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The capacity of 25 different amidines, guanidines and biguanidines to suppress the thrombocytes aggregation, induced by adenosinodiphosphate, was studied. Good prospects of a search for antiaggregation agents in this series of compounds are shown. N-benzyl-N1-propionylguanidine was found to reduce by more than 4 times the induced adhesiveness of the blood platelets.
We have recently reported that aromatic polyamidines are powerful inhibitors of in vitro proliferation of tumour cell lines and in vivo tumorigenicity of melanoma cells xenografted into nude mice. Interestingly, we have found that tetrabenzamidines are able to bind DNA, and to inhibit the interaction between transacting factors and specific target DNA sequences. In order to obtain more detailed information on structure-activity relationships, we have analysed the effects of different aromatic polyamidines on the binding of a recombinant protein, the Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1), to the target sequence of EBV DNA, containing the 12 bp palindromic consensus TAGCATATGCTA. The results obtained suggest that aromatic polyamidines inhibit the interactions between DNA-binding proteins and target DNA sequences with different efficiency, depending (i) on the number of amidine residues and (ii) on the presence of halogen substitutions (Cl, Br or I) on the benzene rings of tetra-benzamidine molecules.
The synthesis of furo[2,3-b]pyridine formamidines (D/1-D/11, F) was realized by the reaction of the 3-amino-furo[2,3-b]pyridines C/1-C/11 and E, substituted in position 2 with a carbonyl moiety with dimethylformamide/phosphoroxide chloride or with N-formyl-piperidine or N-formyl-morpholine and phosphoroxide chloride. The acetamidines H were yielded from 4-oxo-4H-3-methyl-pyrido[3',2':4,5]furo[3,2-d]1,3-oxazines with aminoethanol. The 4-oxo-4H-3-amino-3,4-dihydro-pyrido[3',2':4,5]furo[3,2-d]pyrimidines K and M reacted with dimethylformamide/phosphoroxide chloride to give the tricyclic formamidines L and K. The described amidines showed antianaphylactic activity.
Fermentative hydrolysis of 3 derivatives of 6-beta-amidinopenicillanic acid and I derivative of 7-beta-amidinodeacetoxycephalosporanic acid by penicillinase produced by Bacillus licheniformis 749/c was studied. It was found that 6-beta-[(hexahydro-IH-azepin-I-yl) methyleneamino] penicillanic acid, 6-beta-(N1 N-dimethylformamidino-N1) penicillanic acid and 6-beta [(morpholin-I-yl) methylenemino] penicillanic acid were hydrolyzed by the enzyme 50, 70, and 160 times respectively slower than benzylpenicillin. 7-beta-[(Hexahydro-IH-azepin-I-yl)' methylenemino] deacetoxycephalosporanic acid proved to be at least 10 times more stable to the effect of penicillinase than methicillin. In addition unlike the amidine analogues of penicillin the above compound had an inhibitory effect on penicillinase produced by Bacillus licheniformis 749/c.
A set of heterocyclic N-acetamidinium hydrochlorides were prepared from the corresponding N-acetonitriles. The antiparasitic screening showed that, while all amidines are practically inactive, some nitriles present leishmanicide properties.
Anticarsia gemmatalis nucleopolyhedrovirus (AgMNPV) is a baculovirus specific for the control of an important soybean defoliator. The baculovirus is comprised of double-stranded DNA, occluded in a proteinaceous structure called a polyhedron. Ultraviolet sunlight is the most destructive factor that affects the persistence of the virus in the field. In the present study, we use a model system wherein the pathogen is covered by another particle of opposite charge in order to test the effectiveness of a physical barrier as a protection against sunlight. Heteroflocculation experiments were carried out using two different age batches of AgMNPV and amidine polystyrene latex particles. The assessment of heteroflocculation was achieved by zeta potential and adsorption isotherm measurements, and by scanning electron microscopy. Despite the great difference in potentials between latex particles and the baculovirus, low-affinity isotherms were obtained in both pure water and 0.1 mM KCl. Adsorbed latex particles were easily washed out from the polyhedron surface. This low affinity could be attributed to the presence of a strongly repulsive hydration force of short range operating on the system. The results suggest that the failure to obtain a good physical barrier against sunlight might be attributed to the difficulty in keeping the polyhedron surface covered. Copyright 2000 Academic Press.
