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A significant increase in the production of plastic materials and the expansion of their areas of application contributed to the accumulation of a large amount of waste of polymeric materials. Most of the polymer composition is made up of plasticizers. Phthalate plasticizers have been recognized as potentially hazardous to humans and the environment due to the long period of their biodegradation and the formation of persistent toxic metabolites. It is known that the industrial plasticizer dioctyl adipate is characterized by reduced toxicity and a short biodegradation period. The paper describes the synthesis of a number of new asymmetric esters based on adipic acid and ethoxylated butanol by azeotropic esterification. The receipt of the products was confirmed by IR spectra. The physicochemical properties of the synthesized compounds were investigated. The glass transition temperatures of PVC composites plasticized with alkyl butoxyethyl adipates were determined using DSC analysis. The ecological safety of esters was assessed by the phytotesting method. Samples of adipates were tested for fungal resistance, and the process of their biodegradation in soil was also studied. It is shown that the synthesized esters have good plasticizing properties and are environmentally safe. When utilized under natural conditions, they can serve as a potential source of carbon for soil microorganisms and do not form stable toxic metabolites; therefore, they are not able to accumulate in nature; when the plasticizers under study are disposed of in the soil, toxic substances do not enter.

Green synthesis of adipic acid from renewable biomass is a very attractive goal of sustainable chemistry. Herein, we report efficient catalysts for a two-step transformation of cellulose-derived glucose into adipic acid via glucaric acid. Carbon nanotube-supported platinum nanoparticles are found to work efficiently for the oxidation of glucose to glucaric acid. An activated carbon-supported bifunctional catalyst composed of rhenium oxide and palladium is discovered to be powerful for the removal of four hydroxyl groups in glucaric acid, affording adipic acid with a 99 % yield. Rhenium oxide functions for the deoxygenation but is less efficient for four hydroxyl group removal. The co-presence of palladium not only catalyzes the hydrogenation of olefin intermediates but also synergistically facilitates the deoxygenation. This work presents a green route for adipic acid synthesis and offers a bifunctional-catalysis strategy for efficient deoxygenation., (© 2020 Wiley-VCH GmbH.)

Ralstonia solanacearum ( R. solanacearum )-induced bacterial wilt of the nightshade family causes a great loss in agricultural production annually. Although there has been some efficient pesticides against R. solanacearum , inaccurate pesticide releasing according to the onset time of bacterial wilt during the use of pesticides still hinders the disease management efficiency. Herein, on the basis of the soil pH change during R. solanacearum growth, and pH sensitivity of the Schiff base structure, a pH-sensitive oxidized alginate-based double-crosslinked gel was fabricated as a pesticide carrier. The gel was prepared by crosslinking oxidized sodium alginate (OSA) via adipic dihydrazide (ADH) and Ca 2+ . After loading tetramycin into the gel, it showed a pH-dependent pesticide releasing behavior and anti-bacterial activity against R. solanacearum . Further study also showed that the inhibition rate of the tetramycin-loaded gel was higher than that of industrial pesticide difenoconazole. This work aimed to reduce the difficulty of pesticide administration in the high incidence period of bacterial wilt and we believe it has a great application potential in nightshade production.

Synthesis of adipic acid, a key monomer of nylon-66 and polyurethane, from biomass is highly attractive for establishing green and sustainable chemical processes. Here, we report that zirconia-supported rhenium oxide (ReO x /ZrO 2 ) efficiently catalyses the deoxydehydration of cellulose-derived d-glucaric acid, offering adipic acid ester with a yield of 82% by combining with a Pd/C catalyst in subsequent reactions.

Adipic acid (AA) was obtained by catalyzed oxidation of cyclohexene, epoxycyclohexane, or cyclohexanediol under organic solvent-free conditions using aqueous hydrogen peroxide (30%) as an oxidizing agent and molybdenum- or tungsten-based Keggin polyoxometalates (POMs) surrounded by organic cations or ionically supported on functionalized Merrifield resins. Operating under these environmentally friendly, greener conditions and with low catalyst loading (0.025% for the molecular salts and 0.001⁻0.007% for the supported POMs), AA could be produced in interesting yields.

