Preparation of a disulfide-linked precipitative soluble support for solution-phase synthesis of trimeric oligodeoxyribonucleotide 3´-(2-chlorophenylphosphate) building blocks

The preparation of a disulfide-tethered precipitative soluble support and its use for solution-phase synthesis of trimeric oligodeoxyribonucleotide 3´-(2-chlorophenylphosphate) building blocks is described. To obtain the building blocks, N-acyl protected 2´-deoxy-5´-O-(4,4´-dimethoxytrityl)ribonucleosides were phosphorylated with bis(benzotriazol-1-yl) 2-chlorophenyl phosphate. The “outdated” phosphotriester strategy, based on coupling of PV building blocks in conjunction with quantitative precipitation of the oligodeoxyribonucleotide with MeOH is applied. Subsequent release of the resulting phosphate and base-protected oligodeoxyribonucleotide trimer 3’-pTpdCBzpdGibu-5’ as its 3’-(2-chlorophenyl phosphate) was achieved by reductive cleavage of the disulfide bond

Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support

An effective method for the synthesis of short oligoribonucleotides in solution has been elaborated. Novel 2'-O-(2-cyanoethyl)-5'-O-(1-methoxy-1-methylethyl) protected ribonucleoside 3'-phosphoramidites have been prepared and their usefulness as building blocks in RNA synthesis on a soluble support has been demonstrated. As a proof of concept, a pentameric oligoribonucleotide, 3'-UUGCA-5', has been prepared on a precipitative tetrapodal tetrakis(4-azidomethylphenyl)pentaerythritol support. The 3'-terminal nucleoside was coupled to the support as a 3'-O-(4-pentynoyl) derivative by Cu(I) promoted 1,3-dipolar cycloaddition. Couplings were carried out with 1.5 equiv of the building block. In each coupling cycle, the small molecular reagents and byproducts were removed by two quantitative precipitations from MeOH, one after oxidation and the second after the 5'-deprotection. After completion of the chain assembly, treatment with triethylamine, ammonia and TBAF released the pentamer in high yields

Synthesis of Protected Amino Hexitol Nucleosides as Building Blocks for Oligonucleotide Synthesis

A new synthesis protocol for the preparation of hitherto unknown 1',5'-anhydro-4'-amino-trityl/MMTr hexitol nucleosides has been developed. Key steps in the synthesis of the pyrimidine analogues (U and C) include the regioselective d- allo-hexitol oxirane and 2',4'-anhydronucleoside ring opening by uracil and azide, respectively. A different strategy using a regioselective epoxide ring opening of d- gulo-oxirane, followed by a SN2 type of azidation reaction, has been adopted for the purine analogues (A and G). These compounds can be easily converted to 6'-phosphoramidites for the solid-phase synthesis of N4' → P6' phosphoramidates of amino hexitol nucleic acids (AHNA).status: publishe

Synthesis of new six- and seven-membered 1-N-iminosugar as promising glycosidase inhibitors

New six- and seven-membered 1-N-iminosugars were prepared from D-glucose by the stereoselective Michael addition of nitromethane to D-glucose derived α,β-unsaturated ester A followed by one pot reduction of nitro/ester functionality and subsequent amine protection to get N-Cbz protected aminol 6. Hydrolysis of 1,2-acetonide and reductive aminocyclization gave seven membered 1-N-iminosugar 5b. While, hydrolysis of 1,2-acetonide followed by NaIO4 oxidative cleavage and hydrogenation using 10% Pd(OH)2/C, H2 gave six membered 1-N-iminosugar 4a; the hydrogenation using 10% Pd/C-H2 however, gave N-methyl substituted 1-N-iminosugar 4b. The hydrochloride salts of 4a/4b and 5b were found to be specific α-galactosidase and moderate α-glucosidae inhibitors, respectively, in micro molar range

Synthesis of 3 '-fluoro-4 '-amino-hexitol nucleosides with a pyrimidine nucleobase as building blocks for oligonucleotides

© 2019 Elsevier Ltd The synthesis of 3′-fluoro-4′-amino-hexitol nucleosides with a uracil and cytosine nucleobase was performed. The synthesis started from 1,5:2,3-dianhydro-4,6-benzylidene-allitol and afforded the target compounds in 15 steps. These protected hexitol nucleosides are valuable building blocks for the preparation of a new class of oligonucleotides.status: publishe

Methylated Nucleobases: Synthesis and Evaluation for Base Pairing In Vitro and In Vivo

