Propyl Analogues Research Articles

Synthesis and Characterization of a Novel Class of Dicopper(I) Bis(carboxylate)-Bridged Complexes

The syntheses, spectroscopic properties, crystal and molecular structures, and bonding of several dicopper(I) bis(carboxylate)-bridged complexes are described in which the bridging dicarboxylate ligand is the dianion of m-xylylenediamine bis(Kemp's triacid imide) (H2XDK, 1). A sterically demanding benzyl derivative of H2XDK was prepared, H2BXDK (6). Reaction of these two ligands as well as the propyl analog, H2PXDK (2), with thallium ethoxide provided dithallium salts Tl2L (L = XDK, 7; PXDK, 8; and BXDK, 9). Reaction of 7, 8, or 9 with excess CuBr(Me2S) in CH2Cl2/MeCN afforded dinuclear acetonitrile adducts [Cu2L(MeCN)] (L = XDK, 10; PXDK, 11; and BXDK, 12) in high yield and multigram quantities. The coordination chemistry of the Cu2(XDK) platform was explored with a range of ancillary ligands. Treatment of 10, 11, or 12 with an excess of the specified neutral donor ligand provided complexes [Cu2(XDK)(PPh3)2] (13), [Cu2(XDK)(2,6-Me2C6H3NC)3] (14a), [Cu2(XDK)(μ-2,6-Me2C6H3NC)(2,6-Me2C6H3NC)2] (14b), [Cu2(X...

Efficacy of 250 mg Trospectomycin Sulfate IM vs. 250 mg Ceftriaxone IM for Treatment of Uncomplicated Gonorrhea

Due to the steadily progressive development of resistance to the drugs used for treatment, Neisseria gonorrhoeae remains a medical concern. Trospectomycin sulfate is a 6' propyl analogue of spectinomycin with potent activity against penicillin sensitive and resistant strains of N. gonorrhoeae. To compare the efficacy of 250 mg trospectomycin sulfate i.m. versus 250 mg ceftriaxone i.m. for single dose therapy for men and women with uncomplicated gonorrhea. Dual-center, randomized comparative trial. Among evaluable male patients with urethral gonorrhea, 36 of 40 (90%, 95% confidence interval [95%CI] 76%-97%) who were treated with trospectomycin sulfate were cured, and 22 of 22 patients (100%, [85%-100%]) treated with ceftriaxone were cured. Among evaluable female patients with cervical gonorrhea all were cured following trospectomycin sulfate (23 of 23) and following ceftriaxone therapy (13 of 13). The cure rates for pharyngeal gonorrhea were 67% (8 of 12 patients, 35%-90%) for trospectomycin sulfate therapy, and 100% (2 of 2) with ceftriaxone therapy. Trospectomycin sulfate, 250 mg i.m., is effective, and well tolerated. However, for treatment of uncomplicated genital and pharyngeal gonorrhea, it is not as reliable for therapy as other recommended regimens.

Infrared Study of Alkyl Isothiocyanates in Carbon Tetrachloride and/or Chloroform Solutions

The νasym.NCS frequencies for alkyl isothiocyanates occur at higher frequency in CHCl3 or CDCl3 solution than in CCl4 solution. The νasym.NCS mode increases in frequency as the mole % CHCl3/CCl4 increases. The νasym.NCS mode for butyl isothiocyanate occurs at an exceptionally high frequency, and this result is explained in terms of the formation of a pseudo-six-membered intramolecularly hydrogen-bonded ring. The νasym.NCS modes for the alkyl isothiocyanates are corrected for Fermi resonance (FR), with the exception of the propyl analog. The propyl analog appears to have three other modes in FR with νasym.NCS, and an equation has not yet been developed to correct for FR in this case. The unperturbed νasym.NCS frequencies for alkyl isothiocyanates decrease in the alkyl order: methyl, butyl, ethyl, and tert-butyl. The decrease in frequency of νasym.NCS in the order methyl, ethyl, and tert-butyl isothiocyanate is attributed to weakening of the N=C=S bonds due to σ electron donation of each alkyl group. In the case of the butyl analog, the σ electron donation is partially compensated for by the postulated existence of a pseudo-six-membered hydrogen-bonded ring.

