Macromolecular synthesis from saccharic lactones. Polyaddition of D-glucaro- and D-mannaro- 1,4:6, 3-dilactones with diisocyanates and hydrolyzability of the resulting polyurethanes having dilactone rings in the main chains

Polyaddition of saccharic acid dilactones prepared from D-glucose and D-mannitol, D-glu-caro-, and D-mannaro-1,4:6,3-dilactones ( 1 and 2 , respectively), with hexamethylene di-isocyanate ( 3a ) and methyl (S)-2,6-diisocyanatocaproate ( 3b ) was carried out by using dibutyltin dilaurate as a catalyst at 50, 25, and 0°C to give polyurethanes ( 4 and 5 ) having dilactone moieties in the main chains. The resulting polymers were found to decompose easily in phosphate buffers under neutral or slightly basic conditions (pH 7 or 8). Therefore, the polyurethanes may be used as novel degradable polymeric materials. © 1995 John Wiley & Sons, Inc.     

Hydroxyl stereochemistry and amine number within poly(glycoamidoamine)s affect intracellular DNA delivery

Nucleic acid drugs have great potential to treat many devastating aliments, but their application has been hindered by the lack of efficacious and nontoxic delivery vehicles. Here, a new library of poly(glycoamidoamine)s (D1-D4, G1-G4, and M1-M4) has been synthesized by polycondensation of esterified d-glucaric acid (D), dimethyl-meso-galactarate (G), and d-mannaro-1,4:6,3-dilactone (M) with diethylenetriamine (1), triethylenetetramine (2), tetraethylenepentamine (3), and pentaethylenehexamine (4). The stereochemistry of the carbohydrate hydroxyl groups and the number of amine units have been systematically changed in an effort to examine how the polymer chemistry affects the plasmid DNA (pDNA) binding affinity, the compaction of pDNA into nanoparticles (polyplexes), the material cytotoxicity, and the efficacy of nucleic acid delivery. The polymers with four secondary amines (D4, G4, and M4) between the carbohydrates were found to have the highest pDNA binding affinity and the galactarate polymers generally yielded the smallest polyplexes. Delivery studies with pDNA containing the firefly luciferase or beta-galactosidase reporter genes in BHK-21, HeLa, and HepG2 cells demonstrated that all of the poly(glycoamidoamine)s deliver pDNA without cytotoxicity. Polymers D4, G4, and M4 displayed the highest delivery efficiency, where G4 was found to be a particularly effective delivery vehicle. Heparin competition assays indicated that this may be a result of the higher pDNA binding affinity displayed by G4 as compared to D4 and M4. Polyplexes formed by polymers with weaker pDNA affinities may dissociate at the cell surface due to interactions with negatively charged glycosaminoglycans, which would cause a decrease in the number of polyplexes that are endocytosed.     

A short route to l-iduronic acid building blocks for the syntheses of heparin-like disaccharides

The effective preparation of differentially protected l-iduronic acid derivatives, as building blocks for the synthesis of heparin-like oligosaccharides, is described in less than nine steps starting from readily available 1,2-O-isopropylidene-6,3-d-glucuronolactone. The pivaloyl group was used as a permanent protecting group of hydroxyl groups. Two heparin-like disaccharides with different sulfation pattern have been prepared by using these l-iduronic acid building blocks.     

Synthesis of new hydrolyzable polyurethanes from L‐gulonic acid‐derived diols and diisocyanates

New polyurethanes with lactone groups in the pendants and main chains were synthesized by the polyaddition of two kinds of L ‐gulonolactone‐derived diols (2,3‐O‐isopropylidene‐L ‐gulono‐1,4‐lactone and 5,6‐O‐isopropylidene‐L ‐gulono‐1,4‐lactone) with hexamethylene diisocyanate and methyl (S)‐2,6‐diisocyanatohexanoate and by the subsequent deprotection of isopropylidene groups. They were hydrolyzed more quickly than the polyurethane derived from methyl β‐D ‐glucofuranosidurono‐6,3‐lactone in a phosphate buffer solution, the pH value of which was 8.0, at 27 °C. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 4158–4166, 2002     

