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PubMedDate not supplied

Synthesis of polyethylene glycol (PEG) derivatives and PEGylated-peptide biopolymer conjugates.

We synthesized a library of 50 poly(ethylene glycol) (PEG) derivatives to expand the extent of conjugation with biologically active molecules (biopolymers, peptides, drugs, etc.) and biomaterial substrates. The formation of PEG derivatives was confirmed with HPLC, (1)H and (13)C NMR. PEG derivatives were polymerized into networks in order to study the role of PEG and terminal functional groups in modulating the hydrophilicity of biomaterials and cell-biomaterial interaction. The resulting surface hydrophilicity and the number of adhered fibroblasts were primarily dependent on the PEG concentration with the molecular weight and the terminal functional group of PEG derivatives being less important. One of PEG derivatives, PEG-bis-glutarate, was utilized to link peptide sequences to gelatin backbone in the formation of novel biomedical hydrogels. PEG-peptide conjugates were characterized by mass spectroscopy. PEG-peptide modified gelatins were characterized by gel permeation chromatography.

Biopolymers↗
PubMedDate not supplied

Asymmetric epoxidation of alpha-olefins having neighboring sugar chiral templates and alternating copolymerization with dicarboxylic anhydrides.

Sugar-substituted epoxides 5-8 were synthesized by asymmetric epoxidation (in CH(2)Cl(2)/water) of alpha-olefins having neighboring sugars (1-4) by use of an achiral oxidant (MCPBA), in which the sugar moiety acted as a chiral template. The diastereoselectivities depend on the methylene spacer between vinyl group and carbohydrate derivatives. The methylene spacer between sugar and vinyl groups influenced the diastereoselectvity. In the case of epoxidation of 4 at 27 degrees C for 24 h, the diastereoselectivity was the highest (99/1). Copolymerizations of 5-8 with succinic anhydride were attained at 100 degrees C for 72 h to give poly(ethylene succinate) having pendant carbohydrate [poly(SAn-alt-5), M(n) = 1.4 x 10(3); poly(SAn-alt-6), M(n) = 2.2 x10(3); poly(SAn-alt-7), M(n) = 2.9 x 10(3); poly(SAn-alt-8), M(n) = 1.8 x 10(3)]. The methylene spacer between sugar and epoxide has an effect on the reactivity of epoxide in copolymerization as well as the diastereoselectivity. Alternating copolymerization of 7 and glutaric anhydride gave a polyester of M(n) 4.2 x10(3).

Anhydrides↗
PubMed2002

Degradation of dicarboxylic acids (C2-C9) upon liquid-phase reactions with O3 and its atmospheric implications.

Aerosols are considered major players in climate change and represent health hazards. Dicarboxylic acids are among a major class of components that form secondary organic atmospheric aerosols. To understand the atmospheric transformation of these compounds, kinetic studies on the ozonolysis and the photoinduced ozonolysis (lambda > or = 250 nm) of aqueous solutions of seven (C2-C9) dicarboxylic acids, which have been identified in atmospheric aerosols, were performed using Fourier transform infrared and ultraviolet-visible spectroscopy. The measured apparent rate constants for dicarboxylic acids in 0.1 mol L(-1) aqueous solutions at 298 +/- 2 K are as follows: oxalic, (2.7 +/- 0.1) x 10(-2); malonic, (5.5 +/- 0.1); succinic, (6.7 +/- 0.4) x 10(-4); glutaric, (1.3 +/- 0.2) x 10(-3); adipic, (1.7 +/- 0.1) x 10(-3); pimelic, (4.4 +/- 0.1) x 10(-3); and pinic, (2.5 +/- 0.1) x 10(-2) (L mol(-1) s(-1)). An empirical equation is provided to estimate the ozonolysis rate constant of dicarboxylic acids containing more than three carbon atoms for which no experimental data exists. A mechanism for malonic acid ozonolysis, which explains its fast ozonolysis rate constant, is also suggested. The implications of our results to atmospheric chemistry indicate that ozonolysis and photoinduced ozonolysis are not significant removal pathways for dicarboxylic acids.

