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Synthesis of 2-fluoro-substituted and 2,6-modified purine 2',3'-dideoxy-2',3'-difluoro-d-arabinofuranosyl nucleosides from d-xylose.

ABSTRACT: A series of novel purine-modified 2',3'-dideoxy-2',3'-difluro-D-arabinonucleosides, including fluorinated analogs of fludarabine and nelarabine, have been prepared via anion glycosylation reactions of salts of 2-fluoropurine derivatives with the glycosyl bromide. A short and efficient synthetic route to the carbohydrate precursor 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranosyl bromide was developed in five steps from d-xylose. Improved synthesis of methyl 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranoside based upon the study of diethylaminosulfur trifluoride (DAST)-reactions with 5-O-protected methyl D-xylosides was explored using mild reaction conditions on the key step. New peculiarities for selective fluorinations of 5-O-benzoylated α- and β-D-pentofuranosides with DAST leading to the formation of mono and difluoro-furanoside derivatives are reported.

SUBMITTER: Sivets GG

PROVIDER: S-EPMC8313018 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synthesis and antiviral evaluation of 2',3'-dideoxy-2',3'-difluoro-D-arabinofuranosyl 2,6-disubstituted purine nucleosides.

Project description:The synthesis of new 2,6-disubstituted purine 2',3'-dideoxy-2',3'-difluoro-D-arabino nucleosides is reported. Their ability to block HIV and HCV replication along with their cytotoxicity toward Huh-7 cells, human lymphocyte, CEM and Vero cells was also assessed. Among them, β-2,6-diaminopurine nucleoside 25 and guanosine derivative 27 demonstrate potent anti-HIV-1 activity (EC50 = 0.56 and 0.65 μM; EC90 = 4.2 and 3.1 μM) while displaying only moderate cytotoxicity in primary human lymphocytes.

| S-EPMC8313041 | biostudies-literature

5-(4-Fluoro-phen-yl)-2-furylmethyl N-(2,6-difluoro-benzo-yl)carbamate.

Project description:The title compound, C(19)H(12)F(3)NO(4), was synthesized by the reaction of 5-(4-fluoro-phen-yl)-2-furan-methanol and 2,6-difluoro-benzoyl-isocyanate. The seven atoms of the fluorophenyl group are disordered over two positions with site occupancy factors ca 0.6 and 0.4. The dihedral angle between the furan and fluorophenyl rings is 1.58°. In the crystal structure, the mol-ecules are linked via inter-molecular N-H?O hydrogen bonds to form chains.

| S-EPMC2960319 | biostudies-literature

N-[3,5-Dichloro-4-(1,1,2,2-tetra-fluoro-eth-oxy)phen-yl]-2,6-difluoro-benzamide.

Project description:In the title compound, C(15)H(7)Cl(2)F(6)NO(2), the conformation of the N-H bond in the amide segment is anti to the C=O bond and the dihedral angle between the two benzene rings is 78.6?(3)°. The terminal -CHF(2) group is disordered over two orientations in a 0.67:0.33 ratio. In the crystal, the mol-ecules are linked by N-H?O hydrogen bonds, generating C(4) chains propagating in [100].

| S-EPMC3007377 | biostudies-literature

2,6-Difluoro-benzoic acid.

Project description:In the title compound, C(7)H(4)F(2)O(2), the dihedral angle between the benzene ring and the carboxyl-ate group is 33.70?(14)°. In the crystal structure, inversion dimers linked by pairs of O-H?O hydro-gren bonds occur, generating R(2) (2)(8) loops. The dimers are linked into sheets lying parallel to (102) by C-H?F hydrogen bonds.

| S-EPMC3007258 | biostudies-literature

(4-Chloro-2-fluoro-phen-yl)[1-(2,6-difluoro-phen-yl)but-3-en-yl]amine.

Project description:In the mol-ecule of the title homoallylic amine, C(16)H(13)ClF(3)N, the dihedral angle between the two benzene rings is 84.63?(4)°. Weak intra-molecular N-H?F hydrogen bonds generate S(6) and S(5) ring motifs. In the crystal structure, weak inter-molecuar N-H?F hydrogen bonds link mol-ecules into centrosymmetric dimers which are arranged in mol-ecular sheets parallel to the ac plane.

| S-EPMC2977711 | biostudies-literature

D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides: synthesis, anti-HIV activity and mechanism of resistance.