Synthesis and characterization of stereoregular AABB‐type polymannaramides

The condensation of D ‐mannaro‐1,4:6,3‐dilactone ( 2 ) with even‐numbered alkylenediamines (C₂, C₆–C₁₂) in a methanol solution and in the presence of triethylamine afforded polymannaramides 3 – 7 , which were isolated directly as white solids with various hydrophobic–hydrophilic characters. Because all the stereocenters in 2 possessed an S configuration, the random polymerization led to optically active, stereoregular polyhydroxypolyamides. The polymers were characterized by elemental analysis and IR, ¹H NMR, and ¹³C NMR spectroscopy. Their number‐average molecular weights were estimated by ¹H NMR spectral integration analysis. Thermal and powder X‐ray diffraction studies revealed that compounds 3 – 7 were poorly crystalline. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1024–1030, 2001     

Selective separation of flavonoids with a polyvinyl alcohol membrane

In order to develop a selective membrane separation process for flavonoids, i.e. baicalin, baicalein and flavone extracted from a crude drug, “Wogon”, we have measured the permeabilities of these flavonoids through a polyvinyl alcohol membrane, together with their aqueous solubilities. The aqueous solubilities of baicalin and baicalein increase with increasing aqueous solution pH due to the acid dissociation of the saccharic carboxyl group of baicalin or the phenolic hydroxyl group of baicalein. The mass transfer coefficients of flavonoids experimentally obtained in both systems of single and mixed constituents agreed well with the calculated values based on a solution-diffusion model together with the acid dissociation of the carboxyl or hydroxyl groups of baicalin and baicalein, respectively. The selective mutual separation of flavonoids can be achieved from mixed solution of constituents in the neutral pH region. Furthermore, a quantitative discussion of the permeation behavior of flavonoids through the PVA membrane is provided from a molecular modelling computational viewpoint.     

Hydroxyoligophosphites and -Phosphonites on the Basis of 1,4:3,6-Dianhydro-D-sorbitol

The interaction of 1,4:3,6-dianhydro-D-sorbitol with phosphorous and phenylphosphonous acid amidochlorides leads to oligophosphites and -phosphonites with free hydroxyl groups on the periphery of their molecules. The obtained compounds were introduced into reactions via the transformation of trivalent phosphorus and hydroxyl groups.     

Synthesis of glycopolymers bearing mannaric pendants as inhibitors on the β‐glucuronidase activity: The inhibition mechanisms of mannaric‐ and glucaric‐compounds

A new styrene derivative having D ‐mannaric moiety, N‐p‐vinylbenzyl‐D ‐mannaramic acid (VB‐D ‐ManaH, 8 ) was synthesized though the ring‐opening reaction of D ‐mannaro‐1,4:6,3‐dilactone (D ‐MDL) with p‐vinylbenzylamine. VB‐D ‐ManaH was copolymerized with acrylamide (AAm) to give novel polymers having D ‐mannaric moiety in the pendants, P(VB‐D ‐ManaH‐co‐AAm), 10 . The resulting glycomonomer and polymer ( 8 and 10 ) bearing D ‐mannaric pendants were found to inhibit the β‐glucuronidase activity, although the inhibition ability of the corresponding saccharodilactone (D ‐MDL) was known to be low. Additionally, the inhibition ability of P(VB‐D ‐ManaH‐co‐AAm), 10 , was almost the same as that of the glycopolymer having D ‐glucaric pendants, P(VB‐6‐D ‐GlcaH‐co‐AAm), 1 , which was one of the most effective inhibitors for β‐glucuronidase, reported in our previous work. Thus, 10 and 8 may be the first D ‐mannaric strong inhibitors to the β‐glucuronidase activity. The Lineweaver–Burk plot suggested that the inhibition mechanisms of 10 and 8 were more complicated than in the case of the competitive and uncompetitive inhibition of N‐p‐(vinylbenzyl)‐6‐D ‐glucaramic ( 11 ) and N‐p‐(vinylbenzyl)‐1‐D ‐glucaramic acids ( 12 ), respectively. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2032–2042, 2009     

