Synthesis and characterization of some hydroxypyridone derivatives and their evaluation as antimicrobial agents

The synthesis, in vitro antimicrobial activities of some novel hydroxy pyridines supported with various pharmacophores is described. Twenty-six out of the tested 58 compounds exhibited variable inhibitory effects on the growth of the tested Gram positive and Gram negative bacteria. The tested compounds revealed better activity against the Gram positive rather than the Gram negative strains. The synthesized hydroxypyridones have shown very significant inhibitory effect against Staphylococcus aureus and Bacillus subtilis. Twelve compounds namely; 5d, 5f, 6a, 6b, 8b, 18b, 18c, 19c, 21d, 22b, 22d and 23d were able to produce appreciable growth inhibitory activity against Candida albicans when compared to Clotrimazole. Among these, 22d proved to be the most potent antifungal agent.     

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO₃ at 70–80°C for 24–72?h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a–c). The latter derivatives underwent reductive lactamization upon treatment with Na₂S₂O₄ in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a–c). Acetylation of 8a–c using acetyl chloride afforded N₄-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a–c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a–c/9a–c) showed appreciable antibacterial activity as compared with ciprofloxacin.     

Synthesis of Novel α-l-Arabinopyranosides of β-Lactams with Potential Antimicrobial Activity

Synthetic routes toward the synthesis of some novel 1-(2,3,4-tri-O-acetyl-α-l-arabinopyranosyl)-azetidin-2-ones are described. Antimicrobial screening of three selected compounds revealed their activity against Bacillus subtilis and Escherichia coli.     

Synthesis of Some Novel 6‐Benzyl(or Substituted Benzyl)‐2‐β‐d‐Glucopyranosyl‐1,2,4‐Triazolo[4,3‐b][1,2,4]Triazines as Potential Antimicrobial Chemotherapeutics

Glucosidation of the new 8‐amino‐6‐benzyl(or substituted benzyl)‐2,8‐dihydro‐1,2,4‐triazolo[4,3‐b][1,2,4]triazin‐7(3H)‐ones (3a–d) with 2,3,4,6‐tetra‐O‐acetyl‐α‐d‐glucopyranosyl bromide 4 gave the corresponding N‐glucosides 5a–d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7–12. Antimicrobial activity of compounds 5a–c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described.     

An Efficient Alternative Route To 3,6-Disubstituted-Furo[2,3-d]Pyrimidin-2-One Analogues

Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2 Robins, M. J. and Barr, P. J. 1983. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides. J. Org. Chem, 48: 1854–1862. [CSA][CROSSREF][Crossref], [Web of Science ®] , [Google Scholar], 3 De Clercq, E., Descamps, J., Balzarini, J., Giziewicz, J., Barr, P. J. and Robins, M. J. 1983. Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem, 26: 661–666. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrimidin-2-one analogues.     

Aryldiazomethane Derivatives as Reagents for Site Specific Labeling of Nucleic Acids at Phosphate

Abstract

An efficient and direct labeling method based on direct alkylation of nucleic acids at phosphates by aryldiazomethane derivatives is described.     

抗肿瘤药物帕玛度胺类似物的合成

目的：设计并合成抗肿瘤药物帕玛度胺的3位N取代的新型类似物。方法：从3-硝基邻苯二甲酸（2）和N-（叔丁氧羰基）．L-谷氨酰胺（4）出发,经过六步反应得到目标化合物。3-硝基邻苯二甲酸（2）经脱水制得3-硝基邻苯二甲酸酐（3）。用N-（叔丁氧羰基）-L-谷氨酰胺（4）经闭环、脱保护制得3-氨基-2,6-哌啶二酮三氟乙酸盐（6）。4与6经缩合、钯碳催化氢化制得免疫调节剂Pomalidomide（8）,（8）经过酰化得到3-乙酰氨基-N-（2,6-二氧代-3-哌啶基）邻苯二甲酰亚胺（1）。以（4）计总收率约34．9％。结果：得到3-乙酰氨基-N-（2,6-二氧代-3-哌啶基）-邻苯二甲酰亚胺（1）,应用于细胞活性测试。结论：改进了帕玛度胺的合成工艺,得到了3位N乙酰化的新型帕玛度胺类似物（1）,初步研究显示（1）的生物活性与帕玛度胺接近。     