A radiation-sensitive polymer poly(hexa-2,4-diynylene adipate) (PHDA) was synthesized and incorporated into polyvinyl butyral films for radiation dose measurements in the 0.5 - 60 kGy range. PHDA undergoes crosslinking polymerization upon exposure to γ-rays, which changes its color from very pale yellow to deep orange-yellow. The color change is directly related to the absorbed dose. The absorption spectrum of the irradiated films features one absorption band around 500 nm with a shoulder around 465 nm. With increasing absorbed dose, the two bands grow in intensity and move towards higher wavelengths. The dosimeter is nearly insensitive to variations of the humidity in the range of 0-54% and temperature in the range of 30-45 °C during irradiation. The color intensifies after irradiation, both in the dark and in the light at room temperature, which reflects the continuing crosslinking polymerization. However, at - 4 °C, the color intensity does not change with time., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Risperidone (RIS)-loaded microspheres based on poly(alkylene adipate)s derived from dicarboxylic acids and different aliphatic diols were prepared by the oil in water emulsion and solvent evaporation method. Specifically, 3 polyesters, namely poly(ethylene adipate), poly(propylene adipate), and poly(butylene adipate), were prepared with the aid of a 2-stage melt-polycondensation method and characterized by gel permeation chromatography, proton nuclear magnetic resonance ( 1 H NMR), differential scanning calorimetry, and X-ray diffraction analysis. Results showed that the molecular weight of the polyesters increased as the diol molecular weight increased, while all polymers were of semi-crystalline nature and the melting temperature was varying from 49.1°C to 51.8°C and 65.9°C for poly(propylene adipate), poly(ethylene adipate), and poly(butylene adipate), respectively. The particle size of the RIS-loaded microspheres varied from 10 to 100 μm depending on the polyester type and the drug loading, while X-ray diffraction analysis revealed amorphous active pharmaceutical ingredient in the cases of high drug-loaded microspheres. In vitro drug release studies along with scanning electron microscopy images of microspheres after the completion of dissolution process showed that in all cases RIS release was controlled by the glass transition temperature of polyesters and physical state of active pharmaceutical ingredients via diffusion., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The development of a system for the operationally simple, scalable conversion of polyhydroxylated biomass into industrially relevant feedstock chemicals is described. This system includes a bimetallic Pd/Re catalyst in combination with hydrogen gas as a terminal reductant and enables the high-yielding reduction of sugar acids. This procedure has been applied to the synthesis of adipate esters, precursors for the production of Nylon-6,6, in excellent yield from biomass-derived sources.

A novel short entry to 3,4-disubstituted adipic acids has been developed by employing an asymmetric NHC-catalyzed [3+2] cycloaddition of enals with masked cinnammates in moderate to good yields and high stereoselectivities. The synthetic utility of the protocol was demonstrated by the basic conversion of the masked cyclopentanone intermediates to 3S,4S-disubstituted adipic acid precursors of pharmaceutically important gababutins., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Adipic acid diselenoester was developed as an efficient cross-linker for covalent protein conjugation with a variety of small molecular haptens, including mono- and disaccharides, peptide, fluorescence dye, and nicotine. Compared to the counterparts of N-hydroxysuccinimide (NHS) and p-nitrophenyl (PNP) linkers, the diselenoester linker demonstrates improved balance between reactivity and stability and coupling of haptens to proteins under mild conditions with high incorporation efficiency.

Nitric acid oxidation of cyclohexane accounts for ~95% of the worldwide adipic acid production and is also responsible for ~5 to 8% of the annual worldwide anthropogenic emission of the ozone-depleting greenhouse gas nitrous oxide (N2O). Here we report a N2O-free process for adipic acid synthesis. Treatment of neat cyclohexane, cyclohexanol, or cyclohexanone with ozone at room temperature and 1 atmosphere of pressure affords adipic acid as a solid precipitate. Addition of acidic water or exposure to ultraviolet (UV) light irradiation (or a combination of both) dramatically enhances the oxidative conversion of cyclohexane to adipic acid., (Copyright © 2014, American Association for the Advancement of Science.)

