Synthesis of a cell-permeable analogue of a glycosylphosphatidylinositol (GPI) intermediate that is toxic to the living bloodstream form of Trypanosoma brucei

The synthesis of two cell-permeable analogues related to a GPI intermediate is described for studies with living trypanosomes and human (HeLa) cells. One of the analogues is metabolised by the former GPI pathway and is toxic to the parasite Trypanosoma brucei but not to human cells.     

Rapid Assembly of Oligosaccharides: Total Synthesis of a Glycosylphosphatidylinositol Anchor of Trypanosoma brucei

Six building blocks, six reaction steps : The recently developed innovative methodology facilitated the convergent synthesis of the complex oligosaccharide core 1 (shown here with protecting groups) for the total synthesis of a glycosylphosphatidylinositol (GPI) anchor. The key factors are the tuning of the reactivity of the building blocks by using 1,2-diacetal protecting groups and the desymmetrization of glycerol and myo-inositol with a chiral bis(dihydropyran).     

Computational prediction of the effects of non-synonymous single nucleotide polymorphisms on the GPI-anchor transamidase subunit GPI8p of Plasmodium falciparum

Drug resistance is increasingly evolving in malaria parasites; hence, it is important to discover and establish alternative drug targets. In this context, GPI-anchor transamidase (GPI-T) is a potential drug target primarily of its crucial role in the development and survival of the parasite in the GPI anchor biosynthesis pathway. The present investigation was undertaken to explore the plausible effects of nsSNP on the structure and functions of GPI-T subunit GPI8p of Plasmodium falciparum. The GPI8p (PF3D7_1128700) was analyzed using various sequence-based and structure-based computational tools such as SIFT, PROVEAN, PredictSNP, SNAP2, I-Mutant, MuPro, ConSurf, NetSurfP, MUSTER, COACH server and STRING server. Of the 34 nsSNPs submitted for functional analysis, 18 nsSNPs (R124 L, N143 K, Y145 F, V157I, T195S, K379E, I392 K, I437 T, Y438H, N439D, Y441H, N442D, N448D, N451D, D457A, D457Y, I458 L and N460 K) were predicted to have deleterious effects on the protein GPI8p. Additionally, I-Mutant 2.0 and MuPro both showed a decrease in stability after mutation as a result of these nsSNPs, suggesting the destabilization of protein. ConSurf findings suggest that most of the regions were highly conserved. In addition, COACH server was used to predict the ligand binding sites. It was found that no mutation was present at the predicted ligand binding site. The results of the STRING database showed that the protein GPI8p interacts with those proteins which either involve the biosynthetic process of attaching GPI anchor to protein or GPI anchor. The present study suggested that the GPI8p could be a novel target for anti-malarial drugs, which provides significant details for further experimentation.     

1,2-Diacetals in synthesis: total synthesis of a glycosylphosphatidylinositol anchor of Trypanosoma brucei

A full account on a total synthesis of GPI anchor 1 employing butanediacetal (BDA) groups and a chiral bis(dihydropyran) is presented. The reactivity of selenium and thio glycosides was tuned by the use of BDA groups. This allowed the assembly of an appropriately protected GPI anchor precursor 2 in just six steps from the six building blocks 5-10 including only one protecting group manipulation. myo-Inositol was desymmetrised with the bis(dihydropyran) derivative 15 and appropriately protected to give inositol acceptor 21 in nine steps and 17% overall yield. The use of common starting materials and BDA-protections give efficient access to building blocks 5, 6, 7 and 8. A new and improved synthesis of the glucosamine donor 28 is included. In summary, a highly convergent and efficient synthesis of GPI anchor 1, which is clearly adaptable to other GPI anchors, has been reported.     

Convergent synthesis of a fully phosphorylated GPI anchor of the CD52 antigen

A fully phosphorylated GPI anchor (1) of the CD52 antigen was synthesized by a highly convergent strategy. After a trimannose and a phospholipidated pseudodisaccharide were prepared separately, they were coupled together to form the GPI core, which was then phosphorylated to introduce two phosphoethanolamine moieties in one step to afford CD52 GPI in its fully protected form. Finally, global deprotection of the product resulted in 1.     

Asymmetric synthesis of macrolactin analogue

Total asymmetric synthesis of macrolactin A analogue was accomplished by the convergent strategy. Rapid access to advanced intermediate 16 through isomerization of ynone to (E,E)-conjugated dienone is a key step of this synthesis. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Rapid assembly of oligosaccharides: 1,2-diacetal-mediated reactivity tuning in the coupling of glycosyl fluorides

This paper describes the application of 1,2-diacetal protecting groups to control the reactivity tuning of glycosyl fluorides in oligosaccharide coupling reactions. The synthetic potential of this new methodology is demonstrated by the ‘one-pot’ synthesis of a linear pentasaccharide and the efficient assembly of the core oligosaccharide of the GPI anchor of yeast (Saccharomyces cerevisiae).     

