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PubMed2002

Cycloaddition reaction of 2-azadienes derived from beta-amino acids with electron-rich and electron-deficient alkenes and carbonyl compounds. Synthesis of pyridine and 1,3-oxazine derivatives.

Functionalized keto-enamines 6 were obtained by nucleophilic addition of enol ethers to the imine moiety of 2-azadienes derived from dehydroaspartic esters 4. Reactions of 2-azadiene 4c containing three electron-withdrawing substituents (CO(2)R) with enol ethers 5 in the presence of lithium perchlorate led to the formation of tetrahydropyridine derivatives 7 in a regio- and stereoselective fashion. 2H-[1,3]-oxazines 10 and pyridine derivatives 12 and 13 were obtained by heterocycloaddition reactions of electron-poor azadienes 4d-g containing two electron-withdrawing substituents (4-O(2)N-C(6)H(4), CO(2)R) in positions 1 and 4 with carbonyl derivatives (ethyl glyoxalate 9a and diethyl ketomalonate 9b) and the electron-deficient olefin tetracyanoethylene 11.

Alkenes↗
PubMed2001

Dicationic dithiocarbamate carbapenems with anti-MRSA activity.

A new class of 1 beta-methylcarbapenems bearing a doubly quaternarized 1,4-diazabicyclooctane (DABCO) substituted dithiocarbamate moiety at the C-2 side chain was prepared, and the biological profiles of the compounds, including in vitro and in vivo anti-MRSA activity and DHP-I susceptibility, were evaluated to identify a carbapenem derivative that was superior to BO-3482 (1). As a result, we discovered a 1 beta-methyl-2-[4-(4-carbamoylmethyl-1,4-diazabicyclo[2,2,2]octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio]carbapenem, 14a showing greater than 2-fold better anti-MRSA activity in a mouse infection model and 3-fold better DHP-I susceptibility as compared with BO-3482 (1).

Animals↗
PubMed2001

Design and structure-activity relationship of thrombin inhibitors with an azaphenylalanine scaffold: potency and selectivity enhancements via P2 optimization.

Theoretical and structural studies followed by the directed synthesis and in vitro biological tests lead us to novel noncovalent thrombin pseudopeptide inhibitors. We have incorporated an azapeptide scaffold into the central part of the classical tripeptide D-Phe-Pro-Arg inhibitor structure thus eliminating one stereogenic center from the molecule. A series of compounds has been designed to optimize the occupancy of the S2 pocket of thrombin. Increased hydrophobicity at P2 provides an enhanced fit into this active site S2 pocket. In the present paper, we also report on the structure of these inhibitors in solution and conformational analysis of inhibitors in the active site in order to asses the consequences of the replacement of the central alpha-CH by a nitrogen functionality. In vitro biological testing of the designed inhibitors shows that elimination of R, S stereoisomerism and restriction of conformational freedom influences the binding of inhibitors in a favorable fashion.

Antithrombins↗
PubMed2006

A zwitterion of 1,5-bis(2-hydroxybenzamido)-3-azapentane: a two-dimensional hydrogen-bonding network involving dimers.

The title compound, 2-{N-[2-(2-hydroxybenzamido)ethylammonioethyl]aminocarbonyl}phenolate, C18H21N3O4, crystallizes in a zwitterionic form as a result of intermolecular proton transfer and possesses a negatively charged phenolate group and a protonated amino group. The 2-hydroxybenzamide and 2-(aminocarbonyl)phenolate moieties attached to the two ends of the C-C-N-C-C backbone adopt a cis conformation in relation to this backbone. All N- and O-bound H atoms are involved in hydrogen-bond formation; the zwitterions are first linked into head-to-tail dimers, which are further organized into a two-dimensional network parallel to the crystallographic bc plane.

Aza Compounds↗
PubMed2002

Conformational control of flexible molecules: design and synthesis of novel chiral 1,5-diaza-cis-decalins.

