N-substituted Benzamides Research Articles

One-pot synthesis of 2,4-benzodiazepin-1-ones using benzotriazole methodology.

2, 4-Benzodiazepin-1-ones were prepared in moderate to good yields by reaction of bis(benzotriazolylmethyl)amines with ortho-metalated N-substituted benzamides.

Mechanism of action for N-substituted benzamide-induced apoptosis.

We have analysed the mechanism of action for induction of apoptosis by N-substituted benzamides using declopramide as a lead compound. We show here that declopramide at doses above 250 μM in the mouse 70Z/3 pre-B cell line or in the human promyeolocytic cancer cell line HL60 induced cytochrome c release into the cytosol and caspase-9 activation. The broad spectrum caspase inhibitor zVADfmk and caspase-9 inhibitor zLEDHfmk inhibited apoptosis and improved cell viability when administrated to cells 1 h before exposure to declopramide, whereas the caspase-8 inhibitor zIEDHfmk had less effect. Also, the over expression of Bcl-2 by transfection in 70Z/3 cells inhibited declopramide-induced apoptosis. Prior to the induction of apoptosis, a G2/M cell cycle block was induced by declopramide. The cell cycle block was also observed in the presence of broad spectrum caspase inhibitor zVADfmk and in a transfectant expressing high levels of Bcl-2. Furthermore, while p53 was induced in 70Z/3 cells by declopramide, neither the apoptotic mechanism nor the G2/M cell cycle block were dependent on p53 activation since both effects were also seen in p53 deficient HL60 cells after addition of declopramide.British Journal of Cancer (2002) 86, 971–978. DOI: 10.1038/sj/bjc/6600136 www.bjcancer.com© 2002 Cancer Research UK

N-substituted benzamides inhibit nuclear factor-κB and nuclear factor of activated T cells activity while inducing activator protein 1 activity in T lymphocytes

N-substituted benzamides are compounds that have recently been reported to inhibit nuclear factor-κB (NF-κB) activity and induce apoptosis in a pre-B cell line. In this study, we focused on the effects of N-substituted benzamides on transcriptional regulation in Jurkat T cells. We used a model system where the cells can be stimulated either through TCR/CD28 or by treatment of the cells with PMA and ionomycin to induce transcription factors typical for T lymphocyte activation. Treatment of the Jurkat cells with procainamide did not influence the transcription factor profile of stimulated cells, while treatment with a derivative having an acetyl group in position 4 of the aromatic ring inhibited NF-κB and nuclear factor of activated T cells (NFAT) activity. Declopramide, which contains a chloride in position 3 of the aromatic ring, was inactive in this system, whereas also the acetylated derivative of this compound inhibited NF-κB and NFAT activity. In contrast, the transcriptional activity and nuclear expression of activator protein 1 induced by TCR/CD28 stimulation or PMA and ionomycin treatment was enhanced by the acetylated variants of the N-substituted benzamides. Finally, we investigated the effect of N-substituted benzamides on intact promoters for two genes central in immune regulation; the CD40 ligand (CD40L) and IL-2 promoters. The transcriptional activity of the CD40L promoter as well as surface expression of the CD40L induced by signaling through TCR/CD28 was inhibited by addition of acetylated N-substituted benzamides, while the transcriptional activity of the IL-2 promoter was enhanced. Taken together, these data indicate that derivatives of N-substituted benzamides are potential drug candidates for quantitative as well as qualitative modulation of immune functions.

N-substituted benzamides inhibit NFkappaB activation and induce apoptosis by separate mechanisms.

Benzamides have been in clinical use for many years in treatment against various disorders. A recent application is that as a sensitizer for radio- or chemotherapies. We have here analysed the mechanism of action of N-substituted benzamides using an in vitro system. We found that while procainamide was biologically inert in our system, the addition of a chloride in the 3′ position of the benzamide ring created a compound (declopramide) that induced rapid apoptosis. Furthermore, declopramide also inhibited NFκB activation by inhibition of IκBβ breakdown. An acetylated variant of declopramide, N-acetyl declopramide, showed no effect with regard to rapid apoptosis induction but was a potent inhibitor of NFκB activation. In fact, the addition of an acetyl group to procainamide in the 4′ position was sufficient to convert this biologically inactive substance to a potent inhibitor of NFκB activation. These findings suggest two potential mechanisms, induction of early apoptosis and inhibition of NFκB mediated salvage from apoptosis, for the biological effect of N-substituted benzamides as radio- and chemo-sensitizers. In addition it suggests that N-substituted benzamides are potential candidates for the development of anti-inflammatory compounds using NFκB as a drug target. © 1999 Cancer Research Campaign

Newly discovered anti-inflammatory properties of the benzamides and nicotinamides.