Aerosols↗
PubMed2004

Thermodynamic properties of multifunctional oxygenates in atmospheric aerosols from quantum mechanics and molecular dynamics: dicarboxylic acids.

Ambient particulate matter contains polar multifunctional oxygenates that partition between the vapor and aerosol phases. Vapor pressure predictions are required to determine the gas-particle partitioning of such organic compounds. We present here a method based on atomistic simulations combined with the Clausius-Clapeyron equation to predict the liquid vapor pressure, enthalpies of vaporization, and heats of sublimation of atmospheric organic compounds. The resulting temperature-dependent vapor pressure equation is a function of the heat of vaporization at the normal boiling point [deltaHvap(Tb)], normal boiling point (Tb), and the change in heat capacity (liquid to gas) of the compound upon phase change [deltaCp(Tb)]. We show that heats of vaporization can be estimated from calculated cohesive energy densities (CED) of the pure compound obtained from multiple sampling molecular dynamics. The simulation method (CED) uses a generic force field (Dreiding) and molecular models with atomic charges determined from quantum mechanics. The heats of vaporization of five dicarboxylic acids [malonic (C3), succinic (C4), glutaric (C5), adipic (C6), and pimelic (C7)] are calculated at 500 K. Results are in agreement with experimental values with an averaged error of about 4%. The corresponding heats of sublimation at 298 K are also predicted using molecular simulations. Vapor pressures of the five dicarboxylic acids are also predicted using the derived Clausius-Clapeyron equation. Predicted liquid vapor pressures agree well with available literature data with an averaged error of 29%, while the predicted solid vapor pressures at ambient temperature differ considerably from a recent study by Bilde et al. (Environ. Sci. Technol. 2003, 37, 1371-1378) (an average of 70%). The difference is attributed to the linear dependence assumption thatwe used in the derived Clausius-Clapeyron equation.

Aerosols↗
PubMed2006

Controlling aggregation of copper(II)-based coordination compounds: From mononuclear to dinuclear, tetranuclear, and polymeric copper complexes.

The use of a strategy combining ligand design and changes of reaction conditions has been investigated with the goal of directing the assembly of mononuclear, dinuclear, tetranuclear, and polymeric copper(II) complexes. As a result, closely related copper monomers, alkoxo dimers, and hydroxo cubanes, along with a carbonate-bridged polymeric species, have been synthesized using the rigid, aliphatic amino ligands cis-3,5-diamino-trans-hydroxycyclohexane (DAHC), cis-3,5-diamino-trans-methoxycyclohexane (DAMC), and the glutaryl-linked derivative glutaric acid bis-(cis-3,5-diaminocyclohexyl) ester (GADACE). The composition of the monomeric complex has been determined by X-ray crystallography as [Cu(DAHC)2](ClO4)2 (1), the two dimers as [{Cu(DAHC)(OMe)}2](ClO4)2.MeOH (2) and [{Cu(DAMC)(OMe)(ClO4)}2] (3), the three Cu4O4 cubanes as [{Cu(DAHC)(OH)}4](ClO4)(4).2.5MeOH (4), [{Cu(DAMC)(OH)}4](ClO4)4.H2O (5), and [{Cu2(OH)2(GADACE)}2]Cl4.2MeOH.6H2O (6), and an infinite-chain structure as [{Cu(DAHC)(CO3)}n] (7). Furthermore, the cubane structures 4 and 5 have been investigated magnetically. Our studies indicate that formation of the monomeric, dimeric, and tetranuclear DAHC and DAMC complexes can be controlled by small changes in reaction conditions and that further preorganization of the ligand moiety by linking the DAHC cores (GADACE) allows more effective direction of the self-assembly of the Cu4O4 cubane core.

Journal Article↗
PubMed2006

Active-site models of bacterial nitric oxide reductase featuring tris-histidyl and glutamic acid mimics: influence of a carboxylate ligand on Fe(B) binding and the heme Fe/Fe(B) redox potential.