Control of the conformational equilibria of 1,5-diaza-cis-decalins, a new class of chiral diamine ligands, has been investigated. Chiral 2,6- and 3,7-substituted derivatives of 1,5-diaza-cis-decalins were designed to stabilize the conformational form needed to chelate a lithium. These derivatives were synthesized in optically pure form starting from 1,5-diaza-cis-decalin. Due to the rigid and conformationally well-defined nature of these compounds, the potential of these compounds as chiral diamine ligands was investigated. Asymmetric lithiation-substitution reactions of N-Boc-pyrrolidine and N,N-diisopropyl-o-ethylbenzamide were performed using these ligands and up to 60% ee was obtained. For the latter substrate, results spanning a range from 32% ee (R) to 60% ee (S) were obtained (Delta ee = 92%) with 1,5-diaza-cis-decalin ligands differing only in the location of two methyl substituents. Unlike many other diamines that have been employed in asymmetric lithiation-substitution reactions, the limited conformational flexibility of the 1,5-diaza-cis-decalins is analogous to (-)-sparteine such that these results may permit the construction of structure-activity relationships.

Aza Compounds↗
PubMed2005

2,9-disubstituted-N6-(arylcarbamoyl)-8-azaadenines as new selective A3 adenosine receptor antagonists: synthesis, biochemical and molecular modelling studies.

A number of N6-(N-arylcarbamoyl)-2-substituted-9-benzyl-8-azaadenines, obtained by a modification of the synthetic scheme used to prepare selective A1 ligands, by only three or two steps, are described. At first we prepared a series of 2-phenyl-9-benzyl-8-azaadenines having as N6 substituent a variously substituted N-phenylcarbamoyl group. Some of these derivatives demonstrated good affinity towards the A3 subtype but low selectivity. Compounds having p-CF3, p-F and p-OCH3, as substituents on the phenylcarbamoyl group were selected as lead compounds for the second part of this study. Without modifying the N6 substituent, which would assure A3 affinity, we varied the 9 and 2 positions on these molecules to enhance selectivity. Some compounds having a p-methyl group on the 2-phenyl substituent showed a very good affinity and selectivity for the A3 subtype, revealing the first class of A3 adenosine receptor selective antagonists with a bicyclic structure strictly correlated to the adenine nucleus. The molecular modelling work, carried out using the DOCK program, supplied two models which may be useful for a better understanding of the binding modes. Both models highlighted the preferred interacting tautomeric forms of the antagonists for human A1 and A3 receptors.

Adenine↗
PubMed2005

Liquid chromatography-tandem mass spectrometry method for determination of phencynonate in rat blood and urine.

A sensitive and specific high-performance liquid chromatographic assay with electrospray ionization mass spectrometry detection (LC-ESI-MS) has been developed and validated for the identification and quantification of the novel anticholinergic drug phencynonate in rat blood and urine. The sample pretreatment involves basification and iterative liquid-liquid extraction with ethyl ether-dichloromethane (2:1, v/v) solution, followed by LC separation and positive electrospray ionization mass spectrometry detection. The chromatography was on BetaBasic-18 column (150 mm x 2.1mm i.d., 3 microm). The mobile phase was composed of methanol-water (85:15, v/v), containing 0.5 per thousand formic acid, which was pumped at a flow-rate of 0.2 ml/min. Thiencynonate was selected as the internal standard (IS). Simultaneous MS detection of phencynonate and IS was performed at m/z 358.4 (phencynonate), m/z 364 (thiencynonate), and the selected reaction ion monitoring (SRM) of the two compounds was at 156. Phencynonate eluted at approximately 5.25 min, thiencynonate eluted at approximately 5.10 min and no endogenous materials interfered with their measurement. Linearity was obtained over the concentration range of 1-100 ng/ml in rat blood and 1-500 ng/ml in rat urine. The lower limit of quantification (LLOQ) was reproducible at 1 ng/ml in both of rat blood and urine. The precision measured was obtained from 2.92 to 9.76% in rat blood and 4.17 to 9.76% in rat urine. Extraction recoveries were in the range of 69.57-79.49% in blood and 56.85-64.86% in urine. This method was successfully applied to the identification and quantification of phencynonate in pharmacokinetic studies.

Animals↗
PubMed2006

Determination of ofloxacin and moxifloxacin and their penetration in human aqueous and vitreous humor by using high-performance liquid chromatography fluorescence detection.

