Investigations of Nucleoside H-Phosphonamidate in the Design of Nucleotide Prodrug

Abstract

The synthesis, anti-HIV activity and stability studies of a H-phosphonamidate derivative of 3′-azido-2′,3′-dideoxythymidine (AZT) incorporating a N,N-diisopropylamino residue as first model of alkylamino group are reported. The results demonstrate that such phosphorylated structure exerts its biological effects via chemical hydrolysis into the corresponding H-phosphonate, precursor of the parent nucleoside.     

2-Cyanoethyl H-Phosphonate. A Reagent for the Mild Preparation of Nucleoside H-Phosphonate Monoesters

Abstract

2-Cyanoethyl H-phosphonate was condensed with protected nucleoside derivatives and the cyanoethyl group subsequently removed by anhydrous base to give the corresponding nucleoside H-phosphonate in good yield.     

A New Approach to Oligonucleotide Synthesis in Solution

Abstract

A new approach, based on the use of 3′-H-phosphonate building blocks, is described for the synthesis of oligonucleotides and their phosphorothioate analogues in solution.

     

A New Approach to the Synthesis of Linear and Cyclic Oligoribonucleotides

Abstract

The tetraribonucleoside triphosphate 15 and the cyclic tetraribonucleotide 16 have been prepared by a recently reported triester approach in solution, involving H-phosphonate coupling.     

Studies on Reactions of Nucleoside H-Phosphonates with Bifunctional Reagents. Part VI. Reaction with Diols

Abstract

Reactions of nucleoside H-phosphonates with various diols using different types of condensing agents have been studied. Depending on the coupling procedure and the length of a polymethylene chain of the diol, acyclic H-phosphonate diesters or cyclic phosphite triesters were formed. The course of oxidation with iodine to produce cyclic nucleoside alkyl phosphotriesters or hydroxyalkyl nucleoside phosphodiesters can be controlled by the amount of water present in the reaction medium.     

Stereochemistry of Internucleotide Bond Formation by the H-Phosphonate Method. 1. Synthesis and 31P Nmr Analysis of 16 Diribonulceoside (3′-5′)-H-Phosphonates and the Corresponding Phosphorothioates

Sixteen diribonucleoside (3′-5′)-H-phosphonates were synthesized via condensation of the protected ribonucleoside 3′-H-phosphonates with nucleosides, and the influence of a nucleoside sequence on the observed stereoselectivity was analyzed. ₃₁P NMR spectroscopy was used to evaluate a relationship between chemical shift and absolute configuration at the phosphorous center of the H-phosphonate diesters as well as of the corresponding phosphorothioate diesters. Although for the most cases such correlation was found, there was however several exceptions to the rule where the relative positions of resonances arising from R _P and S _P diastereomers were reversed.     

A Synthesis of Dolichyl Phosphorofluoridate

An improved method for the synthesis of dolichyl H-phosphonate was developed using 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (salicyl chlorophosphite) as a reagent. Dolichyl phosphorofluoridate was for the first time synthesized from dolichyl H-phosphonate by its treatment with chlorotrimethylsilane,followed by oxidation with iodine in the presence of fluoride in pyridine.     

Di-ddU-α-Hydroxyphosphonate and α-Hydroxy- α- METHYLPHOSPHONATES as Potential Prodrugs of Antiviral Nucleoside Analogues

Abstract

The synthesis of a potential new prodrug system for the antiviral nucleoside ddU 1 based on α-hydroxybenzylphosphonates 2 and 3 is described. In principle, 2, 3 are able to hydrolyze via different mechanisms yielding ddU H-phosphonate 4 or ddU monophosphate 5, respectively.     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

Glycosylation via mixed disulfide formation using glycosylthio-phthalimides and -succinimides as glycosylsulfenyl-transfer reagents

The silver salts of tetra-O-acetyl α- or -β-d-glycopyranosyl thiols 1a–4a react smoothly with N-bromophthalimide and N-bromosuccinimide to furnish glycosylthio-phthalimide (1b–4b) and -succinimide (1c–3c) derivatives. Reactions of these reagents with aliphatic, aromatic, and glycosyl thiols as well as with cysteine and glutathione result in the formation of glycosylated mixed disulfides under mild conditions and in good yields. The S-glycosyl-N-acylsulfenamides described here represent novel, convenient glycosylsulfenyl-transfer reagents in effecting glycosylation of various thiols, including sugars, amino acids and peptides, through disulfide formation and can, therefore, be useful in controlled glycosylation of proteins as well.     

