Synthesis of protected 2-amino-2-deoxy-D-xylothionolactam derivatives and some aspects of their reactivity

The synthesis of polyfunctionalized delta-lactams as key intermediates of glycomimetics in the 2-acetamido-2-deoxy sugar series is presented. Starting from a chiral gamma-amino vinylic ester synthesized from Garner's aldehyde and after regioselective reduction, 1-azido-3-(N-tert-butyloxycarbonyl-2,2-dimethyloxazolidin-4-yl)-2-propene was obtained. Next, a cis-dihydroxylation reaction provided the protected D-xylitol and L-arabinitol azides. A simple protection-deprotection sequence, followed by an oxidation and a reductive cyclization, led to protected 2-amino-delta-lactams bearing a tert-butyloxycarbonyl group on the amine functionality. To explore the reactivity of such compounds, activation of the lactam into the corresponding thionolactam was performed. The resulting 2-amino-D-xylothionolactam derivative, a versatile intermediate, allowed access to a first generation of protected 2-amino-D-xylosamidoxime derivatives which are of interest as precursors of N-acetylhexosaminidase and N-acetylglucosaminyltransferase inhibitors. In this series of compounds, epimerization at C-2 was observed. AM(1) calculations performed on these analogs showed that they adopted a B(2,5) conformation and that the axial epimer was favored in the protected series whereas the equatorial epimer was preferred in the unprotected series.     

Identification of neutral 4-O-alkyl quinolone nonpeptide GnRH receptor antagonists

A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.     

The synthesis of N2,N6-substituted diaminopurine ribosides

A series of new 2,6-substituted diaminopurine riboside derivatives were synthesized by activation of protected xantosine with sulfonyl chlorides followed by treatment with various amines. The relationship between the reactivity of intermediates and the nature of the activating agents was studied.     

The synthesis of <Emphasis Type="Italic">N</Emphasis><Superscript>2</Superscript>,<Emphasis Type="Italic">N</Emphasis><Superscript>6</Superscript>-substituted diaminopurine ribosides

A series of new 2,6-substituted diaminopurine riboside derivatives were synthesized by activation of protected xantosine with sulfonyl chlorides followed by treatment with various amines. The relationship between the reactivity of intermediates and the nature of the activating agents was studied.     

New and general synthesis of beta-C-glycosylformaldehydes from easily available beta-C-glycosylpropanones

A highly effective method for the introduction of a formyl group at the anomeric position of pyranosides was developed via enolisation of beta-C-D-glycopyranosylpropan-2-one using thermodynamic conditions then oxidative cleavage of the more substituted double bond. This sequence affords the desired aldehydes that are conveniently protected as aminals for purification and storage and easily regenerated using Dowex resin H+. In this paper, the syntheses of nine differently protected aldehydes derived from d-glucose, d-galactose, lactose and N-acetyl-d-glucosamine are presented. Our strategy proved to be very efficient in most cases excepted in the D-mannose series.     

Preparation and antitubercular activities of alkylated amino alcohols and their glycosylated derivatives

A series of N- and C-alkylated amino alcohols and of their protected galactopyranosyl derivatives was synthesized and evaluated for antitubercular activity. Five of these compounds displayed good activity, with a MIC below 12.5 μg/mL. The presence of the carbohydrate slightly affected the antibacterial activity.     

Studies toward the site specific incorporation of sugars into proteins: synthesis of glycosylated aminoacyl-tRNAs

A series of glycosylated serine derivatives was synthesized from peracetylated sugars and Fmoc-protected serine; these were chemically esterified with the tris-(tetrabutylammonium) salt of pdCpA. The fully protected and deprotected glycosylated aminoacyl pdCpAs were ligated enzymatically to an abbreviated tRNA (tRNA-C(OH)) to provide the title compounds that are key intermediates in the elaboration of glycoproteins using readthrough of a nonsense codon.     

Protein binding to a single termination-associated sequence in the mitochondrial DNA D-loop region.

A methylation protection assay was used in a novel manner to demonstrate a specific bovine protein-mitochondrial DNA (mtDNA) interaction within the organelle (in organello). The protected domain, located near the D-loop 3' end, encompasses a conserved termination-associated sequence (TAS) element which is thought to be involved in the regulation of mtDNA synthesis. In vitro footprinting studies using a bovine mitochondrial extract and a series of deleted mtDNA templates identified a approximately 48-kDa protein which binds specifically to a single TAS element also protected within the mitochondrion. Because other TAS-like elements located in close proximity to the protected region did not footprint, protein binding appears to be highly sequence specific. The in organello and in vitro data, together, provide evidence that D-loop formation is likely to be mediated, at least in part, through a trans-acting factor binding to a conserved sequence element located 58 bp upstream of the D-loop 3' end.     