Muscarinic receptor subtype specificity of (N,N-dialkylamino)alkyl 2-cyclohexyl-2-phenylpropionates: cylexphenes (cyclohexyl-substituted aprophen analogues).

A series of aprophen [(N,N-diethylamino)ethyl 2,2-diphenylpropionate] analogues, called cylexphenes, were synthesized with alterations in (1) the chain length of the amine portion of the ester, (2) the alkyl groups on the amino alcohol, and (3) a cyclohexyl group replacing one of the phenyl rings. The antimuscarinic activities of these analogues were assessed in two pharmacological assays: the inhibition of acetylcholine-induced contraction of guinea pig ileum, and the blocking of carbachol-stimulated release of alpha-amylase from rat pancreatic acinar cells. These two tissues represent the M3(ileum) and M3(pancreas) muscarinic receptor subtypes. In addition, the analogues were also evaluated for their competitive inhibition of the binding of [3H]NMS to selected cell membranes, each containing only one of the m1, M2, m3, or M4 muscarinic receptor subtypes. The m1 and m3 receptors were stably transfected into A9 L cells. The replacement of one phenyl group of aprophen with a cyclohexyl group increased the selectivity of all the analogues for the pancreatic acinar muscarinic receptor subtype over the ileum subtype by more than 10-fold, with the (N,N-dimethylamino)propyl analogue exhibiting the greatest selectivity for the pancreas receptor subtype, over 30-fold. The cylexphenes also showed a decrease in potency in comparison to the parent compound when examined for the binding of [3H]NMS to the M2 subtype. In agreement with the pharmacological data obtained from the pancreas, the (N,N-dimethylamino)propyl cylexphene 3 demonstrated the greatest selectivity for the m3 subtype, and additionally showed a preference for the m1 and M4 receptor subtypes over the M2 receptor subtype in the binding assay. Thus, this compound showed a potent selectivity according to the pharmacological and binding assays between the muscarinic receptor subtypes of the pancreas and ileum. In both the pharmacological and binding assays, the potency of the analogues decreased markedly when the chain length and the bond distance between the carbonyl oxygen and protonated nitrogen were increased beyond three methylene groups. When the structures of these analogues were analyzed using a molecular modeling program, the bond distance between the carbonyl oxygen and protonated nitrogen was deduced to be more important for the antagonist activity than subtype specificity.

The activity in vitro of trospectomycin sulphate (U-63366F) against aminoglycoside-resistant enterococci

Trospectomycin (U-63366F), a 6'-propyl analogue of spectinomycin, was tested against aminoglycoside-resistant enterococci. The MIC90 for Enterococcus faecalis was 4 mg/l and that for E. faecium was 8 mg/l. Trospectomycin alone was not bactericidal for enterococci, with MBC90 4096 mg/l for both E. faecalis and E. faecium. The addition of commercially available polyvalent immunoglobulin decreased significantly both the MICs and the MBCs and the rendered trospectomycin bactericidal for enterococci. Chequerboard titration of a combination of trospectomycin with ampicillin revealed an FIC index of 1.0 for all the isolates tested. Time-kill curves also did not show any enhancement of bactericidal activity of ampicillin when combined with trospectomycin. A combination of ampicillin and gentamicin was synergistic for enterococci under similar experimental conditions. Trospectomycin can be used as a safe alternative to aminoglycosides or beta-lactam antibiotics in enterococcal infection where bactericidal activity is not required, or in the event of serious side effects from these two classes of antibiotics.

Tissue fluid penetration and anti-treponemal activity of trospectomycin (a new spectinomycin analog) in the rabbit syphilis model.