Biodegradable polymers based on renewable resources. IX. Synthesis and degradation behavior of polycarbonates based on 1,4:3,6‐dianhydrohexitols and tartaric acid derivatives with pendant functional groups

Novel polycarbonates, with pendant functional groups, based on 1,4:3,6‐dianhydrohexitols and L ‐tartaric acid derivatives were synthesized. Solution polycondensations of 1,4:3,6‐dianhydro‐bis‐O‐(p‐nitrophenoxycarbonyl)hexitols and 2,3‐di‐O‐methyl‐L ‐threitol or 2,3‐O‐isopropylidene‐L ‐threitol afforded polycarbonates having pendant methoxy or isopropylidene groups, respectively, with number average molecular weight (M_n) values up to 3.6₁ × 10⁴. Subsequent acid‐catalyzed deprotection of isopropylidene groups gave well‐defined polycarbonates having pendant hydroxyl groups regularly distributed along the polymer chain. Differential scanning calorimetry (DSC) demonstrated that all the polycarbonates were amorphous with glass transition temperatures ranging from 57 to 98 °C. Degradability of the polycarbonates was assessed by hydrolysis test in phosphate buffer solution at 37 °C and by biochemical oxygen demand (BOD) measurements in an activated sludge at 25 °C. In both tests, the polycarbonates with pendant hydroxyl groups were degraded much faster than the polycarbonates with pendant methoxy and isopropylidene groups. It is noteworthy that degradation of the polycarbonates with pendant hydroxyl groups was remarkably fast. They were completely degraded within only 150 min in a phosphate buffer solution and their BOD‐biodegradability reached nearly 70% in an activated sludge after 28 days. The degradation behavior of the polycarbonates is discussed in terms of their chemical and physical properties. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 3909–3919, 2005     

Effects of interaction of tannins with co-existing substances. VII. Inhibitory effects of tannins and related polyphenols on xanthine oxidase

The inhibitory effects of hydrolyzable tannins, condensed tannins and related polyphenols on the activity of xanthine oxidase (XOD), catalyzing uric acid formation from xanthine, were investigated. Marked differences in the strength of the inhibition were observed. Some of the differences among the monomeric hydrolyzable tannins were due to their molecular weights, reflecting the number of phenolic hydroxyl groups in the molecule. However, the inhibitory activity of several oligomeric hydrolyzable tannins seemed particularly low in spite of their large molecular size. It was also observed that differences in location of acyl groups on the carbohydrate cores caused differences in the inhibitory activity among monomeric and oligomeric hydrolyzable tannins. A caffeic acid derivative (caffeetannin), 3,5-di-O-caffeoylquinic acid (24), also inhibited this enzyme. Galloylation and the degree of polymerization in proanthocyanidins were also shown to affect remarkably the strength of the inhibition. Among the compounds tested in the present study, valoneic acid dilactone (29), isolated from Mallotus japonicus, inhibited the enzyme most effectively. A kinetic study showed that this dilactone inhibited XOD non-competitively. Comparison of the inhibitory effect on XOD, with the binding activity to hemoglobin, for each tannin, suggests that their inhibition of XOD is not based on non-specific binding to the protein. Similar comparison of the inhibitory effect on XOD with the inhibitory effect on the generation of superoxide anion radical (O2-.) from the hypoxanthine-XOD system revealed that the inhibition of O2-. generation by tannins is due to their radical-scavenging activity, and not due to their inhibitory activity upon the enzyme.     