An efficient and concise regioselective synthesis of alpha-(1 --> 5)-linked L-arabinofuranosyl oligosaccharides

A series of alpha-(1 --> 5)-linked L-arabinofuranosyl di-, tetra-, hexa- and octameric derivatives were synthesized efficiently. The process was carried out in a regio- and stereoselective manner using perbenzoylated arabinofuranosyl trichloroacetimidates as glycosyl donors and unprotected or partially protected arabinofuranosides as glycosyl acceptors in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf).     

Expedient synthesis of a series of N-acetyllactosamines.

A series of poly-N-acetyllactosamines representative of those found on complex N-glycans was synthesized for use in the kinetic characterization of recently cloned glycosyltransferases. The syntheses involved the iterative addition of a selectively protected N-acetyllactosaminyl donor to an octyl alpha-D-mannopyranosyl-1,6-beta-D-mannopyranoside acceptor, followed by deprotection. In addition, non-reducing galactosyl residues were removed with beta-galactosidase to furnish GlcNAc terminated compounds. In this manner tetra- to octasaccharides were efficiently produced.     

Design,synthesis, and biological evaluation of 1,5-benzothiazepine-4-one derivatives targeting factor VIIa/tissue factor

The 1,5-benzothiazepine-4-one scaffold was earlier shown to provide efficient protease inhibitors. In this contribution, we describe its use in the design of factor VIIa/tissue factor inhibitors. A series containing a scaffold non-substituted on its aryl part led to compound 20 with an IC₅₀ of 2.16 μM. Following molecular modelling studies of this compound, a second series was prepared, which necessitated the synthesis of protected 7- or 8-substituted 1,5-benzothiazepine-4-one derivatives.     

Cyclopropane amino acid ester dipeptide sweeteners

A series of esters of L-aspartyl-1-aminocyclopropane carboxylic acid has been prepared and their sweet tastes determined. The sweetest ester prepared was about 300 times sweeter than sucrose. An attempt to use basic conditions during preparation of the dipeptide allyl ester led to succinimide formation of the aspartyl peptide even though the beta-carboxyl group was protected by a t-butyl ester function. The X-ray structure of the propyl ester (1c) was determined and its conformation is discussed.     

Synthesis and biological evaluation of novel 2-deoxy-4-thio-imidazole nucleosides

A study on the use of 3'-directing groups for the synthesis of imidazole 2'-deoxy-4'-thionucleosides led to varying alpha:beta ratios in the glycosylation reaction. The para-nitrobenzoyl group gave the optimum result in the glycosylation step; therefore, this protected thiosugar 10b was used for the synthesis of a series of novel 2'-deoxy-4'-thio-imidazole nucleosides which have been evaluated for antiviral activity in vitro.     

Design, synthesis, and biological evaluation of a novel class of fluorescein-based N-glycosylamines

A series of fluorescein-based N-glycosylamines was synthesized from the corresponding fluorescein amine and a partially protected d-glucose. The physiochemical investigation of these compounds by spectral and morphological studies reveals their gelation potential. The exclusive localization of fluorescence in the cytoplasm through cell imaging studies reveals the anti-cancer potentials of N-glycosylamines.     

Selective formation of C-2 azidodeoxy-D-glucose derivatives from D-glucal precursors using the azidonitration reaction

A series of glucals, protected by cyclic acetal protecting groups to conformationally constrain the C-4 and C-6 hydroxyl groups, were subjected to the azidonitration reaction to furnish the corresponding C-2 azidodeoxy-D-glucoses. 4,6-O-Isopropylidene-3-O-triisopropylsilyl-D-arabino-hex-1-enit ol afforded 2-azido-2-deoxy-4,6-O-isopropylidene-3-O-triisopropylsilyl-D-gluco pyranosyl nitrate and its D-manno isomer in a 20:1 ratio. These findings allow the azidonitration reaction to be now used for the preparation of a variety of glucosamine building blocks from differentially protected glucal precursors.     