Active-site models of bacterial nitric oxide reductase (NOR) featuring a heme Fe and a trisimidazole- and glutaric acid-bound non-heme Fe (Fe(B)) have been synthesized. These models closely replicate the proposed active site of native NORs. Examination of these models shows that the glutamic acid mimic is required for both Fe(B) retention in the distal binding site and proper modulation of the redox potentials of both the heme and non-heme Fe's.

Bacterial Proteins↗
PubMed2002

Integration of polyaniline/poly(acrylic acid) films and redox enzymes on electrode supports: an in situ electrochemical/surface plasmon resonance study of the bioelectrocatalyzed oxidation of glucose or lactate in the integrated bioelectrocatalytic systems.

Electropolymerization of aniline in the presence of poly(acrylic acid) on Au electrodes yields a polyaniline/poly(acrylic acid) composite film, exhibiting reversible redox functions in aqueous solutions at pH = 7.0. In situ electrochemical-SPR measurements are used to identify the dynamics of swelling and shrinking of the polymer film upon the oxidation of the polyaniline (PAn) to its oxidized state (PAn(2+)) and the reduction of the oxidized polymer (PAn(2+)) back to its reduced state (PAn), respectively. Covalent attachment of N(6)-(2-aminoethyl)-flavin adenin dinucleotide (amino-FAD, 1) to the carboxylic groups of the composite polyaniline/poly(acrylic acid) film followed by the reconstitution of apoglucose oxidase on the functional polymer yields an electrically contacted glucose oxidase of unprecedented electrical communication efficiency with the electrode: electron-transfer turnover rate approximately 1000 s(-1) at 30 degrees C. In situ electrochemical-SPR analyses are used to characterize the bioelectrocatalytic functions of the biomaterial-polymer interface. The current responses of the bioelectrocatalytic system increase as the glucose concentrations are elevated. Similarly, the SPR spectra of the system are controlled by the concentration of glucose. The glucose concentration controls the steady-state concentration ratio of PAn/PAn(2+) in the film composition. Therefore, the SPR spectrum of the film measured upon its electrochemical oxidation is shifted from the spectrum typical for the oxidized PAn(2+) at low glucose concentration to the spectrum characteristic of the reduced PAn at high glucose concentration. Similarly, the polyaniline/poly(acrylic acid) film acts as an electrocatalyst for the oxidation of NADH. Accordingly, an integrated bioelectrocatalytic assembly was constructed on the electrode by the covalent attachment of N(6)-(2-aminoethyl)-beta-nicotinamide adenine dinucleotide (amino-NAD(+), 2) to the polymer film, and the two-dimensional cross-linking of an affinity complex formed between lactate dehydrogenase and the NAD(+)-cofactor units associated with the polymer using glutaric dialdehyde as a cross-linker. In situ electrochemical-SPR measurements are used to characterize the bioelectrocatalytic functions of the system. The amperometric responses of the system increase as the concentrations of lactate are elevated, and an electron-transfer turnover rate of 350 s(-1) between the biocatalyst and the electrode is estimated. As the PAn(2+) oxidizes the NADH units generated by the biocatalyzed oxidation of lactate, the PAn/PAn(2+) steady-state ratio in the film is controlled by the concentration of lactate. Accordingly, the SPR spectrum measured upon electrochemical oxidation of the film is similar to the spectrum of PAn(2+) at low lactate concentration, whereas the SPR spectrum resembles that of PAn at high concentrations of lactate.

Acrylic Resins↗
PubMed2002

A mild and efficient catalytic alkylative monofunctionalization of cyclic anhydrides.

Substituted succinic and glutaric anhydrides undergo a nickel-catalyzed monofunctionalization with organozinc reagents as nucleophiles. The reaction proceeds readily with a variety of substrates, employs commercially available or readily attainable reagents, tolerates sensitive functionality on both partners, and affords the product ketoacids in moderate to high yields. The use of a chiral phosphinooxazoline results in a desymmetrization of a meso anhydride to provide the ketoacid in 85% yield and 79% ee.

