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PubMed2003

Synthesis and characterization of volatile, thermally stable, reactive transition metal amidinates.

A series of homoleptic metal amidinates of the general type [M(R-R'AMD)(n)](x) (R = (i)Pr, (t)Bu, R' = Me, (t)Bu) has been prepared and structurally characterized for the transition metals Ti, V, Mn, Fe, Co, Ni, Cu, Ag, and La. In oxidation state 3, monomeric structures were found for the metals Ti(III), V(III), and La(III). Bridging structures were observed for the metals in oxidation state 1. Cu(I) and Ag(I) are held in bridged dimers, and Ag(I) also formed a trimer that cocrystallized with the dimer. Metals in oxidation state 2 occurred in either monomeric or dimeric form. Metals with smaller ionic radii (Co, Ni) were monomeric. Larger metals (Fe, Mn) gave monomeric structures only with the bulkier tert-butyl-substituted amidinates, while the less bulky isopropyl-substituted amidinates formed dimers. The new compounds were found to have properties well-suited for use as precursors for atomic layer deposition (ALD) of thin films. They have high volatility, high thermal stability, and high and properly self-limited reactivity with molecular hydrogen, depositing pure metals, or water vapor, depositing metal oxides.

Journal Article↗
PubMed2004

Synthesis and characterization of binucleating bis(amidinate) ligands and their dialuminum complexes.

Two general routes to binucleating bis(amidinate) ligands based on dibenzofuran and 9,9-dimethylxanthene backbones are reported. The free-base form of one of the ligands, (Ph,Mes)L(DBF)H(2), forms a 1:1 adduct with acetone. Single-crystal X-ray diffraction of this adduct reveals bidentate H-bonding of the bis(amidine) to the ketone oxygen. Bond lengths suggest that the individual H-bonds are relatively weak, yet IR spectroscopy shows a significant -26 cm(-1) shift for the carbonyl stretch relative to free acetone. Additionally, the new dialuminum complexes (i)(Pr)L(DBF)Al(2)Me(4) (3), (i)(Pr)L(Xan)Al(2)Me(4) (4), (t)(Bu,Et)L(DBF)Al(2)Me(4) (5), and (t)(Bu,Et)L(Xan)Al(2)Me(4) (6) are prepared by reaction of Al(2)Me(6) with the bis(amidines) in toluene solution. (1)H NMR spectroscopic studies indicate that 3 and 4 interact weakly with certain Lewis bases (DMSO, DMF, pyridine) to effect the exchange of the Al-bound Me groups. Other bases, such as THF and TMEDA, fail to interact. Solid-state structures for 3 and 4 are reported.

Journal Article↗
PubMed2006

Synthesis and structural investigation of tungsten imido amidinate and guanidinate complexes.

The tungsten imido guanidinate and amidinate complexes W(NR)Cl(3)[R'NC(NMe(2))NR'] and W(NR)Cl(3)[R'NC(Me)NR'] (R = Ph, (i)Pr, Cy; R' = (i)Pr, (t)Bu, TMS) were synthesized by reacting the corresponding imido complex W(NR)Cl(4)(OEt(2)) with the appropriate lithium amidinate or guanidinate. Crystallographic structure determination of W(N(i)Pr)Cl(3)[(i)PrNC(NMe(2))N(i)Pr] and W(N(i)()Pr)Cl(3)[(i)PrNC(Me)N(i)Pr] allows comparison of structural features between the guanidinate and amidinate ligand in the presence of an identical ancillary ligand set.

Journal Article↗
PubMed2004

One ligand fits all: cationic mono(amidinate) alkyl catalysts over the full size range of the group 3 and lanthanide metals.

Using a sterically demanding amidinate ancillary ligand and an in situ alkylation procedure, neutral mono(amidinate) dialkyl and cationic mono(amidinate) monoalkyl complexes were prepared for metals spanning the full size range of the group 3 and lanthanide metals. The activity of the cationic monoalkyls in catalytic ethene polymerization was found to vary by over 2 orders of magnitude depending on the metal ionic radius, the intermediate metal sizes being found to be the most effective.

Journal Article↗
PubMed1999

Synthesis, characterization, and structure-activity relationships of amidine-substituted (bis)benzylidene-cycloketone olefin isomers as potent and selective factor Xa inhibitors.

Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in blood coagulation linking the intrinsic and extrinsic pathways to the final common pathway of the coagulation cascade. During our initial studies, we observed facile photochemical conversion of the known FXa/tPA inhibitor, BABCH ¿(E,E)-2, 7-bis(4-amidinobenzylidene)cycloheptan-1-one, 1a, to the corresponding (Z,Z) olefin isomer, 1c (FXa K(i) = 0.66 nM), which was over 25,000 times more potent than the corresponding (E,E) isomer (1a, FXa K(i) = 17 000 nM). In order to determine the scope of this observation, we expanded on our initial investigation through the preparation of the olefin isomers in a homologous series of cycloalkanone rings, 4-substituted cyclohexanone analogues, and modified amidine derivatives. In most cases the order of potency of the olefin isomers was (Z,Z) > (E,Z) > (E,E) with the cycloheptanone analogue (1c) showing the most potent factor Xa inhibitory activity. In addition, we found that selectivity versus thrombin (FIIa) can be dramatically improved by the addition of a carboxylic acid group to the cycloalkanone ring as seen with 8c (FXa K(i) = 6.9 nM, FIIa K(i) > 50,000 nM). Compounds with one or both of the amidine groups substituted with N-alkyl substituents or replaced with amide groups led to a significant loss of activity. In this report we have demonstrated the importance of the two amidine groups, the cycloheptanone ring, and the (Z,Z) olefin configuration for maximum inhibition of FXa within the BABCH template. The results from this study provided the foundation for the discovery of potent, selective, and orally active FXa inhibitors.

Benzylidene Compounds↗
PubMed2006

A convenient route to silyl linked bis(amidinate) ligands and synthesis of group(I) metal derivatives.

A novel type of linked bis(amidinate) ligands (D) were developed successfully. Their lithium derivatives 1-4 were synthesized by treating the silyl-bridged diamines I-IV with two equivalents of LiBu(n) and PhCN in sequence, which underwent a silyl-bridge migration process. In addition, the linked bis(amidinate) configuration proved to be the thermodynamically stable form rather than the mono(amidinate) type by contrasting reaction of I with one equivalent of LiBu(n) and PhCN in sequence.

Journal Article↗
PubMed1987

Hepatic microsomal N-demethylation of N-methylbenzamidine. N-dealkylation vs N-oxygenation of amidines.

The microsomal oxidative N-demethylation of N-methylbenzamidine, a model compound for active substances containing the basic amidine function, was investigated. N-Methylbenzamidine was converted into benzamidine and formaldehyde by aerobic incubation with non-induced microsomal fractions of rabbit liver homogenates and NADPH. The formation of benzamidine in the incubation mixtures under widely differing conditions was assayed using a newly-developed, high-performance, ion pair, reverse-phase partition chromatographic method. Optimal reaction conditions were determined. The benzamidine formation in the incubation mixture followed Michaelis-Menten kinetics and required the presence of molecular oxygen and NADPH. The effects of the inducer phenobarbital, methylcholanthrene, ethanol and N-methylbenzamidine itself on the activity were studied. Neither superoxide anion nor hydrogen peroxide was directly involved in the demethylation reaction. The direct involvement of cytochrome P-450 in this reaction is supported by the observation that the presence of inhibitors of cytochrome P-450, in particular of carbon monoxide, markedly decreased the rate of N-demethylation. This N-demethylation of N-methylbenzamidine proves the hypothesis that benzamidines with hydrogen atoms in the alpha-position to the amidine nitrogen atoms are N-dealkylated instead of N-oxygenated by the microsomal mixed function oxidase system.

Amidines↗
PubMed1996

Double long-chain amidine liposome-mediated self replicating RNA transfection.

We present experimental evidence that a complex made of a double long chain cationic amphiphile and recombinant mRNA facilitates the entry and expression of genetic material into cells. Combining the properties of the self replicating recombinant mRNA driven by the Semliki Forest Virus (SFV) replicon and the transfection potentialities of a new cationic amphiphile (N-t-butyl-N'-tetradecyl-3-tetradecylaminopropionamidine) yields a highly efficient mRNA transfection system conferring up to 100% infectivity. The preparation and characterization of the long chain amidine cationic amphiphile-mRNA complex as well as the influence of the diC14-amidine/RNA ratio on the infective activity are described.

Amidines↗
PubMed1996

Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists.