Synthesis and biological evaluation of polyhydroxycurcuminoids

A series of curcumin analogs (1-3, 5a-5t) was synthesized through the condensation of appropriately protected hydroxybenzaldehydes with acetylacetone, followed by deprotection. The antioxidant activity of these analogs was determined by superoxide free radical nitroblue tetrazolium and DPPH free radical scavenging methods and the polyhydroxycurcuminoids (5l-5s) displayed excellent antioxidant activity. These analogs showed cytotoxicity to lymphocytes and promising tumor-reducing activity on Dalton's lymphoma ascites tumor cells.     

浙江重点生态地区蝶类生物多样性及其森林生态系统健康评价

选取浙江龙王山、天目山、古田山、乌岩岭和百山祖等为样地以网捕方法,对上述重点生态地区的蝶类种类及种群动态进行了系统研究,将所采集的蝶类种类及个体数,以微软的Excel列表、计算及作图,进行蝶类群落的种-多度曲线、多样性指数、均匀度与优势度等数据分析,并以此类昆虫作为指示生物对各重点生态地区的森林环境健康状况进行了评价。结果表明：5个重点生态地区的蝶类分布均呈对数正态分布,各重点生态区蝶类个体数分布规律更接近对数级数法则。天目山和乌岩岭分别有国家二级保护动物中华虎凤蝶Luehdorfia chinensis和一级保护动物金斑喙凤蝶Teinopalpus aureus,分别有4种和3种中国保护种,有25种和11种中国特有种,多样性指数分别为0.9757和1.7570,暗示该2处生态地区的环境质量优越;而古田山和百山祖均没有国家级保护动物,中国保护种分别有2种和3种,中国特有种5种和15种,多样性指数分别为1.3492和1.1593,也说明此2处生态地区的环境质量较好;龙王山没有国家级保护动物,中国保护种仅1种,中国特有种11种,多样性指数为0.8491,暗示该生态地区的环境质量相对较差或该生态地区的环境质量正在趋向恶化。近年来,由于酸雨和台风等自然气候,以及人为干扰引起森林环境健康受到不同程度影响,龙王山森林环境不稳定,退化严重,部分区域已不适合保护蝶类种昆虫的生存。     

Amino acids and peptides. XLII. Synthesis of an octapeptide sequence (A20-A27) of rubredoxin.

A protected octapeptide corresponding to a section found in the first half of the protein chain of rubredoxin has been prepared by standard peptide methods. Alternative approaches of this fragment are discussed in some detail. This work completes the series of subunits necessary to synthesize the molecule.     

Flavonoids protect mice from two types of lethal shock induced by endotoxin

The protective effect of flavonoids on two types of lethal endotoxic shock was studied. A lethal endotoxic shock was induced by administration of lipopolysaccharide (LPS) into D-galactosamine (D-GalN)-sensitized mice and another one was done by administration of a high dose of LPS into normal mice. Pretreatment with a series of flavonoids protected mice from two types of endotoxin lethality. Flavonoid pretreatment reduced the serum tumor necrosis factor-alpha (TNF-alpha) level in mice injected with D-GalN and LPS, but not in mice injected with a high dose of LPS. TNF-alpha-induced lethal shock in D-GalN-sensitized mice was also protected by pretreatment with flavonoids, suggesting that flavonoids augmented the resistance to TNF-alpha lethality. On the other hand, flavonoids reduced the plasma level of lipid peroxides in mice injected with a high dose of LPS, but not in D-GalN-sensitized mice. Taken together, these results indicated that flavonoids might protect mice from two types of endotoxin lethality. The protective mechanism of flavonoids in each endotoxin lethality is discussed.     

Significant effects of Z-Gln-Val-Val-OME, common sequences of thiol proteinase inhibitors on thiol proteinases

The first studies on a series of the small synthetic thiol proteinase inhibitors, conservative common sequences in several thiol proteinase inhibitors, are described. Among the many interesting findings with synthetic thiol proteinase inhibitors was the observation that the most effective analogue, Z-Gln-Val-Val-Ala-Gly-OMe, whose amino and carboxyl groups were protected with Z and OMe, respectively, showed inhibitory activity on papain and cathepsin B and protected papain from egg cystatin, human low-molecular-weight kininogen and T-kininogen-induced inhibition but not from leupeptin-induced inhibition. Moreover, it was revealed that Z-Gln-Val-Val-OMe was the smallest peptide to exhibit a protective effect on papain.