Five new derivatives of nonactic and homo-nonactic acids from Streptomyces globisporus

In addition to the known compounds of the type of nonactic and homononactic acids and their lactones, dilactones and tetralactones, five new compounds, namely homononactyl-nonactoate, a dilactone consisting of nonactic and homononactic acids and three cyclic trimers with nonactic and homononactic acids, were isolated from a strain of Streptomyces globisporus. Their structures, including the absolute configurations of the hydroxyl and methyl groups, were determined by extensive spectroscopic techniques such as UV, IR, MS, 1D and 2D NMR.     

Hydrolytic stability of oligoesters: comparison of steric with anchimeric effects

A comparison of steric and anchimeric effects on the hydrolytic stability of polyesters was studied. Twelve monomers were selected based on their propensity toward steric and anchimeric interactions: adipic acid, isophthalic acid, phthalic anhydride, hexahydrophthalic anhydride, 1,4-cyclohexanedicarboxylic acid, maleic anhydride, ethylene glycol, 1,2-propanediol, 1,3-propanediol 1,4-butanediol, 1,5-pentanediol, and neopentyl glycol. Hydroxyl terminated oligoesters consisting of one diacid and one diol and one hydroxyl terminated oligoester consisting of two diacids and one diol were prepared. The hydrolytic stability was evaluated in an acetone/water solution. The acid number was monitored as a function of time. It was found that telechelic groups favor anchimeric interactions, while steric groups determine the rate of hydrolysis for the main chain.     

The binding sites of carboxylic acid group contacting to Cu electrode

In this work, the binding sites of carboxylic acid binding to Cu electrode are explored by electrochemical jump-to-contact STM break junction. Single molecular conductance of benzene-based molecules with ending groups of carboxylic acid, carbonyl and hydroxyl are measured and compared. The conductance values of 1,4-benzenedicarboxaldehyde can be found in those of 1,4-benzenedicarboxylic acid, which shows that carboxylic acid can bind to Cu electrode through carbonyl group. Carboxylic acid can also bind to the electrode through carboxylate group, and gives out larger conductance values than those of carbonyl group. However, molecule with hydroxyl group is difficult to form single molecular junction with Cu. The current work demonstrates that the carboxylic acid can bind to the electrode through carbonyl and carboxylate groups, and a new anchoring group of carbonyl group can be used to form effective single molecular junction.     

Synthesis and Antiradical Activity of 5-Acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic Acid Nitriles

The alkylation of 3-cyano-1,4-dihydropyridine-2(3H)-thiones or the condensation of an aromatic aldehyde, cyanothioacetamide, acetylacetone, and methyl iodide in the presence of piperidine has given a series of novel 5-acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic acid nitriles. A compound was obtained from 3,5-di(tert-butyl)-4-hydroxybenzaldehyde in the molecule of which were combined the active part of the antioxidant ionol and a 1,4-dihydropyridine ring. It was found that, among the compounds synthesized, the highest antiradical activity occurred in a compound having two hydroxyl groups in the 4-phenyl substituent.     

Conversion of 1,4-diketones into para-disubstituted benzenes

Reaction of acetylides with aldehydes to form but-2-yne-1,4-diols, followed by triple bond reduction and oxidation of the hydroxyl groups, gives 1,4-diketones; these react with vinyllithium, and the resulting diols undergo ring-closing metathesis to form 2-cyclohexene-1,4-diols. Dehydration, usually by acid treatment, then gives benzenes carrying substituents in a 1,4 relationship. Use of substituted vinyllithiums provides further substitution on the final benzene rings. The method can be applied to the synthesis of C5-aryl carbohydrates.     

