Synthesis and anti-HIV activities of phosphate triester derivatives of 3′-fluoro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine

Fatty acyl-glycol phosphate triester conjugates of 3′-fluoro-2′,3′-dideoxythymidine (FLT) were prepared in three steps from the reaction of diisopropylphoramidous dichloride with fatty acyl-substituted glycols, followed by a coupling reaction with FLT and oxidation with tert-butyl hydroperoxide (t-BuOOH). Additionally, a number of fatty alcohols were reacted with diisopropylphoramidous dichloride to produce the phosphitylating intermediates, which underwent coupling reactions with 3′-azido-2′,3′-dideoxythymidine (AZT) and FLT followed by oxidation with t-BuOOH to yield fatty alcohol phosphate triester derivatives of AZT and FLT.     

On the design of polymeric 5′-O-ester prodrugs of 3′-azido-2′,3′-dideoxythymidine (AZT)

A new 5′-O-AZT prodrug was synthesized by conjugating 3′-azido-2′,3′-dideoxythymidine (AZT) with poly(oxyethylene H-phosphonate) at room temperature under Atherton-Todd reaction conditions. The acute toxicity of poly(5′-O-AZT-oxyethylene phosphate) was reduced significantly in comparison with non-immobilized AZT.     

Synthesis and biological evaluation of 5′-O-dicarboxylic fatty acyl monoester derivatives of anti-HIV nucleoside reverse transcriptase inhibitors

A number of 5′-O-dicarboxylic fatty acyl monoester derivatives of 3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine, d4T), and 3′-fluoro-3′-deoxythymidine (alovudine, FLT) were synthesized to improve the lipophilicity and potentially the cellular delivery of parent polar 2′,3′-dideoxynucleoside (ddN) analogs. The compounds were evaluated for their anti-HIV activity. Three different fatty acids with varying chain length of suberic acid (octanedioic acid), sebacic acid (decanedioic acid), and dodecanedioic acid were used for the conjugation with the nucleosides. The compounds were evaluated for anti-HIV activity and cytotoxicity. All dicarboxylic ester conjugates of nucleosides exhibited significantly higher anti-HIV activity than that of the corresponding parent nucleoside analogs. Among all the tested conjugates, 5′-O-suberate derivative of AZT (EC₅₀ = 0.10 nM) was found to be the most potent compound and showed 80-fold higher anti-HIV activity than AZT without any significant toxicity (TC₅₀ >500 nM).     

Effect of structure on thermal behaviour of epoxy resins

The paper deals with the curing behaviour of diglycidyl ether of bisphenol-A (DGEBA) using three novel multifunctional aromatic amines having phosphine oxide and amide-acid linkages. The amines were prepared by reacting tris(3-aminophenyl)phosphine oxide (TAP) with 1,2,4,5-benzenetetracarboxylic acid anhydride (P)/4,4^′-(hexafluoroisopropylidene)diphthalic acid anhydride (F)/3,3^′,4,4^′-benzophenonetetracarboxylic acid dianhydride (B). Amide-acid linkage in these amines is converted to thermally stable imide linkage during curing reaction. Curing temperatures of DGEBA were higher with phosphorylated amines than the conventional amine 4,4^′-diamino diphenyl sulphone (D). A decrease in initial decomposition temperature and higher char yields were observed when phosphorus containing amide-acid amines were used as curing agents for DGEBA.     

Design, synthesis, and evaluation of a novel bridged nucleic acid, 2′,5′-BNA, with S-type sugar conformation fixed by N-O linkage

We designed a novel 2′-O,5′-N bridged nucleic acid, 2′,5′-BNA^ON, whose sugar puckering was fixed to S-type conformation by an N-O linkage. A dimer unit formed from 2′,5′-BNA^ON-U and thymidine was synthesized via a coupling reaction between a protected 2′,5′-BNA^ON-U monomer and a thymidine derivative. Introduction of 2′,5′-BNA^ON-U into DNA was carried out using conventional phosphoramidite chemistry with a DNA synthesizer. The hybridization abilities of 2′,5′-BNA^ON-U-modified oligonucleotides against DNA or RNA complement were evaluated.     