The antitreponemal activity of trospectomycin (a novel 6'-propyl analog of spectinomycin) was correlated with concentrations in serum and tissue chamber fluid in a cutaneously-infected rabbit model of syphilis. After single-dose intramuscular (im) injections of trospectomycin, spectinomycin hydrochloride, and aqueous procaine penicillin G(APPG), concentrations of the drugs in paired specimens of serum and tissue fluid were determined and correlated with response of Treponema pallidum-infected lesions. Lesions responded most rapidly in APPG-treated animals. Rapid response correlated with more prolonged levels of APPG in both serum and tissue fluid. Trospectomycin, when given in single doses exceeding 40 mg/kg, surpassed penicillin in peak serum levels (greater than 60 micrograms/ml at 1 hr) but not in duration of activity. Higher and prolonged concentrations of trospectomycin in tissue fluid correlated with more effective clearance of treponemes from cutaneous lesions. Animals treated with less than 40 mg of trospectomycin/kg or with 20-80 mg/kg of the parent compound (spectinomycin hydrochloride) had cutaneous lesions that were persistently darkfield-positive, as confirmed by three or more consecutive smears.

Pancreatic carboxypeptidase hydrolysis of bile acid-amino acid conjugates: Selective resistance of glycine and taurine amidates

To find a possible explanation for the selective hepatic conjugation of bile acids with glycine or taurine, the N-acyl amidates of cholic acid and a number of amino acids and amino acid analogues were synthesized, and their susceptibility to hydrolysis by pancreatic juice, gastric juice, serum, or small intestinal mucosal enzymes was measured. Deconjugation by pure carboxypeptidase A and B was also examined, and hydrolysis by these tissue fluids and enzymes was compared with that mediated by a bacterial cholylglycine hydrolase. Human pancreatic juice efficiently hydrolyzed cholyl conjugates of all neutral-l-amino acids (cholyl-l-alanine, cholyl-l-valine, cholyl-l-leucine, and cholyl-l-tyrosine), except cholylglycine. The net hourly rate of hydrolysis (in micromales per milligram protein per hour) increased when the terminal residue was aromatic or branched aliphatic, and appeared to be specific for l-α-amino acids as cholyl-β-alanine and cholyl-d-valine were not cleaved. From cholyl glycylglycine, only the terminal glycine was efficiently removed. Cholyltaurine and cholyl conjugates with the methyl and propyl analogues of taurine were resistant to hydrolysis. Two basic amino acid conjugates (cholyl-l-lysine and cholyl-l-arginine) were cleaved, whereas conjugates of acidic amino acids (cholyl-aspartate and cholyl-cysteate) were not cleaved. Studies using pure enzymes showed that bovine carboxypeptidase A hydrolyzed the cholyl conjugates of the neutral l-α-amino acids with similar specificity as observed for the human pancreatic juice, whereas bovine carboxypeptidase B cleaved the basic amino acid conjugates. Cholyl-l-lysine and cholyl-l-arginine were also cleaved by serum and plasma, which are known to possess carboxypeptidase activity. Cholyl conjugates were not cleaved by gastric juice, by trypsin, or by homogenates of rat small intestinal mucosa. In contrast, all cholyl conjugates were cleaved by a bacterial cholylglycine hydrolase. These experiments indicate that glycine and taurine amidates of cholic acid differ from a number of other conjugates with neutral and basic amino acid in being resistant to hydrolysis by pancreatic and plasma carboxypeptidases. These data, together with other data indicating that bile acid conjugation greatly decreases passive intestinal absorption, indicate that a physiologic function of bile acid conjugation with glycine or taurine is to form surfactants that remain indigestible and rather nonabsorbable during digestion in the proximal small intestine.