Information on comparing the penetration of ofloxacin and moxifloxacin in the human eye is unavailable, although these two antibiotics are commonly used in ophthalmic surgery. There is a need for a rapid, reliable, and sensitive methodology for their determination in ocular fluids. We developed a robust HPLC procedure with fluorescence detection for simultaneous analysis of ofloxacin and moxifloxacin in human and rabbit aqueous and vitreous samples. The linearity of the method ranged from 10 ng/ml to 100 microg/ml with r(2) > 0.996. Most inter- and intrabatch imprecision was about 5% (range 1.6-7.6%), recoveries between 95 and 104%, and accuracies between 93 and 104% at 0.1 and 1 microg/ml. The detection limits of both compounds were 10 ng/ml (0.028 nmol/ml for ofloxacin and 0.023 nmol/ml for moxifloxacin). No sample treatment was necessary for aqueous humor and only acetonitrile precipitation was required for vitreous humor. The chromatographic time was short, 22 min. We applied this method to study penetrations of ofloxacin and moxifloxacin in aqueous and vitreous humors of human and rabbits. There was no significant difference of penetration between the two antibiotics into aqueous and vitreous but ofloxacin was found at significantly higher concentrations in aqueous than in vitreous. We also detected contralateral transfer of the antibiotics in rabbit eyes.

Animals↗
PubMed2005

[Anticonvulsant effect of phencynonate hydrochloride on maximal electroshock seizure and the metrazol seizure threshold test in mice].

AIM: To test the antiepileptic effect of phencynonate hydrochloride and investigate its antiepileptic mechanism. METHODS: Through establishment of different epilepsy models, antiepileptic effects of phencynonate hydrochloride and other drugs were examined. Besides, the effect of phencynonate hydrochloride and other compounds against NMDA-induced lethality in mice, NMDA-induced injury in rat primary hippocampal neuronal cultures and NMDA-induced current were also observed. RESULTS: Phencynonate hydrochloride produced a significant anticonvulsant effect on different epilepsy models. Furthermore, phencynonate hydrochloride also exerted its obvious protection against the lethal effects of NMDA in mice, antagonized the NMDA-induced injury in rat primary hippocampal neuronal cultures and blocked NMDA-induced current in a dose-dependent manner. CONCLUSION: Phencynonate hydrochloride had a notable anticonvulsant effect on typical epilepsy models, its antiepileptic mechanism might relate to its antagonism against NMDA receptor.

Animals↗
PubMed2006

Computer-aided design of promising photochemical alkoxy radical precursors.

A computer-aided design of alkoxyl radical precursors is performed. The new precursors should combine the advantages of N-alkoxypyridine-2(1H)thiones (less reactive radicals) and N-alkoxythiazole-2(3H)thiones (stable with respect to daylight). Additionally, the radical liberation process should be initiated by light with a wavelength of around 350 nm. To find promising compounds, 18 test candidates were obtained by a systematic variation of the parent compound N-alkoxythiazole-2(3H)thione. The properties of the test molecules were computed by a protocol that was already successfully used to rationalize the photochemical behavior of N-alkoxypyridine-2(1H)thiones and N-alkoxythiazole-2(3H)thiones. The computations identify two promising new compounds. For N-methoxy-(1,3)dihydro-[1,3]azaphosphole-2-thione (6a), they predict that the fragmentation process will be initiated by an absorption at 348 nm. An analysis of its fragmentation process indicates that the free excess energy of the resulting radicals should more resemble the situation found for N-alkoxypyridine-2(1H)thiones. For N-methoxy-(1,3)dihydro-pyrrole-2-thione (3a), the excitation energy is somewhat higher (330 nm), but the computed fragmentation paths again indicate that the remaining excess energy of the released radicals is quite favorable. The test molecules also contained the experimentally well-known N-methoxypyridine-2(1H)one (1b). For this molecule, our computed data rationalizes nicely the experimental findings.

Alcohols↗
PubMed1993

Substituted benzamides with conformationally restricted side chains. 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants.

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.

Animals↗
PubMed2006

Three in one: TSA, TSA', and SA units in one crystal structure of a yttrium(III) complex with a monophosphinated H4dota analogue.

