Synthesis, Biophysical and Biological Evaluation of Splice-Switching Oligonucleotides with Multiple LNA-Phosphothiotriester Backbones.

Polyanionic antisense oligonucleotides hold great promise as RNA targeting drugs but issues with bioavailability hinder their development. Uncharged phosphorus-based backbones are promising alternatives but robust methods to produce them are limited. We report the synthesis and properties of oligonucleotides containing charge-neutral LNA alkyl phosphothiotriester backbones combined with 2'--methyl phosphorothioate nucleotides for therapeutic applications.

Synthesis and Properties of Oligonucleotides Containing LNA-Sulfamate and Sulfamide Backbone Linkages.

Oligonucleotides hold great promise as therapeutic agents but poor bioavailability limits their utility. Hence, new analogues with improved cell uptake are urgently needed. Here, we report the synthesis and physical study of reduced-charge oligonucleotides containing artificial LNA-sulfamate and sulfamide linkages combined with 2'-O-methyl sugars and phosphorothioate backbones.

Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis.

Sulforaphane, a naturally occurring isothiocyanate, has gained attention due to its tremendous anticancer potential. Thus, an array of sulforaphane analogs were synthesized and evaluated for their cytotoxic potentials on a wide range of malignant cell lines. Among these derivatives, compound displayed exceptional potency in inhibiting the proliferation of cancer cell lines and a negligible effect on normal cell lines through G2/M phase arrest.

Expedient synthesis of l-heptose derived septacidin building blocks from l-glucose.

Bacterial natural products containing heptosides such as septacidin represent interesting scaffolds for the development of drugs to combat antimicrobial resistance. However, very few synthetic strategies have been reported to grant access to these derivatives. Here, we have devised a synthetic pathway to l-glycero-l-glucoheptoside, a key building block en route to septacidin, directly from l-glucose.

Scalable Synthesis of Versatile Rare Deoxyamino Sugar Building Blocks from d-Glucosamine.

We report the syntheses of 1,3,4-tri--acetyl-2-amino-2,6-dideoxy-β-d-glucopyranose and allyl 2-amino-2,6-dideoxy-β-d-glucopyranoside from d-glucosamine hydrochloride. The potential of these two versatile scaffolds as key intermediates to a diversity of orthogonally protected rare deoxyamino hexopyranosides is exemplified in the context of fucosamine, quinovosamine, and bacillosamine. The critical C-6 deoxygenation step to 2,6-dideoxy aminosugars is performed at an early stage on a precursor featuring an imine moiety or a trifluoroacetamide moiety in place of the 2-amino group, respectively.

Protecting group principles suited to late stage functionalization and global deprotection in oligosaccharide synthesis.

Chemical synthesis is a powerful tool to access homogeneous complex glycans, which relies on protecting group (PG) chemistry. However, the overall efficiency of chemical glycan assembly is still low when compared to oligonucleotide or oligopeptide synthesis. There have been many contributions giving rise to collective improvement in carbohydrate synthesis that includes PG manipulation and stereoselective glycoside formation and some of this chemistry has been transferred to the solid phase or adapted for programmable one pot synthesis approaches.

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e.

Exploratory N-Protecting Group Manipulation for the Total Synthesis of Zwitterionic Shigella sonnei Oligosaccharides.

Shigella sonnei surface polysaccharides are well-established protective antigens against this major cause of diarrhoeal disease. They also qualify as unique zwitterionic polysaccharides (ZPSs) featuring a disaccharide repeating unit made of two 1,2-trans linked rare aminodeoxy sugars, a 2-acetamido-2-deoxy-l-altruronic acid (l-AltpNAcA) and a 2-acetamido-4-amino-2,4,6-trideoxy-d-galactopyranose (AAT). Herein, the stereoselective synthesis of S.

Syntheses of Salmonella Paratyphi A Associated Oligosaccharide Antigens and Development towards Anti-Paratyphoid Fever Vaccines.

With the emergence of multidrug resistant Salmonella strains, the development of anti-Salmonella vaccines is an important task. Currently there are no approved vaccines against Salmonella Paratyphi A, the leading cause of paratyphoid fever. To fill this gap, oligosaccharides corresponding to the O-polysaccharide repeating units from the surface of Salmonella Paratyphi A have been synthesized through convergent stereoselective glycosylations.

Synthetic and immunological studies of Salmonella Enteritidis O-antigen tetrasaccharides as potential anti-Salmonella vaccines.

The first synthetic carbohydrate based potential anti-Salmonella Enteritidis vaccine has been developed by conjugating a synthetic tetrasaccharide antigen with bacteriophage Qβ. High levels of specific and long lasting anti-glycan IgG antibodies were induced by the conjugate, which completely protected mice from lethal bacterial challenges in a passive transfer model.

Convergent Synthesis of Oligosaccharide Fragments Corresponding to the Cell Wall O-Polysaccharide of Salmonella enterica O53.

Conventional glycoconjugate vaccines are prepared with polysaccharides isolated from bacterial fermentation, an approach with some significant drawbacks such as handling of live bacterial strains, the presence of biological impurities, and inter-batch variations in oligosaccharide epitope structure. However, it has been shown in many cases that a synthetic fragment of appropriate structure conjugated to a protein can be an effective vaccine that circumvents the shortcomings of using full-length oligosaccharides. The development of synthetic strategies to prepare glycoconjugate derivatives against pathogenic bacterial strains is therefore of great interest.

C-cinnamoyl glycosides as a new class of anti-filarial agents.

A series of C-cinnamoyl glycosides has been synthesized in good yield by the BF3·OEt2 catalyzed aldol condensation of C-glycosylated acetone derivative with a variety of aromatic aldehydes. The synthesized compounds were evaluated for their potential as anti-filarial agents against bovine filarial parasite Setaria cervi and human filariid Wuchereria bancrofti using a number of biological assays such as relative movability (RM) assessment and MTT reduction assay. Among twenty seven test compounds six compounds were found active in terms of MIC, IC50 and LC50 values.

Convergent synthesis of a tetrasaccharide repeating unit of the O-specific polysaccharide from the cell wall lipopolysaccharide of Azospirillum brasilense strain Sp7.

A straightforward convergent synthesis has been carried out for the tetrasaccharide repeating unit of the O-specific cell wall lipopolysaccharide of the strain Sp7 of Azospirillum brasilense. The target tetrasaccharide has been synthesized from suitably protected monosaccharide intermediates in 42% overall yield in seven steps by using a [2 + 2] block glycosylation approach.