Novel and efficient syntheses of 3′,5′-diamino derivatives of 2′,3′,5′-trideoxycytidine and 2′,3′,5′-trideoxyadenosine. Protonation behavior of 3′,5′-diaminonucleosides

High yielding synthetic routes to 3′,5′-diamino-2′,3′,5′-trideoxycytidine and 3′,5′-diamino-2′,3′,5′-trideoxyadenosine are described. In addition, the protonation behavior of 3′,5′-diamino-2′,3′,5′-trideoxycytidine, 3′,5′-diamino-2′,3′,5′-trideoxyadenosine, 3′,5′-diamino-3′,5′-dideoxythymidine, and 3′,5′-diamino-2′,3′,5′-trideoxyuridine has been studied by means of pH-metric measurements and NMR spectroscopy. The ionization constants and the sequence of protonation sites have been determined.     

Proton NMR study on two structures of 3′-O-(acetylimino)3′-de(phosphinico)-thymidylyl-(3,5′)-deoxythymidine in aqueous solution

The solution structure of one of dithymidine monophosphate (TpT) analogues, containing an (N-acetyl)imino backbone linkage (NCOCH₃) of 3′-O-(acetylimino)3′-de(phosphinico)-thymidylyl-(3,5′)-deoxythymidine (T_NT), has been determined by proton NMR. Two structures, designated as major and minor forms, in a ratio of about 3:2 coexist when the solution temperature is <25°C. Both forms adopt anti conformation with respect to the glycosidic bond, S-type deoxyribofuranose pucker, and have no base stacking. The backbone torsion angles ε′, φ_ON, φ_NC, and γ′ are trans, gauche⁺, gauche⁺, and gauche⁺ for the major form; and gauche⁻, gauche⁻, gauche⁻, and gauche⁺ for the minor form. Only major form is found at >25°C.     

Synthesis of phosphodiester-type nicotinamide adenine dinucleotide analogs

Fourteen phosphodiester-type β-nicotinamide adenine dinucleotide (NAD⁺) analogs were prepared starting from nicotinamide. The phosphodiester linkage was effectively assembled in 69-93% yields via condensation reaction between 2′,3′-di-O-acetyl nicotinamide mononucleotide and alcohols in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride. The analog β-nicotinamide ribose-5-(2-phenylethyl) phosphate showed beneficial effects on cell growth of model microorganisms.     

Emission of 2-phenylethanol from its β-d-glucopyranoside and the biogenesis of these compounds from [H8] l-phenylalanine in rose flowers

The hydrolysis of 2-phenylethyl β-d-glucopyranoside (3) was found to be partially inhibited by feeding with 2-phenyl-N-glucosyl-acetamidiumbromide (8), a β-glucosidase inhibitor, resulting in a decrease in the diurnal emission of 2-phenylethanol (2) from Rosa damascena Mill. flowers. Detection of [1,1,2,2′,3′,4′,5′,6′-²H₈]-2 and [1,2,2′,3′,4′,5′,6′-²H₇]-2 from R. ‘Hoh-Jun’ flowers fed with [1,1,2,2′,3′,4′,5′,6′-²H₈]-3 suggested that β-glucosidase, alcohol dehydrogenase, and reductase might be involved in scent emission. Comprehensive GC-SIM analyses revealed that [1,2,2,2′,3′,4′,5′,6′-²H₈]-2 and [1,2,2,2′,3′,4′,5′,6′-²H₈]-3 must be biosynthesized from [1,2,2,2′,3′,4′,5′6′-²H₈] l-phenylalanine ([²H₈]-1) with a retention of the deuterium atom at α-position of [²H₈]-1.     