Doxorubicin (DOX)-loaded nanoparticles (NPs) based on interconnected hyaluronic acid-ceramide (HACE) structure were fabricated and their anti-tumor efficacy was evaluated in vitro. Interconnected HACE was synthesized by cross-linking HACE with adipic acid dihydrazide (ADH) and its synthesis was identified by (1)H NMR analysis. DOX-loaded NPs with <200nm mean diameter, negative zeta potential, and spherical shape were prepared. Interconnected HACE-based NPs increased drug-loading capacity and in vitro drug release, compared to HACE-based NPs. DOX release was dependent on the environmental pH, implying the feasibility of enhancing drug release in tumor region and endosomal compartments. Synthesized interconnected HACE did not show cytotoxic effect up to 1000μg/ml concentration in NIH3T3 and MDA-MB-231 cells. In cellular uptake studies using confocal laser scanning microscopy (CLSM) and flow cytometry in MDA-MB-231 cells, higher uptake of DOX was observed in the interconnected HACE-based NPs than HACE NPs. In vitro anti-tumor efficacy was assessed by MTS-based assay, in which cytotoxic effect of DOX-loaded interconnected HACE NPs was higher than that of DOX-loaded HACE NPs. Thus, these results suggest the feasibility of interconnected HACE-based NPs to be used for efficient tumor-targeted delivery of anticancer drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cancer is one of the most fatal diseases in the world and it has been years that finding new drugs and chemotherapeutic techniques with lowest side effects become one of the most important challenging matters needs really hard efforts. Chlorambucil (CBL), an ancient direct-acting alkylating anticancer agent, is commonly used for initial treatment of some kinds of cancers but the use of CBL is often limited because of the unpleasant side effects due to its lack of specificity for targeting cancer cells. In this research we tried to increase the specificity of CBL by producing a novel conjugate by using glutamine amino acid (Glut). Based on previous studies, poly amines and nitrogen compounds noticeably are used by cancer cells increasingly; therefore we decided to increase the efficiency and specificity of CBL by designing and producing a novel anti cancer conjugate using glutamine amino acid as an uptake enhancer, CBL, and Adipic acid Dihydrazide (ADH) as a spacer and linker. The biological tests were carried out on HT29 colorectal cancer cell line to evaluate its anticancer properties. Biological tests like MTT assay, finding IC50, evaluating the induced mechanism of the death of our novel CBL-Glutamine conjugate on HT29 cells, testing abnormal toxicity of this conjugate on mice in comparison with CBL drug were careid out. We found that not only CBL-Glutamine conjugate preserved its anti cancer property with regard to CBL drug, but also it represent lower abnormal toxicity in mice. Apoptosis was detected as its mechanism of the death. Our present study provides a promising strategy for targeting cancer cells using amino acids nano-conjugate drugs. The future perspectives have also been highlighted in continuing similar and relative researches.

(2S,4R)-2-amino-4-hydroxyadipic acid (Ahad) building block 45 was synthesized in 11 steps and 6.5% overall yield from commercially available materials. Key steps in stereocontrol were an asymmetric conjugate addition employing a proline-based catalyst and a syn-selective intramolecular-conjugate addition of an oxygen nucleophile to an α,β-unsaturated ester. To enable incorporation of α-amino-adipic acid (α-AAA) and Ahad into peptides, a truly orthogonal protecting group scheme was developed, encompassing an allyloxycarbonyl (Alloc) carbamate for Nα, a tert-butyl ester for the δ-COOH, an acetol ester for the α-COOH, and a tert-butyldimethylsilyl ether for the γ-hydroxy group of Ahad.

