Nitro Analogue Research Articles

Calculated structures and heats of formation of some predicted C, N, O, F molecules

Twelve molecules containing only C, N, O, and F, which are of interest in the context of energetic materials, were found to have true local energy minima at the HF/6-31G* computational level. Both HF/6-31G* and MP2/6-31G* geometries are presented. A density functional procedure was used to find gas phase heats of formation. These are strongly positive for most of the molecules. The nitroso group significantly increases δH o f.25‡C compared to the nitro analogue.

Thermal decomposition of ?-(difluoroamino)polynitroalkanes

The compounds RC(NO2)2NF2 differ little from their nitro analogs, RC(NO2)3, in stability. They decompose in the gas and liquid phases at identical rates and the decomposition is controlled by cleavage of a C-NO2 bond. For R=NO2, F, and Me the Arrhenius parameters, E (kJ mol−1) and log (A/s), are: 161.3 and 16.00; 180.2 and 16.20; 168.4 and 16.00, respectively.

A nitro analogue of staurosporine and other minor metabolites produced by a Streptomyces longisporoflavus strain.

From the staurosporine-producing strain Streptomyces longisporoflavus R-19 various minor metabolites were isolated: They include a new compound with a nitro function in C-4' and other metabolites related to staurosporine. The new structures were elucidated by spectroscopic methods, mainly 1H NMR and 13C NMR and by comparison with TAN-1030A. The new compounds inhibited protein kinase C with IC50 values in the nanomolar range.

Some Fluoro and Nitro Analogues of Hallucinogenic Amphetamines

Abstract The preparation of the fluoro and nitro analogues (2)-(5) of the hallucinogens 2,4,5-trimethoxy- and 2-methoxy-4,5-methylenedioxy-amphetamine is described.

Pharmacological evaluation of iodo and nitro analogs of Δ8-THC and Δ9-THC

One aspect of cannabinoid structure-activity relationships (SARs) that has not been thoroughly investigated is the aromatic (A) ring. Although halogenation of the side chain enhances potency, our recent observation that iodination of the A ring also enhanced activity was surprising. The purpose of this investigation was to establish the steric and electrostatic requirements at these sites of the cannabinoid molecule via molecular modeling, while determining pharmacological activity. Molecular modeling was performed using the Tripos molecular mechanics force field and the semiempirical quantum mechanical package AM1. The K i values for novel cannabinoids were determined in a [ 3H]CP-55,940 binding assay and ED 50 values generated from four different evaluations in a mouse model. The present studies underscore the increase in potency produced by a dimethylheptyl (DMH) side chain. Trifluoro substitutions on the pentyl side chain, or bromination of the DMH side chain, had little effect on the pharmacological activity. Any substitution at the C4 position of the aryl ring resulted in a loss of activity, which appears to be due to steric hindrances. Nitro, but not iodo, substitution at the C2 position essentially produces an inactive analog, and the drastic alteration of the electrostatic potential appears to be responsible. The altered pharmacological profile of the 2-iodo analog seems to be related to an alteration in the highest occupied molecular orbital because there is no alteration in the electron density map compared to Δ 8-tetrahydrocannibinol.

Probing the Mechanism of Staphylococcal Nuclease with Unnatural Amino Acids: Kinetic and Structural Studies

Staphylococcal nuclease is an enzyme with enormous catalytic power, accelerating phosphodiester bond hydrolysis by a factor of 10(16) over the spontaneous rate. The mechanistic basis for this rate acceleration was investigated by substitution of the active site residues Glu43, Arg35, and Arg87 with unnatural amino acid analogs. Two Glu43 mutants, one containing the nitro analog of glutamate and the other containing homoglutamate, retained high catalytic activity at pH 9.9, but were less active than the wild-type enzyme at lower pH values. The x-ray crystal structure of the homoglutamate mutant revealed that the carboxylate side chain of this residue occupies a position and orientation similar to that of Glu43 in the wild-type enzyme. The increase in steric bulk is accommodated by a backbone shift and altered torsion angles. The nitro and the homoglutamate mutants display similar pH versus rate profiles, which differ from that of the wild-type enzyme. Taken together, these studies suggest that Glu43 may not act as a general base, as previously thought, but may play a more complex structural role during catalysis.