Assignment of absolute configuration at phosphorus of P-chiral diastereomers of deoxyribonucleoside methanephosphonamidates by means of NMR spectroscopy

Recently, we have prepared a novel class of DNA analogues containing the [3′-NH-P(CH₃)(O)-O-5′] methanephosphonamidate linkage. Synthesis of such analogues requires preparation of the dinucleoside methanephosphonamidates N×N, where N is a 2′-deoxyribonucleoside moiety and × is the methanephosphonamidate linkage. Dimers T×T and C×T were obtained in a non-stereospecific manner giving rise to a pair of P-chiral diastereomers. Such diastereomers were effectively separated into fast and slow migrating ones by means of chromatographic methods (TLC). As described in our previous work (Nawrot et al. Nucleic Acids Res.1998, 26, 2650), the stereochemistry of the phosphorus chiral center of T×T fast migrating diastereomer is R_P and of T×T slow migrating diastereomer is S_P, as established by means of 2D ROESY experiments. Here we describe assignment of the absolute configuration at the phosphorus center of fast and slow migrating diastereomers of C×T dimer. The 2D ROESY sequence with phosphorus decoupling during acquisition used in these measurements allowed observation of the P-Me group as a singlet instead of a ¹H-³¹P-coupled doublet. The apparent advantage of this approach was a much better signal to noise ratio and improved resolution in the F1 dimension. For the fast migrating C×T diastereomer an R_P and for slow migrating C×T diastereomer an S_P configuration was assigned. Conformational analysis of both pairs of diastereomers T×T and C×T indicates significant differences in sugar ring puckering, which strongly depend on the nature of the nucleobase at the 5′-terminus of the dimer. The ribose rings of the 3′-amino-2′,3′-dideoxycytidine moiety of both diastereomers of C×T adopt predominantly a C3′-endo (North) conformation, while thymine-substituted ribofuranoses originating either from C×T or T×T dimers prefer a C2′-endo (South) conformation.     

Synthesis and structural investigation of 1′,3′,3′-trimethyl-6-hydroxy-spiro(2H-1-benzopyran-2,2′-indoline), 1′,3′,3′-trimethyl-6-methacryloyloxy-spiro(2H-1-benzopyran-2,2′-indoline) and a copolymer with methyl methacrylate by 1D and 2D NMR spectroscopy

Photo-responsive spiropyran-based compounds, such as, 1′,3′,3′-trimethyl-6-hydroxy-spiro(2H-1-benzopyran-2,2′-indoline) [OHSP], its monomer, such as 1′,3′,3′-trimethyl-6-methacryloyloxy-spiro(2H-1-benzopyran-2,2′-indoline) [MOSP] and its copolymers with methyl methacrylate [MMA] were synthesised using conventional synthetic routes. The copolymerisation was carried out either in tetrahydrofuran [THF] or in toluene using 2,2′-azobisisobutyronitrile [AIBN] as an initiator. The structures of these materials were investigated using ¹H and ¹³C NMR spectroscopy. DEPT-135, HCCOSW and COSY45 NMR experiments were used to assign and interpret the complex structure of spiropyran based materials.     

Syntheses of C-substituted icosahedral dicarbaboranes bearing the 8-dioxane-cobalt bisdicarbollide moiety

The treatment of 1,2-, 1,7- and 1,12-carbaborane lithiated isomers with [3,3′-Co-8-(CH₂CH₂O)₂-(1,2-C₂B₉H₁₀)-(1′,2′-C₂B₉H₁₁)] (1) at molar ratios 1:1 or 1:2 at room temperature in THF leads generally to the formation of a series of orange double-cluster mono and dianions. These were characterized by NMR and MS methods as [1′′-X-1′′,2′′-closo-C₂B₁₀H₁₁]⁻, [2]⁻; [1′′-X-1′′,7′′-closo-C₂B₁₀H₁₁]⁻, [3]⁻ and [1′′-X-1′′,12′′-closo-C₂B₁₀H₁₁], [4]⁻ for the monoanions, whereas [1′′,2′′-X₂-1′′,2′′-closo-C₂B₁₀H₁₀]²⁻, [2]²⁻; [1′′,7′′-X₂-1′′,7′′-closo-C₂B₁₀H₁₀]²⁻, [3]²⁻; and [1′′,12′′-X₂-1′′,12′′-closo-C₂B₁₀H₁₀]²⁻, [4]²⁻ for the dianions (where X = 3,3′-Co-8-(CH₂CH₂O)₂-(1,2-C₂B₉H₁₀)-1′,2′-(C₂B₉H₁₁)). Moreover, these borane-cage subunits can be easily modified via attaching variable substituents onto cage carbon and boron vertices, which makes these compounds structurally flexible potential candidates for BNCT of cancer and HIV-PR inhibition.     