Production and characterization of specific antibody for radioimmunoassay of procainamide

The production and characterization of a specific antibody for use in the radioimmunoassay of procainamide are described. Cross-reactivity was measured by a nonequilibrium competitive procedure. Procainamide analog concentrations resulting in 50% inhibition were: procainamide, 1.59nmoles/ml; N-acetylprocainamide, 3.55nmoles/ml; a propyl analog of procainamide, 398nmoles/ml; procaine, 316nmoles/ml; lidocaine, >8000nmoles/ml; and practolol, > 16,000nmoles/ml. Variations in the ability to inhibit binding of labeled procainamide were related to structural similarities and differences. The affinity constant of the antibody for procainamide was 2.9 × 108 liters/mole as measured from a Scatchard plot. The assay allows the direct measurement of procainamide in a 0.1-ml aliquot of diluted serum. The advantages of this method over currently available techniques are its sensitivity, specificity, and simplicity. Furthermore, prior extraction of serum samples is not required. As little as 1ng of drug/ml of serum can be detected by this method. The accuracy and precision were determined by adding known amounts of procainamide to human serum and then assaying five replicates of each concentration. The within-day and between-day coefficients of variation were 2 and 5%, respectively. The proposed method was used to determine the serum concentration after an intravenous dose of procainamide. A comparison of the radioimmunoassay results with values obtained by a GLC procedure showed excellent agreement.

Dimerization of coralyne and its propyl analogue and their association with DNA.

Dimerization of coralyne, Ia, and its propyl analogue Ic has been analyzed at neutral pH as a function of ionic strength. Even at low ionic strength (I = 0.02) dimerization constants (molar units) for both compounds are 10(5) or greater, which is considerably larger than values obtained for similar intercalating molecules. Coralyne seems to undergo association to higher aggregates somewhat easier than Ic, which could be due to the fact that the propyl group on Ic provides some steric hinderance in forming higher aggregates. Both compounds readily associate with DNA. At high ratios of ligand to DNA, the spectra for Ia or Ic are similar to that of a highly aggregated complex. At low ratios of ligand to DNA, the spectra for both compounds approach a limit, which is relatively independent of ionic strength and concentration, and can be identified with the intercalated species. The slight differences between Ia and Ic in dimerization or in association with DNA do not seem capable of explaining the significant differences in antileukemic activity of these compounds.

Reduction of α-ω dibromoalkanes on aluminium and mercury cathodes

1,3-Dibromopropane and 1,4-dibromobutane have each been reduced from non-aqueous solutions of quaternary ammonium salts on cathodes of mercury and aluminium. Product analysis and kinetic measurements have shown that reduction on mercury proceeds through adsorbed radicals whereas on aluminium products are explained in terms of free radical reactions initiated by solvated electrons. Products on mercury include solid organomercury polymer and dibutylmercury from dibromobutane and by contrast cyclopropane and propane from dibromopropane. The difference is explained in terms of the kinetic facility of formation of cyclopropane and the greater stability of the adsorbed butyl diradical relative to its propyl analogue. Products on aluminium cathodes include higher bromides and dibromides.

Reduction of α-ω dibromoalkanes on aluminium and mercury cathodes

Summary 1,3-Dibromopropane and 1,4-dibromobutane have each been reduced from non-aqueous solutions of quaternary ammonium salts on cathodes of mercury and aluminium. Product analysis and kinetic measurements have shown that reduction on mercury proceeds through adsorbed radicals whereas on aluminium products are explained in terms of free radical reactions initiated by solvated electrons. Products on mercury include solid organomercury polymer and dibutylmercury from dibromobutane and by contrast cyclopropane and propane from dibromopropane. The difference is explained in terms of the kinetic facility of formation of cyclopropane and the greater stability of the adsorbed butyl diradical relative to its propyl analogue. Products on aluminium cathodes include higher bromides and dibromides.

Identification of cannabivarins in hashish by a new method of combined gas chromatography-mass-spectrometry.

Abstract The cannabis constituents cannabidiol, tetrahydrocannabinol and cannabinol in hashish are accompanied by the propyl analogues cannabidivarin, tetrahydrocannabivarin and cannabivarin. A new method was developed to identify these compounds by means of the combined gas chromatograph-mass spectrometer.