Journal Article↗
PubMed2002

Rotation of the exo-methylene group of (R)-3-methylitaconate catalyzed by coenzyme B(12)-dependent 2-methyleneglutarate mutase from Eubacterium barkeri.

2-Methyleneglutarate mutase from the anaerobe Eubacterium (Clostridium) barkeri is an adenosylcobalamin (coenzyme B(12))-dependent enzyme that catalyzes the equilibration of 2-methyleneglutarate with (R)-3-methylitaconate. Two possibilities for the mechanism of the carbon skeleton rearrangement of the substrate-derived radical to the product-related radical are considered. In both mechanisms an acrylate group migrates from C-3 of 2-methyleneglutarate to C-4. In the "addition-elimination" mechanism this 1,2-shift occurs via an intermediate, a 1-methylenecyclopropane-1,2-dicarboxylate radical, in which the migrating acrylate is simultaneously attached to both C-3 and C-4. In the "fragmentation-recombination" mechanism the migrating group, a 2-acrylyl radical, becomes detached from C-3 before it starts bonding to C-4. In an attempt to distinguish between these two possibilities we have investigated the action of 2-methyleneglutarate mutase on the stereospecifically deuterated substrates (Z)-3-methyl[2'-(2)H(1)]itaconate and (Z)-3-[2'-(2)H(1),methyl-(2)H(3)]methylitaconate. The enzyme catalyzes the equilibration of both compounds with their corresponding E-isomers and with a 1:1 mixture of the corresponding (E)- and (Z)-2-methylene[2'-(2)H(1)]glutarates, as shown by monitoring of the reactions with (1)H and (2)H NMR. In the initial phase of the enzyme-catalyzed equilibration a significant excess (8-11%) of (E)-3-methyl[2'-(2)H(1)]itaconate over its equilibrium value was observed ("E-overshoot"). The E-overshoot was only 3-4% with (Z)-3-[2'-(2)H(1),methyl-(2)H(3)]methylitaconate because the presence of the deuterated methyl group raises the energy barrier from 3-methylitaconate to the corresponding radical. The overshoot is explained by postulating that the migrating acrylate group has to overcome an additional energy barrier from the state leading back to the substrate-derived radical to the state leading forward to the product-related radical. It is concluded that the fragmentation-recombination mechanism can provide an explanation for the results in terms of an additional energy barrier, despite the higher calculated activation energy for this pathway.

Catalysis↗
PubMed2003

The surface chelate effect.

The presence of a surface chelate effect is established in the model system of Cu2+ adsorption on a self-assembled monolayer of 16-mercaptohexadecanoic acid (MHA) on Au. The formation constant of Cu2+ with the MHA surface was found to be 119 +/- 3.2 times greater than that of Cu2+ with succinic acid (HOOC-(CH2)2-COOH), and 213 +/- 4.0 times greater than that of Cu2+ with glutaric acid (HOOC-(CH2)3-COOH) in aqueous solutions. Both of these molecules are known to chelate to metal ions forming seven- and eight-membered rings. The greater surface chelate effect is attributed to the presence of the two-dimensional array of ligands on the surface. We believe the surface chelate effect demonstrated here is of general significance to adsorption on molecular surfaces and should depend strongly on chemical functionality and monolayer structure.

Journal Article↗
PubMed2003

Sidewall carboxylic acid functionalization of single-walled carbon nanotubes.