Safe only in a microreactor! The synthesis of adipic acid from cyclohexene by tungstic acid-catalyzed oxidation using hydrogen peroxide following the classical Noyori protocol can be accomplished in good yields with residence times as short as 20 min at 140 °C using a safe and scalable microreactor environment. Under these intensified conditions the use of a phase-transfer catalyst is not required., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Encapsulation of nucleus pulposus (NP) cells within in situ forming hydrogels is a novel biological treatment for early stage intervertebral disc degeneration. The procedure aims to prolong the life of the degenerating discs and to regenerate damaged tissue. In this study we developed an injectable oxidized hyaluronic acid-gelatin-adipic acid dihydrazide (oxi-HAG-ADH) hydrogel. High molecular weight (1900 kDa) hyaluronic acid was crosslinked with various concentrations of gelatin to synthesize the hydrogels and their viscoelastic properties were analyzed. Interactions between the hydrogels, NP cells, and the extracellular matrix (ECM) were also evaluated, as were the effects of the hydrogels on NP cell gene expression. The hydrogels possess several clinical advantages, including sterilizability, low viscosity for injection, and ease of use. The viscoelastic properties of the hydrogels were similar to native tissue, as reflected in the complex shear modulus (∼11-14 kPa for hydrogels, 11.3 kPa for native NP). Cultured NP cells not only attached to the hydrogels but also survived, proliferated, and maintained their round morphology. Importantly, we found that hydrogels increased NP cell expression of several crucial ECM-related genes, such as COL2A1, AGN, SOX-9, and HIF-1A., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Adipic acid is a key compound in the chemical industry, where it is mainly used in the production of polymers. The conventional process of its generation requires vast amounts of energy and, moreover, produces environmentally deleterious substances. Thus, there is interest in alternative ways to gain adequate amounts of adipic acid. Experimental reports on a one-pot iron-catalyzed conversion of cyclohexane to adipic acid motivated a theoretical investigation based on density functional theory calculations. The process investigated is interesting because it requires less energy than contemporary methods and does not produce environmentally harmful side products. The aim of the present contribution is to gain insight into the mechanism of the iron-catalyzed cyclohexane conversion to provide a basis for the further development of this process. The rate-limiting step of the process is discussed, but considering the accuracy of the calculations, it is difficult to ensure whether the rate-limiting step is in the substrate oxidation or in the generation of the catalytically active species. It is shown that the slowest step in the substrate oxidation is the conversion of cyclohexanol to cyclohexane-1,2-diol. Hydrogen-atom transfer from one of the OH groups of cyclohexane-1,2-diol makes the intradiol cleavage occur spontaneously.

Chiral C(2)-symmetric 3,4-bis-silyl-substituted adipic acid derivatives have been synthesised by a Mg/trimethylsilyl chloride-mediated intramolecular reductive coupling of symmetrical disiloxanes of beta-silylacrylic acid N-oxazolidinone derivatives. Efficient and short syntheses of enantiomerically pure enantiomers of 2,6-dioxabicyclo[3.3.0]octane-3,7-dione have been achieved from the bis-silylated adipic acid derivatives using Fleming-Tamao oxidation as the key step.

In the present study solid dispersions of Raloxifene HCl were prepared by melt mixing. As drug carriers, biodegradable/biocompatible aliphatic polyesters were used. These formulations were compared to those based on extensively used drug carriers such as PEG and Gelucire 50/13. The used aliphatic polyesters namely poly(propylene succinate) (PPSu) and poly(propylene adipate) (PPAd) were prepared by melt polycondensation. The polyesters have melting points close to human body temperature and were used for first time as drug carries. Polymer cytocompatibility based on HUVEC cells viability in the presence of increasing concentrations of polymer was investigated and it was found that PPSu and PPAd exhibit comparable cytocompatibility with poly(dl-lactide). The physical state of solid dispersions was evaluated by FTIR, SEM and XRD techniques. In all cases the interactions between drug and carriers are limited and thus the dispersed drug was mainly in the crystalline state. SEM revealed that the particles size of the dispersed drug increases with increasing the drug amount. The release behavior of the drug is affected from both the drug amount and the kind of the used carrier. The drug is released almost immediately from PEG formulations while Gelucire results in sustained release. In formulations that polyesters were used as drug carriers the release is slower.

