

New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of the 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Interestingly, these 5'-O-carbonate prodrug series show increased anti-HIV potencies in conjunction with, or without, reduced cytotoxicity as compared to AZT that lead to a gain in selectivity indexes. The cytotoxicity of AZT could be reduced with these 5'-O-carbonate prodrug series by delaying the 5'-O-glucuronidation of AZT, which is one of the major limitations of AZT.     

3'-Deoxythymidin-2'-ene permeation of human lymphocyte H9 cells by nonfacilitated diffusion.

3'-Deoxythymidin-2'-ene (d4T) is a potent and selective inhibitor of human immunodeficiency virus replication in a variety of human cell types and is currently undergoing phase I clinical trials for the treatment of acquired immunodeficiency syndrome. As part of our ongoing studies of the cellular pharmacology of d4T, and in light of recent reports in which such nucleoside analogs as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyadenosine were shown to permeate cells by the unusual mechanism of nonfacilitated diffusion, we have investigated the uptake of d4T in the human lymphocyte cell line H9. Several lines of evidence suggest that d4T permeation of H9 cells occurs by nonfacilitated diffusion; 1) [3H]d4T influx was linear for the first 10 sec and was nonconcentrative, reaching equilibrium with the extracellular drug concentration in 2-3 min, 2) the initial rates of influx were a linear function of concentration over the range from 1 microM to 5 mM, with no sign of uptake by a saturable mechanism, and 3) the uptake of [3H]d4T was insensitive to the nucleoside transport inhibitors nitrobenzylthioinosine and dipyridamole, as well as a large molar excess of AZT, thymidine, or adenosine. The octanol/water partition coefficient of d4T was 0.179, intermediate between those of thymidine and AZT. Thus, d4T does not appear to be a substrate for the nucleoside transport system responsible for the uptake of physiological nucleosides as well as most nucleoside analogs, and it enters the cell by nonfacilitated diffusion.     

Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines

3'-azido-3'-deoxythymidine (AZT) has been shown to be a potent inhibitor of thymidine kinase 2 in work from this laboratory. Inhibition results in decreased salvage of thymidine to TTP, which may lead to depletion of the TTP pool and result in the mitochondrial dysfunction and mt-DNA depletion observed with AZT toxicity. The effect of AZT on thymidine phosphorylation in growing cells expressing thymidine kinase 1 has not been shown. Three cell lines were used in these experiments: H9c2, derived from rat cardiomyoblasts; U-937, derived from human monocytes; and Raji, derived from human lymphoblasts. AZT inhibited growth in a concentration-dependent manner in U-937 cells, but not the other cell lines. The phosphorylation of [3H]-thymidine or [3H]-AZT was determined during log growth. All cell lines salvaged and phosphorylated thymidine to TTP, with TTP the major product. The U-937 cells had a much more active salvage pathway than the other cells. All cell lines phosphorylated AZT to the triphosphate, but the major product was AZTMP. The AZT inhibition of growth of the U-937 cells did not correlate with levels of the phosphorylated AZT. In contrast, pro-drug AZT was shown to inhibit thymidine phosphorylation in all lines with 50% inhibition concentrations (IC50) ranging from 4.4 to 21.9muM. Since the U-937 cells expressed higher activity of the salvage pathway than the other cell lines, the U-937 cells may rely more heavily on the salvage pathway for TTP synthesis, accounting for AZT inhibition of growth.     

Side-chain derivatives of biologically active nucleosides. 1. Side-chain analogs of 3'-azido-3'-deoxythymidine (AZT).