Compound [Y(Hdo3aP(ABn))(H2O)][Y(Hdo3aP(ABn))].6H2O.iPrOH, where H4do3aP(ABn) is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-methyl(4-aminobenzylphosphinic) acid, a monophosphinate analogue of H4dota, was prepared in the solid state and studied using X-ray crystallography. In contrast to all single-crystal structures of complexes of H4dota-like ligands published before, three distinct units were found in one cell: two species adopting a twisted-square-antiprismatic configuration with (TSA) and without (TSA') a coordinated water molecule and one isomer with a square-antiprismatic configuration (SA). In addition, this is the first complex with the H4dota-like ligand for which the structures of three possible species were determined in the solid state.

Aza Compounds↗
PubMed2002

A theoretical study of conformational properties of N-methyl azapeptide derivatives.

The conformational properties of azapeptide derivatives, Ac-azaGly-NHMe (1), Ac-azaAla-NHMe (2), Ac-NMe-azaGly-NHMe (3), Ac-NMe-azaAla-NHMe (4), Ac-azaGly-NMe(2) (5), Ac-azaAla-NMe(2) (6), Ac-NMe-azaGly-NMe(2) (7), and Ac-NMe-azaAla-NMe(2) (8), were systematically examined by using ab initio MO and DFT methods. Structural perturbations in azapeptides resulting from cyclic substitution of a methyl group at three N-positions of an azaamino acid were studied on the basis of the structure of the simplest model azapeptide, 1. Potential energy surfaces were generated at the HF/6-31G level for 1-4 and at the HF/6-31G//HF/3-21G level for 5-8 by rotating two key dihedral angles (phi, psi) in increments of 30 degrees. The backbone (phi, psi) angles of the minima for 1-4 are observed at the i + 2 position to form the betaI(I')-, betaII(II')-, betaVI-turns or the polyproline II structure according to the orientation of the acetyl group and the positions of the N-methyl groups. Compounds 5-8 coupled to a secondary amine were found to preferentially adopt polyproline II, betaI(III)-turn, or alpha-helical structure or even extended conformations depending on the orientation of the acetyl group and the positions of the N-methyl groups. Furthermore, N-methyl groups, depending on their positions, were found to affect the orientation of the amide group in the lowest energy conformations, the pyramidality of the N2 atom, and the bond length in azapeptide derivatives. These unique theoretical conformations of N-methyl azapeptide derivatives could be utilized in the definite design of secondary structure for peptides and proteins, and in the development of new drugs and molecular machines.

Aza Compounds↗
PubMed2002

Precursor of a beta-lactamase inhibitor: allyl (4S,8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylate.

The molecular structure of the title tricyclic compound, C(17)H(21)NO(4), which is the immediate precursor of a potent synthetic inhibitor [Lek157: sodium (8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylate] with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclohexyl ring and the carbonyl group of the beta-lactam ring, which takes part in the formation of the initial tetrahedral acyl-enzyme complex. In this hydrophobic molecule, the overall geometry is influenced by C[bond]H...O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) A, with corresponding normalized H.O distances of 2.30 and 2.46 A], whereas the molecules are interconnected through intermolecular C[bond]H...O hydrogen bonds [3.335 (4)-3.575 (5) A].

Aza Compounds↗
PubMedDate not supplied

De novo synthesis of a new diethylenetriaminepentaacetic acid (DTPA) bifunctional chelating agent.

Diethylene triamine pentaacetic acid (DTPA) has been in extensive use as a metal chelator in the development of radiopharmaceuticals and contrast agents. The former application uses DTPA mostly as a bifunctional chelating agent (BCA) conjugated to tumor-targeting vehicles (TTVs) such as monoclonal antibodies (MAbs) and receptor-directed peptides. A new bifunctional DTPA derivative was synthesized by a fully organic scheme. This compound, N(4),N(alpha),N(alpha),N(epsilon),N(epsilon)-[pentakis(carboxymethyl)]-N(4)-(carboxymethyl)-2,6-diamino-4-azahexanoic hydrazide (20) was prepared by a convergent synthesis strategy using N(alpha)-benzyloxycarbonyl-2,3-diaminopropionic acid as the starting compound. This commercially available material was used to build a functionalized triamine which served as the molecular core template for assembling the target molecule. To evaluate the conjugation and radiolabeling capabilities of this new molecule, it was covalently attached to the anti-TAG-72 MAb, Delta CH2HuCC49, and the conjugate was radiolabeled in near-quantitative yields with yttrium-90 ((90)Y) and lutetium-177 ((177)Lu). Biodistribution of the (177)Lu-labeled DTPA-Delta CH2HuCC49 in tumor-bearing nude mice demonstrated preservation of the immunoreactivity of the MAb as indicated by high tumor uptake. In addition to the introduction of a new bifunctional DTPA, this work reports on a novel synthetic approach for preparation of this useful metal chelator and introduces a new conjugation protocol.