Synthesis and properties of bio‐based polyurethanes bearing hydroxy groups derived from alditols

Four kinds of bio‐based polyurethanes bearing hydroxy groups in the pendants were synthesized by the polyaddition of D ‐mannitol‐ and D,L ‐erythritol‐derived diols (1,2:5,6‐di‐O‐isopropylidene‐D ‐mannitol and 1,2‐O‐isopropylidene‐D,L ‐erythritol) with hexamethylene diisocyanate and methyl (S)‐2,6‐diisocyanatohexanoate and the subsequent deprotection of the isopropylidene groups. They were hydrolyzed much more quickly than the corresponding protected polyurethanes at 50 °C and pH 7.0, although their hydrolytic degradation rate was lower than that of polyurethanes with saccharic and glucuronic lactone groups, which had been reported in our previous articles. The introduction of D ‐mannitol units to the polyether‐polyurethanes containing poly(oxytetramethylene) glycol units also enhanced their hydrolyzibility. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Mechanisms for the Formation of Diamides and Polyamides by Aminolysis of d‐Glucaric Acid Esters

¹H and ¹³C NMR were employed to chart the conversion of the five‐membered lactone esters methyl d‐glucarate 1,4‐lactone (1) and ethyl d‐glucarate 6,3‐lactone (5) to N,N′‐dipropyl‐d‐glucaramide with n‐propylamine in DMSO‐d₆. These experiments were carried out to model the amide forming steps in polycondensation reactions between esterified d‐glucaric acid and diamines to give poly(d‐glucaramides). It was clear from the resulting NMR spectra that the lactones 1 and 5 were each converted in three consecutive steps to the product diamides; aminolysis of the lactone ester to the corresponding acyclic N‐propyl‐d‐glucaramide monoester, followed by lactonization to a five‐membered lactone amide, and concluding with aminolyis of the lactone amide to N,N′‐dipropyl‐d‐glucaramide (4). Comparison of the reaction pathways from 1 and 5 by ¹H NMR analysis suggests that ring opening of the 1,4‐lactone ester (1) and 1,4‐lactone amide (7) is faster than ring opening of the corresponding 6,3‐lactone ester (5) and 6,3‐lactone amide (3). Aminolysis of dimethyl l‐tartrate, which cannot form a five‐membered lactone, with n‐propylamine in DMSO‐d₆ was much slower than aminolysis of esterified glucaric acid, indicating that the lactone forming/lactone aminolysis steps are the dominant aminolysis rate enhancing steps from glucarate.     

Reaction of 1,2-0-Alkylidenehexofuranurono-6,3-Lactones with Diethylaminosulfur Trifluoride (DAST)

Reaction of 1,2-0-alkylidenehexofuranurono-6,3-lactones with diethylaminosulfur trifluoride (DAST) led to 1,2-0-alkylidene-5-deoxy-5-fluorohexofuranurono-6,3-lactones (13–30%) together with 1,2-0-alkylidene-3,6-anhydro-6,6-difluorohexofuranoses (45–58%). Evidence was found for participation of the hydroxyl group at C-5 in the formation of the difluorides. Trifluoro compounds could not be prepared by reaction with DAST but were formed from the difluorides by triflate formation and displacement using tetra-n-butylammonium fluoride.     

The synthesis of kermesic acid by acetylation-aided tautomerism of 6-chloro-2,5,8-trihydroxynaphtho-1,4-quinone

Methodology has been sought towards obtaining a 2-chloro-1,4-naphthoquinone bearing hydroxyl groups in the adjoining ring for obtaining either kermesic or carminic acids. In the first of these objectives, kermesic acid has been synthesised from 6-chloro-2,5,8-trihydroxynaphtho-1,4-quinone by the regioselective cycloaddition of the 1,2-diacetate formed by its acetylation-aided tautomerism and cycloaddition with (E)- and (Z)-3-alkoxycarbonyl-2,4-bis(trimethylsilyloxy)penta-1,3-dienes. The parent unacetylated quinone resists cycloaddition.     

Relationship between the furan ring and six and seven-membered lactone rings in obacunone

The presence of a ,β-epoxy-(β-furyl)-δ-lactone group in obacunone was suggested, from the catalytic reduction and conversion to desoxy compound of the dilactone (V), one of the oxidation products of obacunone with potassium permanganate. The stability of saturated, seven-membered lactone ring in obacunone derivatives was discussed. Degradation of the masked hydroxyl group is tertiary and is bonded to isopropyl group. Formula Ie was proposed for the partial structure of obacunone.