Semiempirical calculations (AM1) together with experimental mass spectrometric (FT-ICR) data indicate the imino nitrogen atom as the favoured site of protonation and the amino nitrogen atom as the site of deprotonation of the amidine group in the gas phase. For tautomerizing N-methyl-N'-phenylbenzamidine the tautomer with the phenyl group at the imino nitrogen atom weakly predominates in tautomeric mixture.
The novel convulsant amidine steroid RU5135 inhibited gamma-aminobutyric acid receptor binding in membranes from seven regions of rat brain (IC50 = 11 +/- 2 nM against [3H]muscimol and 0.8 +/- 0.2 nM against [3H]bicuculline methochloride), apparently lowering the number of binding sites labeled with gamma-aminobutyric acid receptor agonists or antagonists. The steroid reversed the enhancement of benzodiazepine receptor binding by gamma-aminobutyric acid, pentobarbital, and etazolate, but did not inhibit the binding of the convulsant [35S]t-butyl bicylophosphorothionate. Thus, RU5135 shows very potent in vitro actions more resembling those of the gamma-aminobutyric acid site antagonist, bicuculline, than the chloride channel antagonist, picrotoxin.
The synthetic steroid amidine 3-alpha-hydroxy-16-imino-5-beta-17aza androstan-11-one (R 5135) is known to elicit long-lasting spiking in the cortex in the presence of neocortical damage. R 5135 administered to amygdaloid-kindled and naive rats resulted in regular, high-amplitude spiking in the cortex but only occasionally elicited small-amplitude spikes in the amygdala (AMY) and hippocampus (HPC). Interictal spikes from the AMY of kindled rats were not synchronized with cortical spikes induced by the steroid. Given that R 5135 is known to be a GABAA receptor antagonist, these findings suggest that GABAA receptors in AMY and HPC may have lower affinity for 3 alpha-hydroxysteroids.
We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.
The collision-induced dissociation characteristics of amidinated and unmodified tryptic peptides are compared using an ion trap mass spectrometer with both electrospray ionization and matrix-assisted laser/desorption ionization (MALDI). Several fragmentation pathways in a number of tryptic peptides of various precursor charge states are found to be enhanced. The additional information conveyed by the observed fragment ions should facilitate protein identifications.
A chemical derivatization method, amidination, that has recently been effectively employed in peptide mass spectrometry experiments is used to covalently modify lysines in several standard proteins. Protein and peptide mass spectra identify sites at which the reaction does or does not occur. This is therefore a rapid approach to elucidate solvent-accessible regions of folded proteins.
A variety of base-modified nucleotide analogues was prepared and characterized as their alpha-32P- or U-14C-labeled compounds. Carrier-linked nucleotide binding and carrier-catalyzed exchange across the inner membrane of rat liver mitochondria were measured by using an inhibitor (atractyloside) stop method. Kinetic data of carrier-specific bound analogues were evaluated from Dixon plots and indicate that these analogues are competitive inhibitors for mitochondrial [14C]ADP uptake. Km and Vmax values for carrier-mediated uptake of nucleotide analogues were calculated from Lineweaver-Burk plots. By means of the analogues, a systematic mapping of the essential chemical and steric interactions between the transporter protein and the heterocycle of its substrate in the course of the binding as well as transfer step was achieved. Prerequisites for carrier-specific binding (recognition) are (A) an anti- or syn-positioned beta-glycosyl-linked heterocycle, (B) a nitrogen ring atom in position 7 for syn-structured analogues, and (C) an electron-rich region at the N(1) position, i.e., a permanent dipole moment oriented toward N(1) for anti-structured analogues. Additional requirements for subsequent transport catalysis are (A) a non-fixed anti-positioned base moiety with a beta-glycosyl torsion angle of about -20 degrees, (B) a C(6)-positioned amino group, and (C) an unsubstituted C(2) atom. The complementary binding site at the carrier protein to the N(1)-C(6)(-NH2) amidine region is proposed to be represented by two juxtaposed and invariant bonding points, i.e., an asparagine or glutamine residue.
