2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

2-吡啶甲醇及2-吡啶甲醛的合成

以 2 -甲基吡啶为原料、过氧化氢为氧化剂制备 2 -吡啶甲醇和 2 -吡啶甲醛,工艺方法经济、安全     

2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase

It has been found that 2'-deoxy-2'-methyleneuridine (MdUrd), 2'-deoxy-2'-methylenecytidine (MdCyd), and 2'-deoxy-2',2'-difluorocytidine (dFdCyd) 5'-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3' to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3' to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd and dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.     

Synthesis and biological activities of 2-pyrimidinone nucleosides. 2. 5-Halo-2-pyrimidinone 2'-deoxyribonucleosides

1-(2-Deoxy-beta-D-ribofuranosyl)-5-bromo-2-pyrimidinone (BrPdR) and 1-(2-deoxy-beta-D-ribofuranosyl)-5-iodo-2-pyrimidinone (IPdR) have been synthesized by condensation of the appropriate silylated bases 2a and 2b, respectively, with 3,5-bis-O-(p-chlorobenzoyl)-2-deoxy-alpha-D-ribofuranosyl chloride (8) in 1,2-dichloroethane, in the presence of SnCl4, followed by separation of the anomeric blocked nucleosides via column chromatography and subsequent deprotection with methanolic ammonia. Both BrPdR and IPdR exhibited significant antiherpes activities against various strains of HSV-1 and HSV-2, the latter compound (IPdR) showing the higher activity as well as the stronger binding to the virus-specific thymidine kinase.     

Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphate

A rhodopsin-based homology model of the nucleotide-activated human P2Y2 receptor, including loops, termini, and phospholipids, was optimized with the Monte Carlo multiple minimum conformational search routine. Docked uridine 5'-triphosphate (UTP) formed a nucleobase pi-pi complex with conserved Phe3.32. Selectivity-enhancing 2'-amino-2'-deoxy substitution interacted through pi-hydrogen-bonding with aromatic Phe6.51 and Tyr3.33. A "sequential ligand composition" approach for docking the flexible dinucleotide agonist Up4U demonstrated a shift of conserved cationic Arg3.29 from the UTP gamma position to the delta position of Up4U and Up4 ribose. Synthesized nucleotides were tested as agonists at human P2Y receptors expressed in 1321N1 astrocytoma cells. 2'-Amino and 2-thio modifications were synergized to enhance potency and selectivity; compound 8 (EC50 = 8 nM) was 300-fold P2Y2-selective versus P2Y4. 2'-Amine acetylation reduced potency, and trifluoroacetylation produced intermediate potency. 5-Amino nucleobase substitution did not enhance P2Y2 potency through a predicted hydrophilic interaction possibly because of destabilization of the receptor-favored Northern conformation of ribose. This detailed view of P2Y2 receptor recognition suggests mutations for model validation.     

Mass Spectra of Amides of 2-Amino-2-thiazoline

Five fragmentation patterns of the molecular ions of sixteen amides of 2-amino-2-thiazoline and of one deuteriophenyl derivative are described: when R is a phenyl group substituted in ortho position by an R″ group, the [M-R″]⁺ ion is the main fragment, whereas in the other cases R″ = substituent in meta or para position it is the ion [M-H]⁺. The amino?imino tautomerism of these molecular ions was studied. In addition, a correlation was found between the fragmentation patterns of the molecules and their pharmacological activities.     

Penicillin-enhanced chemiluminescence of the luminol-H2O2-Co2+ system.

The luminol-H2O2-Co2+ system has been widely used in chemical and biological analysis. We report here an investigation of the observation that penicillins have the ability to prolong and enhance the intensity of chemiluminescence from luminol. The basis of this phenomenon appears, as revealed by difference spectroscopy, to be the formation of a complex between the beta-lactam and the superoxide ion. The latter is the oxidizing species responsible for the oxidation of luminol in alkaline solution and has a mean lifetime, in solution, of milliseconds. The stabilization of the superoxide ion by penicillin complexation extends the effective lifetime of the superoxide ion by a few orders of magnitude and thereby allows for more efficient oxidation of the beta-lactam. Several penicillins were determined by their enhancement of luminol chemiluminescence. A detection limit of 100 ng mL was obtained for penicillin G with a less-than-ideal detection system.     

m-Cholinergic Properties of 2-Amino-2-thiazoline Derivatives

Pharmaceutical Chemistry Journal -     

4-乙酰氧基-2-甲基-2-丁烯-1-醛的合成

丙酮醛缩二甲醇与氯乙烯格氏试剂反应得叔醇,然后经乙酐酰化制得1,2-二乙酰氧基-2-甲基-1-甲氧基-3-丁烯,进而水解得2-乙酰氧基-2-甲基-3-丁烯-1-醛,最后重排得到维生素A的关键中间体4-乙酰氧基-2-甲基-2-丁烯-1-醛,总收率约49%。     

Antioxidant properties of 2-imidazolones and 2-imidazolthiones

Uric acid has been postulated to be an important antioxidant and free radical scavenger in humans. Other purines, such as xanthine, that lack an 8-oxo group on the imidazole ring do not show antioxidant properties. For this reason, the antioxidative activities of 2-imidazolones and 2-imidazolthiones were compared to that of uric acid. 2-Imidazolthiones reacted with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) at rates comparable to those of uric acid and other antioxidants. 2-Imidazolones also reacted with DPPH, although at a much slower rate than the 2-imidazolthiones. The 2-imidazolthiones protected oxyhemoglobin from oxidation to methemoglobin by sodium nitrite; the 2-imidazolones had little effect on the oxidation of oxyhemoglobin by nitrate. Most of the 2-imidazolthiones and 2-imidazolones protected both porcine and bovine erythrocytes from hemolysis by t-butyl hydroperoxide. Although 2-imidazolthiones were more reactive than 2-imidazolones in the assays using DPPH and the oxidation of oxyhemoglobin, both types of compounds may be useful as antioxidants in vivo.