Starting from 3-O-mesyl-1,2-O-isopropylidene-alpha-D-allofuranose (9) the anomeric mixtures of the requisite carbohydrates 1,2-di-O-acetyl-6-O-benzoyl-5-deoxy-3-O-mesyl-D-allofuranoses++ + 17A alpha/beta, 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-D-allofuranoses 17B alpha/beta, and 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-L-talofuranoses 17C alpha/beta were synthesized. 1,2-Di-O-acetyl-5-O-benzoyl-6-deoxy-3-O-mesyl-D-allofuranoses++ + 17D alpha/beta and the corresponding L-talofuranoses 17E alpha/beta were obtained from 6-deoxy-3,5-di-O-benzoyl-1,2-O-isopropylidene-alpha-D- allofuranose (12) and the corresponding beta-L-talofuranose 13. Coupling of these sugar derivatives with thymine gave the beta-nucleoside derivatives 18A-E. Treatment of compounds 18A-E with DBU produced the corresponding 2,3'-anhydro nucleosides 19A-E with a free 2'-OH group. After deoxygenation of 2'-O-[[(4-methylphenyl)oxy]thiocarbonyl] compounds 20A-E with tributyltin hydride the 2,3'-anhydro bridge of the 2'-deoxynucleosides 21A-E was opened with LiN3 to produce the protected 3'-azido-2,3'-dideoxynucleoside derivatives 22A-G. Saponification with NaOCH3 gave 1-(3'-azido-2',3',5'-trideoxy-beta-D-allofuranosyl)thymine (2; homo-AZT), the 5'-C-(hydroxymethyl) derivatives of AZT 1-(3'-azido-2',3'- dideoxy-beta-D-allofuranosyl)thymine (3) and 1-(3'-azido-2',3'-dideoxy-alpha-L-talofuranosyl)thymine (4), and the 5'-C-methyl derivatives of AZT 1-(3'-azido-2',3',6'-trideoxy-beta-D-allofuranosyl)thymine (5) and 1-(3'-azido-2',3',6'-trideoxy-alpha-L-talofuranosyl)thymine (6). Compounds 2-6 were evaluated for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication in MT-4 cells and found inactive at subtoxic concentrations. Compounds 2-4 and 6 are not effective against herpes simplex virus type 1 (HSV-1) and type 2 (HIV-2), vaccinia virus (VV), and vesicular stomatitis virus (VSV) at 400 micrograms/mL. 5 is slightly active against HSV-1, HSV-2 and VV at 150, 300, and 300 micrograms/mL, respectively.     

Improved brain delivery of AZT using a glycosyl phosphotriester prodrug.

The concentration of AZT in mice plasma and brain was measured using HPLC after an ingestion of 20 mg/kg of AZT or the molar equivalent of hexadecyl 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate 3. The results demonstrated the promising qualities of the prodrug 3 which gave AZT-5'-phosphate as the main metabolite: the total concentration of AZT derivatives detected in brain presented a peak of 156 nmol/g (5 nmol/g for AZT) at 1 h; the half-life was about 24 h (1 h for AZT) with an AUC of 4366 nmol h/g as compared to 4 nmol h/g for AZT. The lipophilic properties of 3 were confirmed by its in vitro transport of inside synaptosomes. The derivative 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate (2) provided also a good delivery of AZT to the central nervous system, with values intermediate between those of AZT and 3.     

3'-Azido-3'-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria

Long-term use of 3'-azido-3'-deoxythymidine (AZT) is associated with various tissue toxicities, including hepatotoxicity and cardiomyopathy, and with mitochondrial DNA depletion. AZT-5'-triphosphate (AZTTP) is a known inhibitor of the mitochondrial DNA polymerase gamma and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart and liver mitochondria, AZT itself was shown to be a more potent inhibitor of thymidine phosphorylation (IC50 of 7.0+/-1.0 microM AZT in heart mitochondria and of 14.4+/-2.6 microM AZT in liver mitochondria) than AZTTP is of polymerase gamma (IC50 of >100 microM AZTTP), suggesting that depletion of mitochondrial stores of TTP may limit replication and could be the cause of the mitochondrial DNA depletion observed in tissues affected by AZT toxicity. The purpose of this work is to characterize the nature of AZT inhibition of thymidine phosphorylation in isolated rat heart and rat liver mitochondria. In both of these tissues, AZT was found to be a competitive inhibitor of the phosphorylation of thymidine to TMP, catalyzed by thymidine kinase 2. The inhibition constant (Ki) for heart mitochondria is 10.6+/-4.5 microM AZT, and for liver mitochondria Ki is 14.0+/-2.5 microM AZT. Since AZT is functioning as a competitive inhibitor, increasing thymidine concentrations may be one mechanism to overcome the inhibition and decrease AZT-related toxicity in these tissues.     

Structure-activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells

The structure-activity relationships of several pyrimidine nucleosides related to 3'-azido-3'-deoxythymidine (AZT) were determined in human immunodeficiency virus type 1 (HIV-1) infected human peripheral blood mononuclear cells. These studies indicated that nucleosides with a 3'-azido group on the sugar ring exhibited the most potent antiviral activity. Substitution at C-5 with H, CH3, and C2H5 produced derivatives with the highest potency, whereas alkyl functions greater than C2, including bromovinyl substitution reduced the antiviral potency significantly. Changing the 3'-azido function to an amino or iodo group reduced the antiviral activity. Replacement of the uracil ring by cytosine or 5-methylcytosine produced analogues with high potency and low toxicity. Modification of the 5'-hydroxy group markedly reduced the antiviral activity. Similarly, various C-nucleoside analogues related to AZT and 2',3'-dideoxycytidine were inactive and nontoxic. From these systematic studies 3'-azido-2',3'-dideoxyuridine (5a), 3'-azido-5-ethyl-2',3'-dideoxyuridine (5c), and 3'-azido-2',3'-dideoxycytidine (7a) and its 5-methyl analogue (7b) were identified as potent and selective anti-HIV-1 agent in primary human lymphocytes.     