We have synthesized a novel mesogenic azobenzene molecule and studied its monolayer film properties at air-water interface (Langmuir film) and air-solid interface (Langmuir-Blodgett film). The material, H-shaped dimer bis[5-(4'-n-dodecyloxy benzoyloxy)-2-(4''-methylphenylazo)phenyl] adipate (12D1H) exhibits a smectic C phase between 51 and 48 degrees C on cooling. Surface manometry studies showed the formation of a stable monolayer at the air-water interface. Brewster angle microscopy (BAM) showed that liquid domains coexisting with the gas region at large area transformed to a uniform liquid phase with increasing surface density and finally to a collapsed state. We have carried out atomic force microscope (AFM) studies on Langmuir-Blodgett (LB) films transferred onto freshly cleaved hydrophilic mica substrate. The AFM images showed domains of height of about 3.8 nm, which corresponds to the estimated height of the molecule confirming the formation of monomolecular film. On a hydrophobic silicon substrate, the LB transfer yields a bilayer film, which dewets to form uniform nanodroplets of diameter of about 100 nm and height in the range 10-50 nm. Our analysis indicated that the mechanism involved in the formation of nanodroplets can be attributed to spinodal dewetting. The 12D1H molecule containing an azobenzene group undergoes a trans to cis transformation in the presence of ultraviolet light. Our surface manometry studies showed that the monolayer in the presence of ultraviolet light was more stable with a collapse pressure three times that of the monolayer in the dark.

Oxidative cleavage of carbon-carbon double bonds of cyclic olefins with hydrogen peroxide in the presence of heteropolyacids has been investigated as a clean and environmentally friendly preparation of polycarboxylic acids. In the presence of 12-tungstophospholic acid (H(3)PW(12)O(40)), adipic acid was obtained in 95% yield from cyclohexene in lipophilic phase and hydrogen peroxide in aqueous phase. In addition, 1,2,3,4-butanetetracarboxylic acid was also obtained in 87% yield from 1,2,3,6-tetrahydrophtharic acid anhydride, while endic acid anhydride did not afford corresponding 2,3,6-cyclopentanetetracarboxylic acid but only lactone compound was obtained. In this oxidation process, oxidative cleavage of carbon-carbon double bonds would proceed as the sequential reactions in which the rate determining step is oxidative cleavage of vicinal-diol compounds.

The lipase-catalyzed ROP of molecularly pure cyclic oligomers with a definite degree of oligomerization is analyzed with respect to the molecular weights of the resulting polymers and certain kinetic parameters of the enzymatic reaction. Cyclic BA dimers, trimers, and tetramers polymerize faster than the equivalent monomer; however, the latter produces PBA of significantly higher molecular weight. The reason is that the ring opening of the cyclic monomer is slow, leading to a lower initiator concentration than that produced by the cyclic BA dimer and trimer. Similarly, the cyclic BS dimer produces PBS of higher molecular weight than that obtained from the cyclic BS trimer.

Hyaluronic acid (HA) hydrogels prepared with three different crosslinking reagents were assessed by in vitro and in vivo degradation tests for various tissue engineering applications. Adipic acid dihydrazide grafted HA (HA-ADH) was synthesized and used for the preparation of methacrylated HA (HA-MA) with methacrylic anhydride and thiolated HA (HA-SH) with Traut's reagent (imminothiolane). (1)H NMR analysis showed that the degrees of HA-ADH, HA-MA, and HA-SH modification were 69, 29, and 56 mol%, respectively. HA-ADH hydrogel was prepared by the crosslinking with bis(sulfosuccinimidyl) suberate (BS(3)), HA-MA hydrogel with dithiothreitol (DTT) by Michael addition, and HA-SH hydrogel with sodium tetrathionate by disulfide bond formation. According to in vitro degradation tests, HA-SH hydrogel was degraded very fast, compared to HA-ADH and HA-MA hydrogels. HA-ADH hydrogel was degraded slightly faster than HA-MA hydrogel. Based on these results, HA-MA hydrogels and HA-SH hydrogels were implanted in the back of SD rats and their degradation was assessed according to the pre-determined time schedule. As expected from the in vitro degradation test results, HA-SH hydrogel was in vivo degraded completely only in 2 weeks, whereas HA-MA hydrogels were degraded only partially even in 29 days. The degradation rate of HA hydrogels were thought to be controlled by changing the crosslinking reagents and the functional group of HA derivatives. In addition, the state of HA hydrogel was another factor in controlling the degradation rate. Dried HA hydrogel at 37 degrees C for a day resulted in relatively slow degradation compared to the bulk HA hydrogel. There was no adverse effect during the in vivo tests.