Structural requirements of some sulphonamides that possess an antifertility activity in male rats

Sulphonamides with different chemical structures were synthesized and these 13 compounds together with 7 commercially available sulpha drugs were tested for antifertility activity by natural mating in male rats. All compounds were given daily by gastric intubation at doses of 125, 150, 250 or 450 mg/kg for 6 weeks. Sulphapyridine caused a dose-related and reversible reduction in fertility at doses between 125 and 450 mg/kg. At the high dose, fertility was reduced to 25.9% of control at 5 weeks after treatment, and complete recovery occurred by 3 weeks after drug withdrawal. This activity was abolished when the pyridine ring was substituted by other heterocyclic rings, except sulphachloropyridazine which had only weak activity. Replacement of the pyridine ring by a hydrogen atom or short aliphatic chains preserved or even enhanced the potency. Thus, sulphanilamide, N1-methylsulphanilamide or N1-diethylsulphanilamide produced a marked but reversible reduction in fertility. Removal or substitution of the N4-amino group on the benzene ring of sulphapyridine with a methyl group destroyed the activity. However, the bromo or nitro analogue (at the para- but not the meta-position of the benzene ring) still possessed some activity. N4-Acetyl derivatives of sulphapyridine, sulphanilamide, and N1-diethylsulphanilamide were as potent as their parent compounds. These results suggest that the presence of pyridine or other heterocyclic rings is not necessary for the antifertility activity of sulphonamide compounds. However, the N4-amino group is indispensable. In addition, acetylation of this amino group does not change the potency. The prototype of the antifertility sulphonamides therefore seems to be sulphanilamide.

1,4-Bis(arylamino)-5-nitro-(and 5-amino-)-8-hydroxyanthraquinones: bluish-green dyes for synthetic polymer fibres

Condensation of 4-arylamino-5-nitro-1,8-dihydroxyanthraquinone with arylamines in presence of boric acid affords 1,4-bis( arylamino )-5-nitro-8-hydroxyanthraquinones. These compounds colour polyester fibres in deep blue-green hues of good fastness to light and sublimation. On reduction they yield the corresponding 5-amino derivatives, which can be alkylated to the 5-alkylamino derivatives, the amino compounds dyeing polyesters in much greener hues than the nitro analogues. The 5-nitro derivatives also result from condensation of 4,5-dinitro-1,8-dihydroxyanthraquinone with arylamines, although with more reactive arylamines the formation of 1,4,5-tris (arylamino)-8-hydroxyanthraquinones also occurs as major by-product. The tris( arylamino ) derivatives are more readily obtained by condensation of 4,5-bis( arylamino )-1,8-dihydroxyanthraquinones with arylamines. Structure-colour relationships in the dyes are discussed.

Formation of amphetamine from its nitro analogue by anaerobic intestinal bacteria

1. Microbial reduction of 1-phenyl-2-nitropropane 1 was carried out using 40 strains of intestinal anaerobic bacteria. Among them, 12 strains (Mitsuokella multiacidus, Clostridium perfringens, C. innocuum, C. clostiriiforme, C. difficile, C. butyricum, C. sp., Eubacterium limosum, E. aerofaciens, E. multiforme, Peptostreptococcus anaerobius and P. productus) had the ability to reduce 1 to amphetamine 2 (0.1-1% yield). 2. Clostridium species were more active than another intestinal anaerobic bacteria. 3. When Clostridium perfringens was used in preparative fermentation, the yield of 2 was increased, and its absolute structure had an (S)-configuration with an optical purity of 68% in enantiomeric excess.

Synthesis of two nitro analogs of tranylcypromine: Relations of aromatic substitution of nitro groups to MAO-Inhibitory activity

Two new nitro analogs of tranylcypromine, (E)-2-(p-nitrophenyl)cyclopropylamine ((E)-p-NTCP) and (E)-2-(m-nitrophenyl)cyclopropylamine ((E)-m-NTCP) were synthesized in order to examine the effect of aromatic nitro substitution on the MAO-inhibitory activity of 2-phenylcyclopropylamines. The compounds were obtained by treatingt-butyl (E)-2-(p-nitrophenyl) cyclopropanecarbamate andt-butyl (E)-2-(m-nitrophenyl)cyclopropanecarbamate withp-toluenesulfonic acid in CH3CN. Inhibitions of rat brain mitochondrial MAO-A and B by the compounds were examined using serotonin and benzylamine as the substrate at bothin vitro andex vivo levels. It was found fromin vitro measurements that(E)-p-NTCP at 6.0×10−5M elicited merely 22.5% inhibition against MAO-B without any effect on MAO-A. In contrast,(E)-m-NTCP showed fair degrees of inhibitions of MAO-A and B with IC50 values, 2.5×10−7M and 1.4×10−6M, respectively. It was also noted from(E)-m-NTCP thatm-nitro substitution caused a shift of selectivity of the inhibition toward MAO-A. According toex vivo measurements at 1.5, 3, 6, and 12 hr following the administration of a dose of 0.015 mmol/kg, i.p. to the rats, the inhibition percents of MAO-A by(E)-m-NTCP were 58.6, 63.7 63.6, and 46.6%, slightly lower than those observed by tranylcypromine. Whereas,(E)-p-NTCP at the same dose level did not show significant inhibitions against both MAO-A and MAO-B. Possible reasons for the difference in potencies between(E)-m-NTCP and(E)-p-NTCP were sought in relation to differing electron withdrawing effects ofm-andp-substituents which will influence electron density of the side chain amino functions and the partitions.