Effect of dipyridamole on transport and phosphorylation of thymidine and 3'-azido-3'-deoxythymidine in human monocyte/macrophages

Dipyridamole (DPM), a commonly used coronary vasodilator and antithrombotic drug, was shown recently to potentiate the antiviral effect of 3'-azido-3'-deoxythymidine (AZT) in HIV-1 infected human monocyte-derived macrophages (M/M) in vitro. We report in the present study that in uninfected M/M, DPM markedly inhibited cellular uptake of [3H]thymidine (dThd) and its incorporation into the nucleotide pools, particularly the dThd-triphosphate pool. In contrast, DPM did not affect cellular uptake and phosphorylation of [3H]AZT. Since dThd counteracts the phosphorylation and antiviral action of AZT, these findings support the hypothesis that the potentiation of the anti-HIV effect of AZT is due, at least in part, to differential inhibition of nucleoside salvage.     

Antiretroviral activity and cytotoxicity of novel zidovudine (AZT) derivatives and the relation to their chemical structure

Zidovudine (AZT) was the first nucleoside analogue licensed for the treatment of HIV infection. Efforts have continuously been made to improve the therapeutic characteristics of this drug, most of them focussed on prodrugs design. Here we describe the anti-HIV-1 activity and cytotoxicity of six novel AZT derivatives namely 3'-azido-3'-deoxy-5'-O-oxalyl-N-valinethymidine, 3'-azido-3'-deoxy-5'-O-oxalyl-N-leucinethymidine, 3'-azido-3'-deoxy-5'-O-oxalyl-N-isoleucinethymidine, 3'-azido-3'-deoxy-5'-O-oxalyl-N-phenylalaninethymidine, 3'-azido-3'-deoxy-5'-O-oxalylthymidine acid, 3'-azido-3'-deoxy-5'-O-isonicotinoylthymidine and 5-chloro-6-hydroxy-5,6-dihydro-3'-azido-3'-deoxythymidine which were perfectly characterized. AZT-Val, AZT-Leu, AZT-iLeu, AZT-Phen, AZT-Ac and AZT-Iso have shown a similar or higher selectivity index than that of AZT itself, in one or both of the different cell cultures used (PBMC and MT2). However, AZT-ClOH showed no anti-HIV activity. These results suggest that using amino acids in the design of AZT derivatives improves AZT activity.     

Synthesis and antiviral activity of several 2,5'-anhydro analogues of 3'-azido-3'-deoxythymidine, 3'-azido-2',3'-dideoxyuridine, 3'-azido-2',3'-dideoxy-5-halouridines, and 3'-deoxythymidine against human immunodeficiency virus and Rauscher-murine leukemia virus

Several 2,5'-anhydro analogues of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-2'3'-dideoxyuridine (AZU), 3'-azido-2'3'-dideoxy-5-bromouridine, 3'-azido-2',3'-dideoxy-5-iodouridine, and 3'-deoxythymidine and the 3'-azido derivative of 5-methyl-2'-deoxyisocytidine have been synthesized for evaluation as potential anti-HIV (human immunodeficiency virus) agents. These 2,5'-anhydro derivatives, compounds 13-17, demonstrated significant anti-HIV-1 activity with IC50 values of 0.56, 4.95, 26.5, 27.1, and 48 microM, respectively. Compared to that of the parent compounds AZT and AZU, the respective 2,5'-anhydro analogues, compounds 13 and 14, were somewhat less active. Whereas AZT was cytotoxic with a TCID50 of 29 microM, the toxicity of the 2,5'-anhydro derivative of AZT, compound 13, was reduced considerably to a TCID50 value of greater than 100 microM. The 2,5'-anhydro analogue of 5-methyl-2'-deoxyisocytidine also demonstrated anti-HIV-1 activity with an IC50 value of 12 microM. These compounds were also evaluated against Rauscher-Murine leukemia virus (R-MuLV) in cell culture. Among them, AZT, 3'-azido-2',3'-dideoxy-5-iodouridine, 3'-azido-2',3'-dideoxy-5-bromouridine, and 2,5'-anhydro-3'-azido-3'-deoxythymidine (13) were found to be most active, with IC50 values of 0.023, 0.21, 0.23, and 0.27 microM, respectively.