In this work, a complementary experimental and theoretical approach is used to unravel the formation of byproducts in the autoxidation of cyclohexane. The widely accepted vision that cyclohexanone would be the most important precursor of undesired products was found inconsistent with several experimental observations. However, the propagation reaction of cyclohexyl hydroperoxide, which we recently put forward as the missing source of cyclohexanol and cyclohexanone, is now unambiguously identified also as the dominant path leading to byproducts. Indeed, this overlooked reaction produces large amounts of cyclohexoxy radicals, able to ring-open via a beta-C--C cleavage to omega-formyl radicals. The pathway by which these radicals are converted into the observed and quantified byproducts is derived in this work. In this liquid-phase reaction, solvent cages were found very important, steering the fate of nascent species.

Poly(ester-anhydride) delivery devices allow flexibility regarding carrier dimensions (micro- versus nanospheres), degradation rate (anhydride versus ester hydrolysis), and surface labeling (through the anhydride functional unit), and were therefore tested for DNA encapsulation and transfection of a macrophage P388D1 cell line. Poly(l-lactic acid-co-sebacic anhydride) and poly(l-lactic acid-co-adipic anhydride) were synthesized through melt condensation, mixed with 25 wt.% poly(beta-amino ester), and formulated with plasmid DNA (encoding firefly luciferase) into micro- and nanospheres using a double emulsion/solvent evaporation technique. The micro- and nanospheres were then characterized (size, morphology, zeta potential, DNA release) and assayed for DNA encapsulation and cellular transfection over a range of poly(ester-anhydride) copolymer ratios. Poly(ester-anhydride):poly(beta-amino ester) composite microspheres (6-12 microm) and nanospheres (449-1031 nm), generated with copolymers containing between 0 and 25% total polyanhydride content, encapsulated plasmid DNA (>or=20% encapsulation efficiency). Within this polyanhydride range, poly(adipic anhydride) copolymers provided DNA encapsulation at an increased anhydride content (10%, microspheres; 10-25%, nanospheres) compared to poly(sebacic anhydride) copolymers (1%, microspheres and nanospheres) with cellular transfection correlating with the observed DNA encapsulation.

Strains of Escherichia coli were constructed and evaluated that synthesized cis,cis-muconic acid from D-glucose under fed-batch fermentor conditions. Chemical hydrogenation of the cis,cis-muconic acid in the resulting fermentation broth has also been examined. Biocatalytic synthesis of adipic acid from glucose eliminates two environmental concerns characteristic of industrial adipic acid manufacture: use of carcinogenic benzene and benzene-derived chemicals as feedstocks and generation of nitrous oxide as a byproduct of a nitric acid catalyzed oxidation. While alternative catalytic syntheses that eliminate the use of nitric acid have been developed, most continue to rely on petroleum-derived benzene as the ultimate feedstock. In this study, E. coli WN1/pWN2.248 was developed that synthesized 36.8 g/L of cis,cis-muconic acid in 22% (mol/mol) yield from glucose after 48 h of culturing under fed-batch fermentor conditions. Optimization of microbial cis,cis-muconic acid synthesis required expression of three enzymes not typically found in E. coli. Two copies of the Klebsiella pneumoniae aroZ gene encoding DHS dehydratase were inserted into the E. coli chromosome, while the K. pneumoniae aroY gene encoding PCA decarboxylase and the Acinetobacter calcoaceticus catA gene encoding catechol 1,2-dioxygenase were expressed from an extrachromosomal plasmid. After fed-batch culturing of WN1/pWN2.248 was complete, the cells were removed from the broth, which was treated with activated charcoal and subsequently filtered to remove soluble protein. Hydrogenation of the resulting solution with 10% Pt on carbon (5% mol/mol) at 3400 kPa of H2 pressure for 2.5 h at ambient temperature afforded a 97% (mol/mol) conversion of cis,cis-muconic acid into adipic acid.

A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.

The structure of WA8242B, a potent novel inhibitor against phospholipase A2, was fully characterized by spectroscopic methods and chemical degradation. The success of total synthesis of WA8242B confirmed the structure and allowed the pharmacological study of WA8242B. The structures of WA8242A1 and A2 were also described.