Chemical and Enzymatic Synthesis of 2′-Deoxy-iso-inosine and Its Incorporation into DNA

Abstract

Two procedures for the preparation of 2′-deoxy-iso-inosine (1) are presented. Synthesis of 3′-phosphoramidite (7) and 3′-phosphonate (8) derivatives are described, as well as an oligodeoxynucleotide containing iso-I.     

Regioselective N1-Alkylation of Guanosine Derivatives Protected at N 2 by an N,N-Dialkyl Amidine Group

Abstract

Under Mitsunobu reaction conditions or in the presence of eiectrophilic alkylating reagents, alkylation of guanosine derivatives protected by an N,N-dialkyl amidine at the exocyclic amino group occurs selectively on nitrogen N ¹ of the purine base.     

DFT study of new bipyrazole derivatives and their potential activity as corrosion inhibitors

In the present work, a theoretical study of five bipyrazolic-type organic compounds, 4-{bis[(3,5-dimethyl-1H-pyrazolyl-1-yl)methyl]-amino}phenol (1), N1,N1-bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl}]-N4,N4-dimethyl-1,4-benzenediamine (2), N,N-bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]aniline (3), 4-[bis(3,5-dimethyl pyrazol-1-yl-methyl)-amino]butan-1-ol (4) and ethyl4-[bis(3,5-dimethyl-1H-pyrazol-1-yl-methyl) aminobenzoate] (5), has been performed using density functional theory (DFT) at the B3LYP/6-31G(d) level in order to elucidate the different inhibition efficiencies and reactive sites of these compounds as corrosion inhibitors. The efficiencies of corrosion inhibitors and the global chemical reactivity relate to some parameters, such as EHOMO, ELUMO, gap energy (ΔE) and other parameters, including electronegativity (χ), global hardness (η) and the fraction of electrons transferred from the inhibitor molecule to the metallic atom (ΔN). The calculated results are in agreement with the experimental data on the whole. In addition, the local reactivity has been analyzed through the Fukui function and condensed softness indices.     

Novel alkyl alkanethiolsulfonate sulfhydryl reagents. Modification of derivatives ofl -cysteine

A simple, general scheme for the synthesis of sulfhydryl-specific alkyl alkanethiolsulfonate (RSSO₂R) reagents where R is methyl, has been developed. Two new reagents, methyl aminoethanethiolsulfonate (2) and methyl benzylthiolsulfonate (3) were synthesized. These were used to modify stoichiometrically and selectively under mild conditions the sulfhydryl groups ofN-acetyl-l-cysteine ethyl ester (4),N-acetyl-l-cysteinep-nitroanilide (7), glutathione, and the A chain of bovine insulin. The corresponding -S-(-aminoethanethiol) and -S-(benzylthiol) derivatives ofl-cysteine and of the peptides were afforded. The characteristics and significance of these reactions and products are discussed.     

Synthesis of chimera oligopeptide including furanoid β-sugar amino acid derivatives with free OHs: mild but successful removal of the 1,2-O-isopropylidene from the building block

Complementary to hydrophobic five membered ring β-amino acids (e.g. ACPC), β-sugar amino acids (β-SAAs) have found increasing application as hydrophilic building blocks of foldamers and α/β chimeric peptides. Fmoc-protected β-SAAs [e.g. Fmoc-RibAFU(ip)-OH] are indeed useful Lego elements, ready to use for SPPS. The removal of 1,2-OH isopropylidene protecting group increasing the hydrophilicity of such SAA is presented here. We first used N₃-RibAFU(ip)-OH model compound to optimize mild deprotection conditions. The formation of the 1,2-OH free product N₃-RibAFU-OH and its methyl glycoside methyl ester, N₃-RibAFU(Me)-OMe were monitored by RP-HPLC and found that either 50% TFA or 8 eqv. Amberlite IR-120 H⁺ resin in MeOH are optimal reagents for the effective deprotection. These conditions were then successfully applied for the synthesis of chimeric oligopeptide: -GG-X-GG- [X=RibAFU(ip)]. We found the established conditions to be effective and—at the same time—sufficiently mild to remove 1,2-O-isopropylidene protection and thus, it is proposed to be used in the synthesis of oligo- and polypeptides of complex sequence combination.