The reactions of single-walled carbon nanotubes (SWNTs) with succinic or glutaric acid acyl peroxides in o-dichlorobenzene at 80-90 degrees C resulted in the addition of 2-carboxyethyl or 3-carboxypropyl groups, respectively, to the sidewalls of the SWNT. These acid-functionalized SWNTs were converted to acid chlorides by derivatization with SOCl(2) and then to amides with terminal diamines such as ethylenediamine, 4,4'-methylenebis(cyclohexylamine), and diethyltoluenediamine. The acid-functionalized SWNTs and the amide derivatives were characterized by a set of materials characterization methods including attenuated total reflectance (ATR) FTIR, Raman and solid state (13)C NMR spectroscopy, transmission electron microscopy (TEM), and thermal gravimetry-mass spectrometry (TG-MS). The degree of SWNT sidewall functionalization with the acid-terminated groups was estimated as 1 in 24 carbons on the basis of TG-MS data. In comparison with the pristine SWNTs, the acid-functionalized SWNTs show an improved solubility in polar solvents, for example, alcohols and water, which enables their processing for incorporation into polymer composite structures as well as for a variety of biomedical applications.

Journal Article↗
PubMed2000

Production and characterization of a monoclonal antibody against the beta-adrenergic agonist ractopamine.

A monoclonal antibody was generated toward the beta-adrenergic agonist ractopamine hydrochloride ¿(1R,3R),(1R, 3S)-4-hydroxy-alpha-[[[3-(4-hydroxyphenyl)-1-methylpropyl]amino]methy l]benzenemethanol hydrochloride¿. Ractopamine-glutarate-keyhole limpet hemocyanin (KLH) was used as the antigen for antibody generation in mice. Clone 5G10, secreted antibody with isotype IgG1kappa, was used for the development of an immunoassay. The selected antibody was specific for racemic ractopamine with an IC(50) of 2.69 +/- 0.36 ng/mL (n = 15). Antibody binding toward ractopamine was stereoselective with (1R,3R)-ractopamine having an IC(50) of 0.55 +/- 0.09 ng/mL (n = 3). IC(50) values for the (1S, 3R)-, (1S,3S)-, and (1R,3S)-ractopamine stereoisomers were 2.00 +/- 0.37, 140 +/- 23, and 291+/- 32 ng/mL (n = 3), respectively. Phenethanolamine beta-agonists showed low cross-reactivity. Studies using a series of ractopamine metabolites and ractopamine analogues demonstrated structural requirements for the antibody binding. A free phenolic group on the N-butylphenol moiety was required for high-affinity binding because methoxylated analogues and metabolites glucuronidated at this phenol generally had IC(50) values greater than 200 ng/mL. Ractopamine analogues methoxylated or glucuronidated at the ethanolamine phenol had IC(50) values of 0.7-2.6 ng/mL. Lack of a benzylic hydroxyl group was of less importance to antibody binding than was the correct stereochemical orientation (3R) of ractopamine's N-phenylalkyl group. In conclusion, a highly specific monoclonal antibody to ractopamine hydrochloride was developed that could be of potential utility in screening assays.

Adrenergic beta-Agonists↗
PubMed1985

Adriamycin analogues. rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives.

N-(Trifluoroacetyl)adriamycin 14-valerate (AD 32), a novel DNA nonbinding analogue of adriamycin with superior experimental antitumor activity, has undergone extensive clinical trial, with documentation of antitumor activity and low toxicity in human subjects. However, poor water solubility necessitates that the drug be administered to patients by continuous intravenous infusion at high dilution in a surfactant-containing formulation, with steroid prophylaxis to protect against a chest pain syndrome associated with the vehicle. On the basis of pharmacologic considerations, the title compounds have been prepared as second-generation analogues of N-(trifluoroacetyl)adriamycin 14-valerate with improved aqueous solubility; use is made of the available carboxylic acid function to solubilize the products in dilute aqueous alkaline medium. Target compounds were made by treating N-(trifluoroacetyl)-14-halodaunorubicin (bromo or iodo) with monosodium salts of dibasic acids (malonic, succinic, glutaric, adipic, pimelic, azelaic, sebacic) in aqueous acetone. All of the products showed significant in vivo antitumor activity against the murine P388 leukemia (ip tumor, ip treatment once daily on days 1, 2, 3, and 4); most compounds were superior to the +181% increase in life span afforded by adriamycin (optimal dose 3.0 mg/kg per day), one of two drugs used as positive controls for the assays. Several of the test compounds showed highly curative activity in this system, similar to N-(trifluoroacetyl)adriamycin 14-valerate, the other positive control agent. The hemiadipate product exhibited the most desirable properties of high antitumor efficacy (86% cure rate all P388 tumor-bearing animals through four levels of a 40-70 mg/kg dose-response range), aqueous solubility (60 mg/mL in pH 7.4 phosphate buffer), and solution stability (no decomposition at 4 degrees C, 0.5% hydrolysis at 27 degrees C, over 24 h at pH 7.4).