The possibility of producing slowly dissolving albuterol salts was investigated as a potential means of extending the duration of action of the drug following aerosol delivery to the lung. Albuterol adipate and stearate were precipitated from alcoholic solutions of albuterol and adipic or stearic acids, respectively. Differential scanning calorimetry and hot stage microscopy showed that albuterol adipate and stearate produced single melting endotherms at 182 and 116 degrees C, respectively, which were distinct from those of albuterol (158 degrees C), adipic acid (152 degrees C), and stearic acid (70 degrees C). The aqueous solubilities of albuterol free base, sulfate, adipate, and stearate were 15.7, 250, 353, and 0.6 mg . mL-1, respectively, at room temperature. Only the solubilities of the adipate and the stearate increased significantly when the temperature was elevated to 37 degrees C (452.5 and 1.4 mg . mL-1, respectively). With a rotating disk dissolution method, albuterol free base, sulfate, and adipate were found to have intrinsic dissolution rates of 1.1, 20.4, and 24.0 mg . min-1 . cm-2, respectively, in pH 7.4 phosphate buffer at 37 degrees C. Albuterol stearate dissolved much more slowly and in a nonlinear fashion; this was explained by the deposition of a stearate-rich layer on the dissolving surface of the compacted salt.

The synthesis of delta-(alpha-aminoadipoyl) aromatic amides and their use in screening for enzymes able to cleave delta-(alpha-aminoadipoyl) residues off the synthetic amides and cephalosporin C are described. A number of commercially available proteases and peptidases were not active with delta-(alpha-aminoadipoyl) chromogenic amides. Also, most tested microbial strains known to produce acylases did not hydrolyze these compounds. Only one microbial strain, Xanthomonas maltophila, had an appreciable activity toward the racemic form of chromogenic substrates. Activity measured in crude extracts from Xanthomonas cells indicated that this bacterium produces predominantly L-specific aminoadipoyl amidohydrolase and gamma-glutamyl hydrolase. A low level of cephalosporin C and glutaryl-cephalosporin acylase activities was also found.

Trichosporon cutaneum, when grown with p-cresol, catalyzed intradiol fission of the benzene nucleus of 4-methylcatechol before the complete catabolism of these two substrates. Steps in their conversion to pyruvate and acetyl coenzyme A were investigated by using cell extracts, and some properties of various new microbial catabolites are also described. These included (-)-2,5-dihydro-3-methyl-5-oxofuran-2-acetic acid (beta-methylmuconolactone) and (-)-3-keto-4-methyladipic acid and its coenzyme A ester; the latter was degraded by an enzymatic reaction sequence that included the coenzyme A esters of methylsuccinic, itaconic, and citramalic acids. A notable feature of this sequence is the formation of beta-methylmuconolactone which can be readily metabolized, in contrast to the analogous reaction in bacteria that gives the "dead-end" compound gamma-methylmuconolactone; this compound cannot be enzymatically degraded and so renders the beta-ketoadipate pathway unavailable for methyl-substituted bacterial sources of carbon that are catabolized by way of 4-methylcatechol.

Increased urinary excretion of medium-chain dicarboxylic acids is a general feature of disordered fatty acid metabolism. The physiological role of the metabolic pathways involved in dicarboxylic acid production has been a subject of controversy. In the present investigation, the existence of 3-hydroxyadipic acid 3,6-lactone, possibly representing a metabolic intermediate in the beta-oxidation of adipic acid to succinic acid, has been demonstrated. The identity of this compound was established by electron-impact mass spectrometry of its trimethylsilyl derivative and by comparison with synthetic authentic samples. 3-Hydroxyadipic acid 3,6-lactone is present in almost every urine sample we have examined. In the nonfasting state, urinary concentrations of 0.9 +/- 0.5 micrograms/mg creatinine were observed in the adults. During fasting, the urinary excretion of this compound increased with time. It reached 19.1 +/- 8.5 micrograms/mg creatinine by the end of the third day. The responses in children were even higher; urinary concentrations of 82 +/- 50 micrograms/mg creatinine were observed by the end of 36 hours. The urinary excretion of the lactone is closely correlated (r2 = 0.8) with that of adipic acid, an indicator of fatty acid omega-oxidation activity. Non-ketotic dicarboxylic aciduria appears to vary in different defects based on the ratio of urinary lactone to adipic acid.