糖基磷脂酰肌醇及其锚定蛋白的合成研究进展

在真核生物中,蛋白质的C-末端以共价键形式与糖基磷脂酰肌醇（GPI）相连是一种常见的翻译后修饰,GPI修饰的蛋白质可以通过GPI锚定在细胞膜的外叶.GPI锚及其锚定蛋白的结构复杂、多样,在众多生物学过程中扮演着不可或缺的重要作用.化学合成结合酶催化反应是获得结构明确、纯度高的GPI锚及GPI锚定蛋白的重要方法,为在分子水平上深入探索此类化合物的结构和生物学功能奠定了基础.本文对此合成领域中所涉及的光学纯且差异性保护的肌-肌醇衍生物的制备、天然来源GPI的合成策略、以结构多样性为导向的GPI衍生物的合成,以及GPI锚定蛋白的合成策略进行综述.     

An efficient and convergent synthesis of the potent and selective H3 antagonist ABT-239

An efficient and convergent process for the preparation of a potent and selective H₃ receptor antagonist, ABT-239, 1A was accomplished with an overall yield of 64%. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-(R)-methylpyrrolidine (9) with 4′-hydroxy-3′-iodo-biphenyl-4-carbonitrile (3). Additionally, the key amine component 2-(R)-methylpyrrolidine (7) was effectively synthesized from the readily available Boc-l-prolinol with a simple catalytical hydrogenolysis as the key step. This column chromatography-free process is highlighted by several simple work-up and purification procedures and is amendable to the large-scale preparation of 1A.     

A general method for the synthesis of oligosaccharides consisting of α-(1→2)- and α-(1→3)-linked rhamnan backbones and GlcNAc side chains

A general method has been developed for the synthesis of oligosaccharides consisting of (1→2)- and (1→3)-linked rhamnans with GlcNAc side chains. As examples, highly effective and convergent syntheses of two decasaccharides in the O polysaccharide moiety of the lipopolysaccharide of the phytopathogenic bacterium Pseudomonas syringae pv. ribicola NCPPB 1010 were achieved. The two decasaccharides consist of O polysaccharide repeating units I+II and II+I, respectively. Allyl 3-O-acetyl-4-O-benzoyl-α-l-rhamnopyranoside, allyl 2-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranoside, 2,4-di-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranosyl trichloroacetimidate, and 3-O-acetyl-2,4-di-O-benzoyl-α-l-rhamnopyranosyl trichloroacetimidate, which were obtained by highly regioselective 3-O-acylations, were used as the key synthons to obtain the required α-(1→2)- and α-(1→3)-linked rhamnoocta saccharide acceptors with 3³- and 3⁷-free hydroxyl groups. Therefore, several disaccharides were synthesized, from which tetrasaccharides and hexasaccharides were then synthesized. Coupling of the hexasaccharide donors with the disaccharide acceptors gave the octasaccharide acceptors. Finally, the coupling of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl trichloroacetimidate with the octasaccharide acceptors, followed by deprotection, afforded the two target decasaccharides. A repeating hexasaccharide unit of the cell wall polysaccharide of β-hemolytic Streptococci Group A was also synthesized in a similar way.     

Four-component one-pot synthesis of a branched manno-pentasaccharide: tert-butyldiphenylsilyl ether as an in situ removable carbohydrate-protecting group

A branched mannose-pentasaccharide was synthesized in a convergent one-pot sequence involving chemo- and regioselective glycosylations of suitable acceptors and in situ removal of tert-butyldiphenylsilyl group. The process demonstrated that a combination of TMSOTf and TfOH can be used as an effective reagent for the fast and selective in situ de-protection of tert-butyldiphenylsilyl group, and also serve as part of the promoter system for the subsequent glycosylation reaction.     

Convergent synthesis of the tetrasaccharide repeating unit related to the O-antigenic polysaccharide of Escherichia coli 78

A convergent synthesis of the tetrasaccharide repeating unit of the O-antigenic cell wall polysaccharide of Escherichia coli 78, as the corresponding methyl glycoside (I), is being reported. It involved stereoselective glycosidation of a β-linked mannodisaccharide acceptor with a β-linked glucosamine based disaccharide thioglycoside donor, which were prepared from the corresponding functionalised monosaccharide based glycosyl donors and acceptors. The resulting tetrasaccharide derivative was finally converted to (I) by selective deprotection and also by global protection and deprotection techniques.     