Animals↗
PubMed1977

Synthesis and kinetic evaluation of S- and N-substituted cysteinylglycines as inhibitors of glyoxalase I.

Eight S- and N-substituted L-cysteinylglycines were prepared by condensation of S-benzyl-L-cysteinylglycine or S-(p-bromobenzyl)-L-cysteinylglycine with glutaric anhydride, succinic anhydride, or the appropriately blocked and activated amino acids. In contrast to the previously prepared S-substituted glutathiones, all of the title compounds exhibited noncompetitive inhibition of yeast glyoxalase I. A kinetic evaluation under Yonetani-Thorell conditions established the existence of two binding sites on the glyoxalase I enzyme.

Binding Sites↗
PubMed2002

Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors.

In an effort to develop highly selective and potent agonists and/or antagonists for the hMC3 and hMC4 receptors, a new approach involving the use of linker arms and a backbone to side chain cyclization strategy was employed. Three key analogues were identified to have the required selectivity and potency at the hMC3 or hMC4 receptors, implicated to play pivotal roles in energy homeostasis and other biological effects. The novel cyclic peptide (O)C-CH(2)-CH(2)-C(O)-c-[His(6)-D-Phe(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2) (1) was found to be a highly selective and potent agonist of the hMC4 receptor. Structure-activity studies have shown that replacing the succinyl linker arm of 1 by an o-phthalic acid group and substituting a D-Nal(2')(7) residue in place of D-Phe(7) results in a potent antagonist 7 at the hMC4 receptor. Furthermore, increasing the 23-membered lactam ring of 1 by one carbon atom (succinyl --> glutaric acid linker) gives a highly selective and potent antagonist 9 for the hMC3 receptor. Analogues 1, 7, and 9 therefore represent the first examples of a class of cyclic melanotropin ligands with high selectivity and defined biological activities at the physiologically important hMC3 and hMC4 receptors.

Adenylyl Cyclases↗
PubMed2006

Validation of a novel CHX-A'' derivative suitable for peptide conjugation: small animal PET/CT imaging using yttrium-86-CHX-A''-octreotide.

A versatile bifunctional chelating reagent based on a preorganized cyclohexyl derivative of DTPA (CHX-A'') has been developed for the convenient N-terminal labeling of peptides with metal ion radionuclides of Bi(III), In(III), Lu(III), or Y(III). This was achieved via the synthesis of a mono-N-hydroxysuccinimidyl penta-tert-butyl ester derivative of CHX-A'' (trans-cyclohexyldiethylenetriaminepenta-acetic acid) featuring a glutaric acid spacer. Commercially obtained octreotide was modified at its N-terminus by this reagent in the solution phase, and its subsequent radiolabeling with (111)In (T(1/2) = 2.8 d) and (86)Y (T(1/2) = 14.7 h) demonstrated. Small animal PET/CT imaging results of (86)Y-CHX-A''-octreotide in a somatostatin receptor-positive tumor-bearing rat model are presented for the validation of the novel agent.

Animals↗
PubMed1998

Design and synthesis of brefeldin A sulfide derivatives as prodrug candidates with enhanced aqueous solubilities.