The synthesis, base pairing properties and in vitro (polymerase) and in vivo (E. coli) recognition of 2'-deoxynucleotides with a 2-amino-6-methyl-8-oxo-7,8-dihydro-purine (X), a 2-methyl-6-thiopurine (Y) and a 6-methyl-4-pyrimidone (Z) base moiety are described. As demonstrated by Tm measurements, the X and Y bases fail to form a self-complementary base pair. Despite this failure, enzymatic incorporation experiments show that selected DNA polymerases recognize the X nucleotide and incorporate this modified nucleotide versus X in the template. In vivo, X is mainly recognized as a A/G or C base; Y is recognized as a G or C base and Z is mostly recognized as T or C. Replacing functional groups in nucleobases normally involved in W-C recognition (6-carbonyl and 2-amino group of purine; 6-carbonyl of pyrimidine) readily leads to orthogonality (absence of base pairing with natural bases).status: publishe

Synthesis, computational study and glycosidase inhibitory activity of polyhydroxylated conidine alkaloids - a bicyclic iminosugar

New bicyclic conidine iminosugars 1d and 1e were synthesized from D-glucose. Thus, D-glucose was converted to sugar β-amino acids 3a and 3b in good yields. Individual treatment of 3a/3b with the Mukaiyama reagent afforded sugar β-lactams 4a/4b that on reduction with LiAlH4/AlCl3 gave azetidines 5a/5b with a sugar appendage. Reductive aminocyclization of sugar azetidines 5a/5b afforded the corresponding conidine iminosugars 1d/1e. Based on the 1H NMR and DFT calculation studies the conformation of 1d was assigned as half chair A2 and that of 1e as a boat B2. The glycosidase inhibitory activities of 1d and 1e such as α-mannosidase, α-glucosidase and α-galactosidase were studied. The α-amylase activity was compared with acarbose. Compound 1d was found to be a moderate inhibitor of glycosidases while 1e was noticed to be a good inhibitor of α-mannosidase and a moderate inhibitor of other glycosidases. These results were substantiated by molecular docking studies using WHAT IF software and the AUTODOCK 3.0 program

Phytochemical analysis and free radical scavenging activity of medicinal plants Gnidia glauca and Dioscorea bulbifera.

Gnidia glauca and Dioscorea bulbifera are traditional medicinal plants that can be considered as sources of natural antioxidants. Herein we report the phytochemical analysis and free radical scavenging activity of their sequential extracts. Phenolic and flavonoid content were determined. Scavenging activity was checked against pulse radiolysis generated ABTS(•+) and OH radical, in addition to DPPH, superoxide and hydroxyl radicals by biochemical methods followed by principal component analysis. G. glauca leaf extracts were rich in phenolic and flavonoid content. Ethyl acetate extract of D. bulbifera bulbs and methanol extract of G. glauca stem exhibited excellent scavenging of pulse radiolysis generated ABTS(•+) radical with a second order rate constant of 2.33 × 10(6) and 1.72 × 10(6), respectively. Similarly, methanol extract of G. glauca flower and ethyl acetate extract of D. bulbifera bulb with second order rate constants of 4.48 × 10(6) and 4.46 × 10(6) were found to be potent scavengers of pulse radiolysis generated OH radical. G. glauca leaf and stem showed excellent reducing activity and free radical scavenging activity. HPTLC fingerprinting, carried out in mobile phase, chloroform: toluene: ethanol (4: 4: 1, v/v) showed presence of florescent compound at 366 nm as well as UV active compound at 254 nm. GC-TOF-MS analysis revealed the predominance of diphenyl sulfone as major compound in G. glauca. Significant levels of n-hexadecanoic acid and octadecanoic acid were also present. Diosgenin (C₂₇H₄₂O₃) and diosgenin (3á,25R) acetate were present as major phytoconstituents in the extracts of D. bulbifera. G. glauca and D. bulbifera contain significant amounts of phytochemicals with antioxidative properties that can be exploited as a potential source for herbal remedy for oxidative stress induced diseases. These results rationalize further investigation in the potential discovery of new natural bioactive principles from these two important medicinal plants

Pulse radiolysis generated OH radical scavenging by plant extracts.

<p>Pulse radiolysis generated OH radical scavenging by plant extracts.</p

Main compounds detected by GC-TOF-MS.

<p>Main compounds detected by GC-TOF-MS.</p