A series of copper(I) amidinates of the general type [(R'NC(R)NR'')Cu](2) (R' and R'' = n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; R = methyl, n-butyl) have been synthesized and characterized. These compounds are planar dimers, bridged by nearly linear N-Cu-N bonds. Their properties (volatility, low melting point, high thermal stability, and self-limited surface reactivity) are well-suited for atomic layer deposition (ALD) of copper metal films that are pure, highly conductive, conformal, and strongly adherent to substrates.
The dinuclear gold(I) amidinate complex [Au(2)(Me(2)-form)(2)], 1, (Me(2)-form = 2,6-Me(2)-formamidinate) reacts with Hg(CN)(2) to form a 2D structure, 1.2Hg(CN)(2).2THF. Each gold center interacts with two Hg(CN)(2) molecules. The Au...Au distance increases from 2.7 Angstroms in the starting dinuclear complex to 2.9 Angstroms in the adduct. The gold centers are connected to four nitrogen atoms with Au-N distances in the range 2.13-2.51 Angstroms. The cyanide stretch is shifted from 2192 cm(-1) in the Hg(CN)(2) to 2147 cm(-1) in the adduct.
A novel ligand-exchange route for the synthesis of amidinate-containing compounds of aluminum is explored. Syntheses of three new compounds, MeC(NiPr)2AlEt2 (4), EtC(NiPr)2AlMe2 (5), and (Me2NC(NiPr)2)2AlH (6), are presented. These mixed-ligand compounds are difficult to make in high yields by the more traditional routes of carbodiimide insertion or salt metathesis. The thermal reactivities of these compounds and their parent homoleptic compounds [MeC(NiPr)2]3Al (1), [Me2NC(NiPr)2](3)Al (2), and [EtC(NiPr)2]3Al (3) are explored in detail and analyzed with respect to their utility as potential atomic-layer-deposition precursors for aluminum-containing films. The major mechanism of thermal decomposition is found to be carbodiimide deinsertion to form aluminum alkyls or amides. Because of their thermal characteristics, both compounds 3 and 5 hold promise for use as precursors.
The use of an amino-oxazolinate (NN(ox) = kappa2-2,6-dimethylphenylamido-4(S)-isopropyloxazoline) as a chiral analogue to amidinate ligands in the chemistry of titanium was found to lead to undesired side reactions. The reaction of 2,6-dimethylphenylamido-4(S)-isopropyloxazoline with [Ti(NMe2)4] afforded the bis(amidinato) complex [Ti(NN(ox))2(NMe2)2] (2) which was thermally converted to the ring-opened decomposition products [Ti(NN(ox)){kappa3-N(2,6-C6H3Me2)C(NMe2)NC(iPr)CH2O}(NMe2)] (3) and [Ti{kappa3-N(2,6-C6H3Me2)C(NMe2)-NC(iPr)CH2O}2] (4). The NMR spectra of 4 recorded at low temperature displayed two sets of resonances corresponding to two symmetric isomers in a 2:5 ratio, the probable geometries of which were established by ONIOM (QM/MM) simulations. To suppress ring opening of the oxazolines, their oxygen atom was formally replaced by a CH2 group in the synthesis of a series of amino-pyrroline protioligands 2-RN(H)(5-C4H5NR') (HN(R)N(R')). Their reaction with [Ti(NMe2)4] gave the thermally stable complexes [Ti(N(R)N(R'))2(NMe2)2], of which three derivatives were characterized by X-ray diffraction. They are stereochemically dynamic and undergo reversible ligand rearrangements in solution, for which the activation parameters were determined by variable-temperature (1)H NMR spectroscopy.
A new synthetic methodology for the generation of cyclic amidines has been developed by the reaction of 1,n-aminoalkynes with electron-deficient azides using a ruthenium catalyst at ambient temperature. The reaction proceeds most likely via a tandem sequence of intramolecular hydroamination of aminoalkynes, cycloaddition of azides with the resulting enamines, and rearrangement of triazoline intermediates. It demonstrates, as the proof-of-principle, that an equilibria cascade sequence can be favorably driven by an irreversible step, thus enabling a facile one-pot synthetic route to deliver molecular complexity under unprecedented mild conditions without relying on the traditional linear approaches.