The addition of a variety of thiols to the alpha,beta-unsaturated lactone functionality present in brefeldin A has been carried out, and the resulting sulfides have been oxidized to the corresponding sulfoxides. These sulfoxides have the potential to undergo syn elimination to regenerate brefeldin A. The sulfoxides were more active than the sulfides as cytotoxic agents in a variety of human cancer cell cultures with the activities of the sulfoxides approaching that of brefeldin A itself. The cytotoxicities of the sulfoxides may be due to their conversion back to brefeldin A. The kinetics of sulfoxide elimination to form brefeldin A were studied in four cases, and the results indicate that substantial amounts of brefeldin A are likely to be generated during the cytotoxicity assays of the sulfoxide derivatives. Since the oxidation of sulfides to sulfoxides is a common metabolic reaction, the sulfides derived from brefeldin A can be considered as potential brefeldin A prodrugs. Several of the sulfide derivatives were determined to have enhanced aqueous solubilities relative to brefeldin A itself. A number of brefeldin A succinates, glutarates, oxidation products, and sulfone derivatives were also prepared and evaluated for cytotoxicity in cancer cell cultures. Some of the more active brefeldin A derivatives were tested in an in vivo animal model in which hollow fibers containing cancer cell cultures were implanted subcutaneously (SC) and intraperitoneally (IP), and the compounds were administered IP. Greater cytotoxic activity was observed at the SC site than at the IP site for the majority of these compounds, an observation which is consistent with the hypothesis that they are acting as brefeldin A prodrugs in vivo.

Animals↗
PubMed1999

5-deazafolate analogues with a rotationally restricted glutamate or ornithine side chain: synthesis and binding interaction with folylpolyglutamate synthetase.

Rotationally restricted analogues of 5-deazapteroyl-L-glutamate and (6R,6S)-5-deaza-5,6,7,8-tetrahydropteroyl-L-glutamate with a one-carbon bridge between the amide nitrogen and the 6'-position of the p-aminobenzoyl moiety were synthesized and tested as substrates for folylpolyglutamate synthetase (FPGS), a key enzyme in folate metabolism and an important determinant of the therapeutic potency and selectivity of classical antifolates. The corresponding bridged analogues of 5-deazapteroyl-L-ornithine and (6R,6S)-5-deaza-5,6,7, 8-tetrahydropteroyl-L-ornithine were also synthesized as potential inhibitors. Condensation of diethyl L-glutamate with methyl 2-bromomethyl-4-nitrobenzoate followed by catalytic reduction of the nitro group, reductive coupling with 2-acetamido-6-formylpyrido[2, 3-d]pyrimidin-4(3H)-one in the presence of dimethylaminoborane, and acidolysis with HBr/AcOH yielded 2-L-[5-[N-(2-acetamido-4(3H)-oxopyrido[2, 3-d]pyrimidin-6-yl)methylamino]-2, 3-dihydro-1-oxo-2(1H)-isoindolyl]glutaric acid (1). When acidolysis was preceded by catalytic hydrogenation, the final product was the corresponding (6R,6S)-tetrahydro derivative 2. A similar sequence starting from methyl N(delta)-benzyloxycarbonyl-L-ornithine led to 2-L-[5-[N-(2-amino-4(3H)-oxopyrido[2, 3-d]pyrimidin-6-yl)methylamino]-2, 3-dihydro-1-oxo-2(1H)-isoindolyl]-5-aminopentanoic acid (3) and the (6R,6S)-tetrahydro derivative 4. Compounds 3 and 4 were powerful inhibitors of recombinant human FPGS, whereas 1 and 2 were exceptionally efficient FPGS substrates, with the reduced compound 2 giving a K(m) (0.018 microM) lower than that of any other substrate identified to date. (6R,6S)-5-Deazatetrahydrofolate, in which the side chain is free to rotate, was rapidly converted to long-chain polyglutamates. In contrast, the reaction of 1 and 2 was limited to the addition of a single molecule of glutamic acid. Hence rotational restriction of the side chain did not interfere with the initial FPGS-catalyzed reaction and indeed seemed to facilitate it, but the ensuing gamma-glutamyl adduct was no longer an efficient substrate for the enzyme.

Cell Division↗