Animals↗
PubMed1988

endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxylic acid, a superior resolving agent for the high-performance liquid chromatographic separation of enantiomers of hydroxylated derivatives of two azaaromatic hydrocarbons.

The high-performance liquid chromatographic (HPLC) separation of enantiomers of oxide and hydroxy derivatives of dibenz[a,j]acridine and 7-methylbenz[c]acridine was investigated on a chiral stationary phase chromatography column using commercially available columns. In most cases either poor or no separation of enantiomers was achieved. Normal-phase separation of diastereoisomeric ester derivatives of the hydroxy compounds, prepared from commercially available (-)-menthoxyacetic acid or (+)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetic acid, was investigated. No separation of the diastereoisomeric esters of trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine was observed. However, diastereoisomeric esters prepared from (+)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxyl ic acid [(+)-HCA] were easily separated. Using the three chiral acids, diastereoisomers were prepared from sixteen hydroxy derivatives of dibenz[a,j]acridine and 7-methylbenz[c]acridine. (+)-HCA esters gave good to excellent HPLC separations which were superior to those achieved using other chiral acids in most cases. The enantiomeric composition of trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine formed as a major rodent liver microsomal metabolite of dibenz[a,j]acridine was determined using (+)-HCA.

Acylation↗
PubMedDate not supplied

[Kinetic parameters of hydrolysis of CpA and UpA sequences in an oligoribonucleotide by compounds functionally mimicking ribonuclease A].

Kinetic parameters of cleavage of CpA and UpA sequences in an oligoribonucleotide under the action of artificial ribonuclease ABL3C1 were measured. The compounds were built of RNA-binding domain B, catalytic fragment C, linker L3 comprising 3 methylene groups, and aliphatic fragment A. The rate of cleavage of phosphodiester bonds in CpA sequence within decaribonucleotide UUCAUGUAAA was shown to be 3.4 +/- 0.2 times higher than in UpA sequence. The rate of cleavage of phosphodiester bonds were found to depend on substrate length: a thousandfold increase in cleavage rate constant was observed for CpA sequence in decaribonucleotide as compared with diribonucleotide monophosphate CpA. A slight decrease in the cleavage rates was observed for the reactions proceeding in different buffers at pH 7.0: imidazole > HEPES > phosphate > cacodylate. At the same time, the ratio of cleavage rates for CpA and UpA sequences remained constant.

Aza Compounds↗
PubMed2005

DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice.

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous membrane-bound enzyme that cleaves the two N-terminal amino acids from peptides with a proline or alanine residue in the second position from the amino end. Potential substrates for DPP IV include several neuropeptides, suggesting a role for DPP IV in neurological processes. We have developed a potent DPP IV inhibitor (IC50 = 30 nM), 1-(2-amino-3-methyl-butyryl)-azetidine-2-carbonitrile (AMAC), which has shown efficacy in two established models of psychosis: mescaline-induced scratching and amphetamine-induced hyperactivity. In the mescaline-induced scratching model, AMAC treatment before mescaline administration reduced the number of scratching paroxysms by 68% (P < 0.01). The compound showed a dose-dependent effect, inhibiting significantly at 6, 20 and 60 mg/kg (37%, 39% and 68%, respectively). In the amphetamine-induced hyperactivity model, 50 and 60 mg/kg AMAC, given before injection of amphetamine, significantly reduced hyper-locomotion by 65% and 76%, respectively. Additionally, AMAC showed no significant activity in binding assays for 20 receptors thought to be involved in the pathology of schizophrenia, including dopamine, serotonin and glutamate. A structurally similar analog, 1-(2-dimethylamino-3-methyl-butyryl)-azetidine-2-carbonitrile (DAMAC), that does not inhibit DPP IV, was inactive in both models. Taken together, these data suggest that the antipsychotic effects of AMAC are the result of DPP IV inhibition.

Amphetamine↗