ADP-ribosylation of Translation Elongation Factor 2 by Diphtheria Toxin in Yeast Inhibits Translation and Cell Separation

Eukaryotic translation elongation factor 2 (eEF2) facilitates the movement of the peptidyl tRNA-mRNA complex from the A site of the ribosome to the P site during protein synthesis. ADP-ribosylation (ADP^R) of eEF2 by bacterial toxins on a unique diphthamide residue inhibits its translocation activity, but the mechanism is unclear. We have employed a hormone-inducible diphtheria toxin (DT) expression system in Saccharomyces cerevisiae which allows for the rapid induction of ADP^R-eEF2 to examine the effects of DT in vivo. ADP^R of eEF2 resulted in a decrease in total protein synthesis consistent with a defect in translation elongation. Association of eEF2 with polyribosomes, however, was unchanged upon expression of DT. Upon prolonged exposure to DT, cells with an abnormal morphology and increased DNA content accumulated. This observation was specific to DT expression and was not observed when translation elongation was inhibited by other methods. Examination of these cells by electron microscopy indicated a defect in cell separation following mitosis. These results suggest that expression of proteins late in the cell cycle is particularly sensitive to inhibition by ADP^R-eEF2.     

EXTL2, a Member of the EXT Family of Tumor Suppressors,Controls Glycosaminoglycan Biosynthesis in a Xylose Kinase-dependent Manner

Mutant alleles of EXT1 or EXT2, two members of the EXT gene family, are causative agents in hereditary multiple exostoses, and their gene products function together as a polymerase in the biosynthesis of heparan sulfate. EXTL2, one of three EXT-like genes in the human genome that are homologous to EXT1 and EXT2, encodes a transferase that adds not only GlcNAc but also N-acetylgalactosamine to the glycosaminoglycan (GAG)-protein linkage region via an α1,4-linkage. However, both the role of EXTL2 in the biosynthesis of GAGs and the biological significance of EXTL2 remain unclear. Here we show that EXTL2 transfers a GlcNAc residue to the tetrasaccharide linkage region that is phosphorylated by a xylose kinase 1 (FAM20B) and thereby terminates chain elongation. We isolated an oligosaccharide from the mouse liver, which was not detected in EXTL2 knock-out mice. Based on structural analysis by a combination of glycosidase digestion and 500-MHz ¹H NMR spectroscopy, the oligosaccharide was found to be GlcNAcα1-4GlcUAβ1–3Galβ1–3Galβ1–4Xyl(2-O-phosphate), which was considered to be a biosynthetic intermediate of an immature GAG chain. Indeed, EXTL2 specifically transferred a GlcNAc residue to a phosphorylated linkage tetrasaccharide, GlcUAβ1–3Galβ1–3Galβ1–4Xyl(2-O-phosphate). Remarkably, the phosphorylated linkage pentasaccharide generated by EXTL2 was not used as an acceptor for heparan sulfate or chondroitin sulfate polymerases. Moreover, production of GAGs was significantly higher in EXTL2 knock-out mice than in wild-type mice. These results indicate that EXTL2 functions to suppress GAG biosynthesis that is enhanced by a xylose kinase and that the EXTL2-dependent mechanism that regulates GAG biosynthesis might be a “quality control system” for proteoglycans.     

Synthesis and acetylcholinesterase inhibitory activity of polyhydroxylated sulfated steroids: Structure/activity studies

Disulfated and trisulfated steroids have been synthesized from cholesterol and their acetylcholinesterase inhibitory activity has been evaluated. In our studies we have found that the activity was not only dependent on the location of the sulfate groups but on their configurations. 2β,3α,6α-trihydroxy-5α-cholestan-6-one trisulfate (18) was the most active steroid with an IC₅₀ value of 15.48 μM comparable to that of 2β,3α-dihydroxy-5α-cholestan-6-one disulfate (1). Both compounds were found to be less active than the reference compound eserine. The butyrylcholinesterase activity of 1 and 18 was one magnitude lower than that against acetylcholinesterase revealing a selective inhibitor profile.