Mode of substrate carboxyl binding to the [4Fe-4S]+ cluster of reduced aconitase as studied by 17O and 13C electron-nuclear double resonance spectroscopy.

The active form of aconitase has a diamagnetic [4Fe-4S]2+ cluster. A specific iron ion (Fea, which is lost during inactivation) is the binding site for substrate, as shown by Mössbauer spectroscopy. We have studied the mode of substrate and analogue binding at equilibrium to the paramagnetic [4Fe-4S]+ cluster of the reduced active form by 17O and 13C electron-nuclear double resonance spectroscopy with specifically labeled substrates. The data show that with substrate, only the carboxyl at C-2 of the propane backbone is strongly bound in addition to H2O or OH- (HxO) from the solvent, whereas in an isocitrate analogue that has a nitro group at C-2, the carboxyl and hydroxyl at C-1 are bound along with solvent HxO. We conclude from these data that, on addition of any one of the three substrates, cis-aconitate is the predominant species bound to Fea of the cluster along with solvent HxO and that cis-aconitate is bound in the citrate mode (carboxyl at C-2). The results with the nitro analogue show that the enzyme can also bind a substrate-like ligand to the cluster in the alternative isocitrate mode (carboxyl at C-1), as is implicit in models proposed for the aconitase reaction.

19F and 1H NMR study of five-membered ring triflones and related σ -adducts. Long range fluorine-proton spin spin coupling.

Fluorine and proton chemical shifts for various trifluoromethylsulfonyl thiophene, selenophene, furan and N-methylpyrrole derivatives are reported and compared with those for nitro analogs. The 19F chemical shift of the SO 2CF 3group is found to be insensitive to its ring position as well as to the nature of the heterocycle. It is also unaffected by the loss of aromaticity and the presence of a negative charge which result from a nucleophilic addition to the ring. In most triflones studied, long range fluorine-proton coupling constants are observed but the proton involved in these couplings depends upon the α or β position of the SO 2CF 3 group as well as the nature of the ring heteroatom.

Isotope effects and mechanism in the base-promoted dehydrochlorination of 1,1-dichloro-2,2-diarylethanes-1- 14C

In the base-promoted dehydrochlorination of 1,1-dichloro-2,2-diphenylethane-1- 14C and its p -nitro analog, the isotope effects, k/ 14k, are 1.045 and 1.024, respectively. These results support an Elcb-like E2 mechanism for both elimination reactions.

Bromination of sydnones. II Bromination of 3‐(2‐aminophenyl)sydnone and related compounds

AbstractBromination of 3‐(2‐aminophenyl)sydnone 2 under a variety of conditions is reported. The products obtained are interrelated by a series of subsequent reactions. One major product is the bromoaryl compound 8, the first example of bromination on the aryl rather than sydnone ring when the two are in competition. Surprisingly, bromoaminosydnone 9, prepared from its nitro analogue, was not among the products obtained by direct bromination of 2.

Bifunctional nitrofluorenes: structure-activity relationships in Salmonella typhimurium

Bifunctional derivatives of fluorene have long been the subject of intense study for their carcinogenic activity in animal systems (reviewed by Arcos and Argus, 1974). In vivo studies typically used the amine derivatives of fluorene and relied on the endogenous metabolic pathways of the test system to activate the chemical to its ultimate carcinogenic form. It is now possible to use shortterm bioassays, e.g. the Ames test (Ames et al., 1975), to investigate the mutagenic activity of many of the fluorene derivatives. Since Salmonella are quite sensitive to many nitroaromatics, it is also possible to study the nitro analogues of the carcinogenic and noncarcinogenic fluorene compounds. The commonality between a nitroand amino-aromatic is that the proximate mutagenic/ carcinogenic form for both is most probably the hydroxylamine derivative. A particular advantage in using the Ames Salmonella is the availability of nitroreductase-deficient strains, developed by H.S. Rosenkranz and his colleagues (Rosenkranz and Speck, 1976), that are otherwise isogenic with the standard tester strains. By combining a microsomal enzyme activating system ($9) with the TA98NR assay, one can test the effect of a nitro group on an aminofluorene and, conversely, the effect of an amino group on a nitrofluorene in TA98 without $9. This principle can be extended to testing the effect of other functional groups