Project description:Introducing 2'-fluoro substitution on the 2',3'-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, D- and L-2',3'-unsaturated 3'-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized L-series nucleosides, compounds 18, 19, 26 and 28 exhibited moderate antiviral activity (EC50 7.1 microM, 6.4 microM, 10.3 microM, and 20.7 microM, respectively), while among the D-series, the guanosine analogue (35, D-3'-F-C-d4G) exhibited the most potent anti-HIV activity (EC50 0.4 microM, EC90 2.8 microM). However, the guanosine analogue 35 was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound 35 in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of L-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of D-3'-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the D-guanine derivative 35.

| S-EPMC2533426 | biostudies-literature

3-Diethyl-carbamoyl-2',4'-difluoro-biphenyl-4-yl 2,6-dichloro-5-fluoro-pyridine-3-carboxyl-ate.

Project description:In the title compound, C(23)H(17)Cl(2)F(3)N(2)O(3), the mol-ecular conformation is significantly strained: atoms O, C(=O) and C attached to the central benzene ring deviate from its plane by 0.118?(2), 0.139?(2) and 0.174?(2)?Å, respectively. In the crystal, weak C-H?O inter-actions link the mol-ecules into chains along [110]. The crystal packing exhibits short inter-molecular Cl?F [2.9840?(16)?Å] and Cl?Cl [3.2957?(12)?Å] contacts.

| S-EPMC3393315 | biostudies-literature

N-{[2,5-Dichloro-4-(1,1,2,3,3,3-hexa-fluoro-prop-oxy)phen-yl]amino-carbon-yl}-2,6-difluoro-benzamide.

Project description:In the mol-ecule of the title compound, C(17)H(8)Cl(2)F(8)N(2)O(3), the two aromatic rings are oriented at a dihedral angle of 50.12?(3)°. Intra-molecular N-H?O, C-H?O and N-H?Cl hydrogen bonds result in the formation of two six- and one five-membered rings. The six-membered rings have flattened-boat conformations, while the five-membered ring adopts an envelope conformation. In the crystal structure, inter-molecular N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers.

| S-EPMC2960696 | biostudies-literature

<i>n</i>-Propyl 6-amino-2,6-dideoxy-2,2-difluoro-?-d-glucopyranoside is a good inhibitor for the ?-galactosidase from <i>E. coli</i>.

Project description:A convenient route has been developed for the synthesis of novel 6-amino-2,2-(or 3,3-difluoro)-2-(or 3),6-dideoxy-hexopyranoses. Biological screening showed these compounds as good inhibitors for several glycosidases. Especially n-propyl 6-amino-2,6-dideoxy-2,2-difluoro-?-d-glucopyranoside (8) was an excellent competitive inhibitor for the ?-galactosidase from E. coli holding a K i of 0.50??M.

| S-EPMC7934981 | biostudies-literature

Design and directed evolution of a dideoxy purine nucleoside phosphorylase.

Project description:Purine nucleoside phosphorylase (PNP) catalyzes the synthesis and phosphorolysis of purine nucleosides, interconverting nucleosides with their corresponding purine base and ribose-1-phosphate. While PNP plays significant roles in human and pathogen physiology, we are interested in developing PNP as a catalyst for the formation of nucleoside analog drugs of clinical relevance. Towards this aim, we describe the engineering of human PNP to accept 2',3'-dideoxyinosine (ddI, Videx((R))) as a substrate for phosphorolysis using a combination of site-directed mutagenesis and directed evolution. In human PNP, we identified a single amino acid, Tyr-88, as a likely modulator of ribose selectivity. RosettaLigand was employed to calculate binding energies for substrate and substrate analog transition state complexes for single mutants of PNP where Tyr-88 was replaced with another amino acid. In parallel, these mutants were generated by site-directed mutagenesis, expressed and purified. A tyrosine to phenylalanine mutant (Y88F) was predicted by Rosetta to improve PNP catalytic activity with respect to ddI. Kinetic characterization of this mutant determined a 9-fold improvement in k(cat) and greater than 2-fold reduction in K(M). Subsequently, we used directed evolution to select for improved variants of PNP-Y88F in Escherichia coli cell extracts resulting in an additional 3-fold improvement over the progenitor strain. The engineered PNP may form the basis for catalysts and pathways for the biosynthesis of ddI.

| S-EPMC2898500 | biostudies-literature

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