Stepwise solid phase synthesis of uridylylated viral genome-linked peptides using uridylylated amino acid building blocks

The uridylylated amino acid building blocks 2-cyanoethyl-(N^α-9-fluorenylmethoxy-carbonyl-tyrosin-4-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate and 2-chlorophenyl-(N^α-fluorenyl-methoxycarbonyl-serin-3-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate have been used successfully in an on-line SPPS of the VPgpU from the polio, coxsackie and cowpea mosaic virus.     

Enantiospecific synthesis, separation and olfactory evaluation of all diastereomers of a homologue of the sandalwood odorant Polysantol

The four stereoisomers of (5E)-4,4-dimethyl-6-(2′,2′,3′-trimethylcyclopent-3′-en-1′-yl)-hex-5-en-3-ol, a homologue of the valuable sandalwood-type odorant Polysantol^®, were enantiospecifically synthesized from (+)- and (−)-α-pinene, through (−)- and (+)-campholenic aldehyde, by aldol condensation with 3-pentanone, deconjugative α-methylation and reduction. The mixtures of epimeric alcohols obtained after reduction were separated by means of derivatization with (−)-(1S)-camphanic chloride. The enantiomerically pure final products were evaluated organoleptically.     

Controlled vinyl-addition-type polymerization of norbornene initiated by several cobalt complexes having substituted terpyridine ligands

A series of cobalt(II) complexes having terpyridine derivatives such as 2,2^′:6^′,2″-terpyridine (1), 4,4^′,4″-^tBu₃-2,2^′:6^′,2″-terpyridine (2), 5,5″-Me₂-2,2^′:6^′,2″-terpyridine (3), 6,6″-Me₂-2,2^′:6^′,2″-terpyridine (4) and 6,6″-(3,5-Me₂C₆H₃)₂-2,2^′:6^′,2″-terpyridine (5) was synthesized. The structures of 1, 3, and 4 were confirmed by X-ray crystallography. The coordination sphere around the cobalt center in 1 can be described as pseudo square pyramidal. On the other hand, complex 4 has pseudo trigonal bipyramidal structure. Upon activation with d-MAO (dried-methylaluminoxane), these complexes showed high activities for the polymerization of norbornene (NBE). In particular, polymerization of NBE with 4/d-MAO system at room temperature resulted in quantitative yield within several hours to give the polymers with relatively narrow molecular weight distributions and controlled molecular weight. The polymerizations of NBE with these cobalt catalyst systems proceeded in vinyl addition polymerization, which was confirmed by ¹H NMR spectra of the resulting polymers.     

rac-Lactide polymerization using aluminum complexes bearing tetradentate phenoxy-amine ligands

A family of aluminum-methyl complexes supported by tetradentate phenoxy-amine ligands has been prepared and employed in the ring-opening polymerization of rac-lactide; the ligands include N,N-bis(3,5-dimethyl-2-hydroxybenyl)-N′,N′-dimethyl-1,2-diaminoethane (L¹), N,N-bis(3,5-diisopropyl-2-hydroxybenyl)-N′,N′-dimethyl-1,2-diaminoethane (L²) and N,N-bis(3,5-dichloro-2-hydroxybenyl)-N′,N′-dimethyl-1,2-diaminoethane (L³). Polymerizations of rac-lactide were carried out by treatment of the aluminum-methyl complexes with PhCH₂OH and rac-lactide at 70 °C, affording well-controlled formation of polylactide (PLA) and a moderate isotactic bias for initiators bearing L¹ and L²; the chloro-substituted ligand L³ afforded largely atactic PLA.     

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione^® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a′R,7a′S)-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.     