Effect of a tetrapeptidamide nitro analog and of morphine on the cerebral circulation

Effect of a tetrapeptidamide nitro analog and of morphine on the cerebral circulation

Nitro analogs of substrates for argininosuccinate synthetase and argininosuccinate lyase

The nitro analogs of aspartate and argininosuccinate were synthesized and tested as substrates and inhibitors of argininosuccinate synthetase and argininosuccinate lyase, respectively. The V max for 3-nitro-2-aminopropionic acid was found to be 60% of the maximal rate of aspartate utilization in the reaction catalyzed by argininosuccinate synthetase. Only the nitronate form of this substrate, in which the C-3 hydrogen is ionized, was substrate active, indicating a requirement for a negatively charged group at the β carbon. The V K of the nitro analog of aspartate was 85% of the value of aspartate after correcting for the percentage of the active nitronate species. The nitro analog of argininosuccinate, N 3-( l-1-carboxy-2-nitroethyl)- l-arginine, was a strong competitive inhibitor of argininosuccinate lyase but was not a substrate. The pH dependence of the observed p K i was consistent with the ionized carbon acid (p K = 8.2) in the nitronate configuration as the inhibitory material. The pH-independent p K i of 2.7 μ m is 20 times smaller than the K m of argininosuccinate at pH 7.5. These results suggest that the tighter binding of the nitro analog relative to the substrate is due to the similarity in structure to a carbanionic intermediate in the reaction pathway.

Reactions with 1,8-naphthosultam. Synthesis of [1,2]benzisothiazolo[2,3,4-cde]benzotriazole 4,4-dioxide. A new ring system

1,8-Naphthosultam (I) coupled with arenediazonium salts to give the 4-arylazo- VII, and the 2,4-bisarylazo-1,8-naphthosultams, VIa-c. On the other hand, coupling of the 4-substituted 1,8-naphthosultams afforded the 2-phenylazo derivatives, IIa,b. Reduction of IIa,b gave the 2-amino compounds IVa,b, which reacted with nitrous acid to give the [1,2]benzisothiazolo[2,3,4-cde]benzotriazoles, Va,b, establishing thus a new ring system. The nitro analogue Vc was also synthesized.

Comparison in animal models of 18F-spiroperidol and 18F-haloperidol: Potential agents for imaging the dopamine receptor

Fluorine-18-labeled haloperidol and spiroperidol have been prepared by an exchange reaction using the corresponding non-labeled compound or the nitro analog. Studies in rats have shown that the distribution of labeled spiroperidol has a high striatum to cerebellum ratio which is not observed with haloperidol. A ratio of 10.66 ± 1.6 is obtained two hours after administration of the 18F-spiroperidol. When 18F-spiroperidol was administered to a baboon and tomographic images obtained, the dopamine receptor rich areas were clearly visualized two hours after administration.

Nitro analogs of substrates for adenylosuccinate synthetase and adenylosuccinate lyase

The reactivities of the nitro analogs of the substrates of adenylosuccinate synthetase and adenylosuccinate lyase, the enzymes which catalyze the penultimate and last step, respectively, in the pathway for AMP biosynthesis have been examined. Alanine-3-nitronate, an aspartate analog, was a substrate for the synthetase from Azotobacter vinelandii, having a k cat K m which was ~30% that for aspartate. The product of this reaction was N 6 -( l-1-carboxy-2-nitroethyl)-AMP. Of nine other substrate analogs tested, only cysteine sulfinate (having 5.5% of the activity of aspartate) was reactive. These results demonstrate the strict requirement of the synthetase for a negatively charged substituent, with a carboxylate-like geometry, at the β-carbon of the α-amino acid substrate. The lyase, purified to homogeneity from brewer's yeast by a new procedure, did not utilize N 6-( l-1-carboxy-2-nitroethyl)-AMP as a substrate. However, the nitronate form of this analog was a good inhibitor of the lyase ( K m K i = 28 when compared to adenylosuccinate), suggesting that it mimics a carbanionic intermediate in the reaction pathway. The avid binding of bromphenol blue by the lyase ( i = 0.95 μM) was used for active site titrations and for displacement of the enzyme, in the purification protocol, from blue Sepharose.