Synthesis of 1-benzyl-8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one via palladium-catalyzed intramolecular arylation

The synthesis of a novel tetracyclic structure, 8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one, has been achieved by a convergent pathway. Coupling of the weakly nucleophilic hindered aromatic amine with 1-benzylimidazole-4-carboxylic acid, 7, afforded the corresponding amide 9 using a DCP/DMF complex; subsequent Heck-type arylation leading to desired tetracyclic molecule imidazo[4,5-c]-pyrrolo[3,2-g]quinolin-4(5H)-one.     

A Suzuki-Miyaura coupling mediated deprotection as key to the synthesis of a fully lipidated malarial GPI disaccharide

Ligandless palladium-catalyzed Suzuki-Miyaura coupling converted an inert p-bromobenzyl ether to a DDQ-labile p-(3,4-dimethoxyphenyl) benzyl ether in the presence of azide functionality and this strategy serves as a key step for the convergent synthesis of a fully lipidated malaria GPI disaccharide.     

Cyclopenta[g]quinazolinone-based inhibitors of thymidylate synthase targeting α-folate receptor overexpressing tumours: synthetic approaches to 4-{N-[(6RS)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid

An advanced intermediate for the synthesis of cyclopenta[g]quinazolinone-based antifolates such as (6RS)-CB300945 was prepared by a convergent methodology. The oxo-functionality required for the formation of the C-6-N-10 bond in 4 was introduced in the initial steps of the synthesis, then the tricyclic ring was constructed and finally the propargyl group was introduced using the (propargyl)Co₂(CO)₆⁺ complex without the need to protect the N-3-H or 2-hydroxymethyl functionalities.     

Assembly of a Complex Branched Oligosaccharide by Combining Fluorous‐Supported Synthesis and Stereoselective Glycosylations using Anomeric Sulfonium Ions

There is an urgent need to develop reliable strategies for the rapid assembly of complex oligosaccharides. This paper presents a set of strategically selected orthogonal protecting groups, glycosyl donors modified by a (S)‐phenylthiomethylbenzyl ether at C‐2, and a glycosyl acceptor containing a fluorous tag, which makes it possible to rapidly prepare complex branched oligosaccharides of biological importance. The C‐2 auxiliary controlled the 1,2‐cis anomeric selectivity of the various galactosylations. The orthogonal protecting groups, 2‐naphthylmethyl ether (Nap) and levulinic ester (Lev), made it possible to generate glycosyl acceptors and allowed the installation of a crowded branching point. After the glycosylations, the chiral auxiliary could be removed using acidic conditions, which was compatible with the presence of the orthogonal protecting groups Lev and Nap, thereby allowing the efficient installation of 1,2‐linked glycosides. The light fluorous tag made it possible to purify the compounds by a simple filtration method using silica gel modified by fluorocarbons. The set of building blocks was successfully employed for the preparation of the carbohydrate moiety of the GPI anchor of Trypanosoma brucei, which is a parasite that causes sleeping sickness in humans and similar diseases in domestic animals.     

Synthesis of new fluorescently labeled glycosylphosphatidylinositol (GPI) anchors

The borondipyrromethene (BODIPY) labeled new glycosylphosphatidylinositol (GPI) molecules were synthesized as cellular probes to study the chemical basis of microdomain organization of GPI-anchored proteins and cholesterol in plasma membrane. The synthesis enabled by a new stereo-selective glycosylation of myo-d-inositol acceptor led to the preparation of optically pure glucosaminyl-(1-6)-α-phosphatidyl-myo-d-inositol and its unnatural stereoisomer.     

Convergent synthesis of the ABCDE ring fragment of ciguatoxins

Synthesis of the ABCDE ring fragment of ciguatoxins has been achieved in a highly stereocontrolled and convergent manner via the B-alkyl Suzuki-Miyaura coupling-based approach.     

‘O-Acyl isopeptide method’: racemization-free segment condensation in solid phase peptide synthesis

We disclosed a novel ‘racemization-free segment condensation’ based on the ‘O-acyl isopeptide method’ in which an N-segment including C-terminal O-acyl isopeptide structure with urethane-protected Ser/Thr residue was employed for the segment condensation, suggesting that the use of this method contributes to the effective convergent synthesis of long peptides/proteins.     

Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands

Gold(III) thiosemicarbazone complexes derived from [Au(damp-C¹,N)Cl₂] (2), where damp = dimeth-ylaminoethylphenyl, have been synthesized. The compounds were characterised using various spectroscopic and analytical techniques, including NMR spectroscopy, mass spectrometry, infrared spectroscopy and elemental analysis. The gold complexes were screened for in vitro antimalarial and antitubercular activity. Although incorporation of the gold(III) centre into thiosemicarbazone scaffolds enhanced their efficacy against the malaria parasite Plasmodium falciparum, this trend was not observed for the antitubercular activity of selected thiosemicarbazones against the Mycobacterium tuberculosis virulent strain H₃₇Rv.