As part of a continuing effort aimed at the development of selective, efficacious, and centrally active m1 muscarinic agonists for the treatment of Alzheimer's disease, a series of amide and hydrazide amidine derivatives (2a-e and 3b-d) was synthesized and examined for muscarinic agonist activity. Preliminary biochemical studies indicated that 2b, 2d, and 3d bound to muscarinic receptors in rat brain and stimulated phosphoinositide (PI) metabolism in rat cerebral cortex. Compounds 2b and 2d were also highly efficacious at m1 muscarinic receptors expressed in cultured A9 L cells. Molecular modeling studies suggest slightly different modes of interaction with m1 receptors for the ester and amide derivatives. Also, hydrogen-bond formation with a Thr residue may be important for m1 muscarinic agonist potency. The data suggest that the amide moiety can replace the ester group found in muscarinic agonists and provide further support for the utility of amidine derivatives in the development of efficacious m1 agonists.

Amidines↗
PubMed2006

Novel amidine analogue of melphalan as a specific multifunctional inhibitor of growth and metabolism of human breast cancer cells.

A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidium displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of beta(1)-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of beta(1)-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK(1) and ERK(2) but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20 microM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.

Amidines↗
PubMed2002

Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1.

A series of noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1 was investigated. While the amidrazone and the amine series displayed limited oral absorption, the amidine series demonstrated generally good oral absorption and strong antithrombotic activity; the single-digit picomolar K(i) achieved from this series is among the best yet reported. The present work highlights the benzamidine compound 11f (LB30812) that exhibits excellent overall profiles of potency, oral absorption and antithrombotic efficacy.

Administration, Oral↗
PubMed1998

Synthesis and kinetic studies of an amidine-containing phosphonofluoridate: a novel potent inhibitor of trypsin-like enzymes.

The amidine-containing alpha-aminoalkyl phosphonofluoridate 3 (Cbz-(4-AmPhGly)P(OPh)(F)) is a very potent inhibitor of trypsin-like enzymes. It was prepared by hydrolyzing the corresponding phosphonate diphenyl ester 4 followed by reaction of fluoride with the phosphonochloridate prepared from the intermediate phosphonic acid monoester 5. Compound 3 is the most potent amidine-containing organophosphorus inhibitor yet reported for trypsin-like enzymes. It inhibits trypsin and thrombin with second-order rate constants (Kobs/[I]) of 2.6 x 10(5) M-1 s-1 and 1.0 x 10(5) M-1 s-1, respectively, showing a 130-fold and a 1250-fold rate enhancement over the corresponding diphenyl ester (4). It also inactivates trypsin 2 orders of magnitude more potently than simple phosphonofluoridates such as DFP,1 Sarin and Soman. The phosphonofluoridate 3 does not inhibit other serine proteases such as porcine pancreatic elastase (PPE) and the esterase acetylcholinesterase (AChE). The phosphonofluoridate 3 is hydrolyzed rapidly in buffer solution and has a t1/2 of 4.5 s at pH 7.5.

Amidines↗
PubMedDate not supplied

Transition from a normal to inverted cylinder for an amidine-bearing lipid/pDNA complex and its excellent transfection.

A cationic lipid (TRX) having an amidine headgroup was synthesized, and a lipoplex (i.e., plasmid DNA+lipid complex) was prepared from the mixture of TRX and two other neutral colipids. Small-angle X-ray scattering showed that the addition of DNA induced a structural transition from normal to inverted hexagonally packed cylinders. Transmission electron microscopy showed a threadlike micelle was transformed to a spherical micelle about 50-200 nm in diameter by adding DNA. A combination of these results leads to the conclusion that the complexed DNA is hexagonally packed (or condensed) into spherical aggregates. The size and morphology are believed suitable for endocytosis uptake or vesicle fusion. The complex made from pDNA (pEGFP-C1) and TRX was transfected to Hep G2. Flow cytometry and confocal microscopy showed that the present system expressed green fluorescence protein (GFP) more than a conventional transfection reagent. Additionally, TRX was less cytotoxic than other transfection reagents. This paper presents the attractive possibility of the amidine group for a transfection device.

Amidines↗
PubMed1980

Preparation of some new neoglycoproteins by amidination of bovine serum albumin using 2-imino-2-methoxyethyl 1-thioglycosides.