     

Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents

Abstract

To explore the pharmacological and structure–activity relationship of a series of N-substituted-(4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl), substituted benzene sulfonamide derivatives (1–25) were synthesized from substituted anthranilic acids derived amino quinazolines and substituted benzene sulphonamides. All the synthesized compounds were evaluated for their diuretic (by Lipschitz et al. method), antihypertensive activity by non-invasive blood pressure (NIBP) using the tail-cuff method and anti-diabetic potential in rats. Six compounds showing significantly excellent activity were compared with metolazone, prazosin and diazoxide as standards. Compound N-[7-chloro-2-(4-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]-4 nitrobenzenesulfonamide (20) exhibited most potent of the series.     

Design and SAR Study of a Novel Class of Nucleotide Analogues as Potent Anti-HCMV Agents

Abstract

We have developed a novel class of 2-phosphonate 1,3-dioxolane nucleotide analogues, from which the guanine derivative displayed weak anti-HCMV activity. Further SAR studies led to the identification of both cis and trans guanine derivatives of tetrahydrofuran analogues as potent anti-HCMV agents, both in vitro and in vivo, compared to ganciclovir and HPMPC.     

Antimicrobial activities of some synthetic butenolides and their pyrrolone derivatives

In the present investigation, 17 new synthetic butenolides, i.e. 2-arylidene-4-(4-chloro/ethyl-phenyl)but-3-en-4-olides (3–19) have been synthesized from 3-(4-chloro-benzoyl)propionic acid or 3-(4-ethyl-benzoyl)propionic acid using appropriate reagents. Some of the selected butenolides were reacted with ammonia and benzylamine to give the corresponding pyrrolones (20–31) and N-benzyl-pyrrolones (32–39) respectively. All the compounds were screened for their antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa and antifungal activity against Candida albicans, Aspergillus niger, and Rhizopus oryza. Minimum inhibitory concentration (MIC) values of the compounds are reported. The pyrrolone derivatives discovered in this study may provide valuable therapeutic intervention for the treatment of microbial diseases, especially against fungal species.     

Asymmetric Synthesis of α-Methylglutamic Acid and α-Methylornithine by a Chiral Isocyano Amide Reagent

An efficient approach to the asymmetric syntheses of α-methylglutamic acid and α-methylornithine is described. Two chiral reagents, (2′S)-N-(2′-methoxymethylpyrrolidine)-2-isocyanopropionamide 4 and (2′S)-N-(2′-hydroxymethylpyrrolidine)-2-isocyanopropionamide 5, were employed for the asymmetric induction. α-Methylglutamic acid 7 was synthesized by the asymmetric Michael-addition of methyl acrylate to 4 and 5 as the key step. The optical yield of 7 was 10~45% (R-form). α-Methylornithine 12 was also synthesized by the reaction of 4 with acrylonitrile as the key step. The optical yield of 12 was 31.7% (R-form).     

Preparation of an unprotected phosphotyrosine building block and its application in solid-phase synthesis of phosphopeptides

Summary A new and facile synthesis of tyrosine phosphorylated peptides has been developed.N ^α-Fmoc-Tyr(tBu)-OPfp was treated with TFA, phosphorylated with phosphorous oxychloride and the resulting phosphoric acid dichloride was hydrolysed to giveN ^α-Fmoc-Tyr(PO₃H₂)-OPfp1 in an overall yield of 98%. Compound1 was used in solid-phase peptide synthesis of phosphopeptides2, 3 and4, which are fragments of murine adipocyte lipid binding protein. The advantage of using the Pfp ester was the absence of pyrophosphates and other byproducts.