Syntheses, topological analyses and photoelectric properties of Ag(I)/Cu(I) metal-organic frameworks based on a tetradentate imidazolate ligand

A new tetradentate imidazolate ligand 1,1′,1″,1′′′-(2,2′,4,4′,6,6′-hexamethylbiphenyl-3,3′,5,5′-tetrayl)tetrakis(methylene)(1H-imidazole) (L) and four Ag(I)/Cu(I) coordination polymers, namely [(MCN)₃L]_n (1: M=Ag; 2: M=Cu), and [(MSCN)₂L]_n (3: M=Ag; 4: M=Cu) are described. All four new coordination polymers were fully characterized by infrared spectroscopy, elemental analysis and single-crystal X-ray diffraction. Compound 1 features a 3D supramolecular framework constructed by 1D chains through inter-chain Ag-N(CN) and inter-layer Ag-N(L) weak interactions with an uninodal 6⁶ topology. Complex 2 presents a 3D framework characterized by a tetranodal (3,4)-connected (3·4·5·10²·11)(3·4·5·6·7·9)(3·6·7)(6·10²) topology. Complexes 3 and 4 are isostructural, and both have a 3D network of trinodal 4-connected (4·8⁵)₂(4²·8²·10²)(4²·8⁴)₂ topology. The luminescent properties for these compounds in the solid state as well as the possible ferroelectric behavior of 1 are discussed.     

Reactions of 4-(dimethylamino)pyridinium activated pentachloropyridine with nitrogen nucleophiles and hydride

Substitution reactions on 2′,3′,5′,6′-tetrachloro-4-dimethylamino-[1,4]bipyridinyl-1-ylium chloride with nitrogen nucleophiles such as n-propylamine, isopropylamine, glycine, morpholine, and piperidine were examined. Highly functionalized Cl²,Cl³,N⁴,Cl⁵,Cl⁶- and N²,Cl³,N⁴,Cl⁵,Cl⁶-substituted pyridines were obtained, in part possessing unsubstituted 4-amino groups due to dealkylation. Detailed NMR studies were performed in order to elucidate the regiochemistry of these dealkylations.     

Topologically novel copper molybdate phases based on 3,4′-dipyridylketone: Hydrothermal synthesis, structural characterization, and magnetic properties

Hydrothermal treatment of CuCl₂·2H₂O, MoO₃, and 3,4′-dipyridylketone (3,4′-dpk) in 1:1:2 mole ratio afforded the new mixed metal oxide phases [Cu₂(MoO₄)₂(3,4′-dpk)(H₂O)] (1) or [Cu₄(3,4′-dpk)₄(Mo₈O₂₆)] (2), depending on the pH of the initial reaction mixture. Compound 1 possesses unique one-dimensional (1-D) [Cu₂(MoO₄)₂(H₂O)]_n ribbons constructed from the linkage of {Cu^II₄O₆} tetrameric units through isolated [MoO₄]^2- tetrahedra. These ribbons in turn are connected into a two-dimensional (2-D) coordination polymer structure by tethering 3,4′-dpk ligands. Compound 2, containing monovalent copper ions, manifests an unprecedented “X-rail” 1-D extended structure with (6²8)₄(6⁶) topology formed from the bracketing of discrete [β-Mo₈O₂₆]^4- anions by four chains. The variable temperature magnetic susceptibility behavior of 1 was fit to a linear tetramer model, with g=2.03(3), J₁=25.8(7) cm^-1 and J₂=−46(1) cm^-1. Antiferromagnetic inter-tetramer interactions (zJ′=−0.21(3) cm^-1) were also evident. Crystallographic data: 1 monoclinic, P2₁/c, a=10.3911(11) Å, b=6.9502(6) Å, c=22.958(2) Å, β=100.658(7)°, V=1629.5(3) Å³, R₁=0.1256, and wR₂=0.2038; 2 triclinic, a=10.9000(3) Å, b=11.7912(4) Å, c=13.5584(4) Å, α=102.482(2)°, β=102.482(2)°, γ=117.481(2)°, V=1450.98(8) Å³, R₁=0.0428, and wR₂=0.0630.