The cyanomethyl 1-thioglycosides of beta-D-galactose, 6-O-methyl-beta-D-galactose, alpha-L-arabinose, beta-D-fucose, beta-L-fucose, beta-D-glucose, beta-D-xylose, beta-D-allose, alpha-D-mannose, 2-acetamido-2-deoxy-beta-D-glucose, 2-acetamido-2-deoxy-beta-D-galactose, 2-deoxy-beta-D-glucose, and 3-O-methyl-beta-D-glucose were prepared from the respective pseudothiourea derivatives and chloroacetonitrile. The nitrile function in the aglycon of the cyanomethyl 1-thioglycosides was converted to a methyl imido ester by treatment with sodium methoxide in methanolic solutions, thereby affording the 2-imino-2-methoxyethyl 1-thioglycosides [Lee, Y.C., Stowell, C.P., & Krantz, M.J. (1976) Biochemistry 15, 3956-3963]. The stability of these reagents was investigated. The 2-imino-2-methoxyethyl 1-thioglycosides were then used to attach carbohydrates to bovine serum albumin. Amidination could be accomplished within a few hours in a pH range of 7-10. The extent of amidination could be controlled by varying the ratio of imido ester to protein amino group. These new neoglycoproteins were used to determine stereospecificity of the rabbit hepatic carbohydrate-binding system [Stowell, C.P., Lee, R.T., & Lee, Y.C. (1980) Biochemistry (following paper in this issue)].

Amidines↗
PubMed1991

Synthesis and copper-dependent antimycoplasmal activity of amides and amidines derived from 2-amino-1,10-phenanthroline.

A series of both aliphatic and aromatic amides and aromatic amidines derived from 2-amino-1,10-phenanthroline (3) according to the Topliss scheme were synthesized and subsequently tested for antimycoplasmal potency. Although the compounds themselves showed no activity, in the presence of a nontoxic copper concentration of 40 microM all compounds appeared to be very active against Mycoplasma gallisepticum K154. The most active compounds were found in the amide series and show growth inhibition in the nanomolar range. These compounds are 4 times more active than tylosin, a macrolide antibiotic, which is used therapeutically in veterinary practice. In the presence of copper, amides derived from 3 are more active than corresponding amidines. Increased activity following derivatization of 3 may be due to the presence of a third coordination site for copper in the title compounds. Evaluation of biological data revealed that antimycoplasmal activity of amides derived from 3 is dependent on lipophilicity. For these amides a good linear correlation was found between antimycoplasmal activity and hydrophobic fragmental values for substituents considered. This quantitative structure-activity relationship study indicated that antimycoplasmal activity was increased upon a decrease of these hydrophobic fragmental values.

Amides↗
PubMed1975

Inhibition of phenylalanyl-tRNA synthetase by aromatic guanidines and amidines.

Aromatic guanidines and amidines were investigated for their ability to inhibit phenylalanyl-tRNA synthetase from E. coli B. 2-Phenylacetamidine (1), benzylguanidine (2), and N-benzylbenzamidine (3) are competive inhibitors with respect to phenylalanine, binding nearly as well as the substrate, The remainder of the inhibitors was unexpectedly found to be noncompetitive, indication the presence of a secondary binding site on the enzyme. Inhibition by these compounds appears to be specific for phenylalanyl-tRNA synthetase and requires the presence of a phenyl ring as well as the amidine or guanidine moiety.

Amidines↗
PubMed1988

Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 4. Amidines.

Two different structural types of 2-aryl-1,3,4-thiadiazole amidines were synthesized and evaluated for anticonvulsant activity. Enhancement of the inherent anticonvulsant activity therein and separation of this activity from the accompanying sedative action of these compounds were attempted. The most potent compounds occurred in the 2-(trifluoromethyl)phenyl series of type 3 amidines, but they also possessed a relatively high level of neurotoxicity and sedation as demonstrated in the rotorod test.

Amidines↗
PubMed1998

Bis-cationic heteroaromatics as macrofilaricides: synthesis of bis-amidine and bis-guanylhydrazone derivatives of substituted imidazo[1,2-a]pyridines.

A series of guanylhydrazone, amidine, and hydrazone derivatives of 2-phenylimidazo[1,2-a]pyridine have been prepared and evaluated for macrofilarial activity against Acanthocheilonema viteae and Brugia pahangi in jirds. Compounds with 4',6-bis-substitution by cyclic guanylhydrazone groups show activity. 4',6-Bis-amidines show some activity but are more toxic; 4'- or 6-monosubstituted compounds are inactive. 2,6-Bis-substituted compounds lacking the phenyl ring are inactive. 4',6-Bis-substituted compounds having additional double bonds inserted between the heterocyclic ring and the phenyl ring or between the substituent and the ring system show reduced activity.

Amidines↗