Our laboratory has concentrated on the possible regulation the benzamides and nicotinamides may have on the processes of DNA repair and apoptosis. Recent reports have suggested that both apoptosis and inflammation are regulated by the transcription factor NF-kappaB. We have initiated studies regarding the hypothesis that the benzamides and nicotinamides could inhibit the production of tumor necrosis factor alpha (TNFalpha) and the inflammatory response as well as induce apoptosis via inhibition of NF-kappaB. Our data have shown that nicotinamide and two N-substituted benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave dose dependent inhibition of lipopolysacharide induced TNFalpha in the mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was prevented in the rat by 3 x 50 mg/kg doses of 3-CPA or MCA, and 100-200 microM doses of MCA could also inhibit NF-kappaB in Hela cells. Taken together these data strongly support the notion that benzamides and nicotinamides have potent anti-inflammatory and antitumor properties, because their primary mechanism of action is regulated by inhibition at the gene transcription level of NF-kappaB, which in turn inhibits TNFalpha and induces apoptosis.

Determination of seven biogenic amines in foods by micellar electrokinetic capillary chromatography

Micellar electrokinetic capillary chromatography was applied to the separation of seven biogenic amines, most frequently occurring in foods. Putrescine, cadaverine, spermidine, spermine, tryptamine, histamine and tyramine were separated as N-substituted benzamides using an uncoated fused-silica capillary column (43 cm×75 μm I.D.). Borate buffer (15 m M) with sodium dodecylsulphate (40 m M) and methanol (25%, v/v) was found to be a suitable system for the determination of these compounds in food samples. The detection limits in the range of 0.2 to 0.7 mg l −1 are sufficient for this type of sample.

264Apoptosis in HL-60 cells as a model for determining sensitization of radio- and chemotherapies by N-substituted benzamides

264Apoptosis in HL-60 cells as a model for determining sensitization of radio- and chemotherapies by N-substituted benzamides

778A comparison of antitumor activities of three N-substituted benzamides: Sensamide, neu-sensamide and 3-chloroprocainamide

778A comparison of antitumor activities of three N-substituted benzamides: Sensamide, neu-sensamide and 3-chloroprocainamide

Progress in identifying clinical relevance of inhibition, stimulation and measurements of poly ADP-ribosylation

Our laboratory, in collaboration with Oxigene Inc, has been involved in identifying commercially feasible clinical applications of measurement or modulation of ADP-ribosylation as a core technology. For this purpose a pivotal regulatory role for ADP-ribosylation in the repair of DNA lesions leading to cytotoxic as well as mutagenic events has been hypothesized. A new class of DNA repair inhibitors, the N-substituted benzamides, has been identified which can react with radiation to produce reactive intermediates that oxidize thiol amino acids. Their proposed mechanisms of action are two-fold: ie they can interact with radiation: i) to directly enhance DNA damage; and ii) to react with thiols in the zinc finger DNA binding domain of poly ADP-ribosyl transferase to inhibit DNA repair and thereby increase DNA damage. Sensamide, a clinically relevant formulation of metoclopramide which is an N-substituted benzamide, has indicated enhancement of tumor response and survival in patients with inoperable squamous cell carcinoma of the lung when it was administered as a radiosensitizer in a phase I/II trial and compared to historical controls. A mechanism of endogenous regulation of human mononuclear leucocyte ADP-ribosylation has been identified to be HOCl/N-chloramine production via the oxidative burst of phagocytes. HOCl/N-chloramines are potent oxidants of thiol-containing proteins. Quantitative estimation of N-chloramine sensitive plasma thiols has been identified as an effective surrogate measure of leucocyte poly ADPRT. Dietary factors and other chemical agents such as tamoxifen that can inhibit HOCl/N-chloramine production by phagocytes are being identified as drugs that can enhance ADP-ribosylation, and thus prevent DNA damage accumulation which in turn is thought to influence the development of age associated diseases.

Novel 5α-reductase inhibitors. Synthesis and structure-activity studies of 5-substituted 1-methyl-2-pyridones and 1-methyl-2-piperidones

In search for nonsteroidal inhibitors of 5α-reductase for the treatment of benign prostatic hyperplasia (BPH) and possibly prostate cancer, substrate mimicks were synthesized comprising of a 1-methyl-2-pyridone ( 2, 4–16) or 1-methyl-2-piperidone ( 1, 3, 17–22) moiety (mimicking steroidal ring A) and a diisopropyl ( 1, 2, (E)-5- (E)-7, (Z)-5- (Z)-7, 11–13, 17–19) or a tert-butyl ( 3, 4, (E)-8- (E)-10, (Z)-8- (Z)-10, 14–16, 20–22) benzamide (mimicking steroidal ring D). The bridge connecting the 5 and 4 positions of the rings consisted of amide (CONH: 1–4), ethenyl (CHCH, CCH 3CH, CHCH 3: (E)-5- (E)-10, (Z)-5- (Z)-10) or ethylene groups (CH 2CH 2, CHCH 3CH 2, CH 2CHCH 3: 11–22). The amides 1–4 were obtained by amidation of the carboxylic acid chlorides with the 4-amino- N-substituted benzamides. The ethenyl compounds (E)-5- (E)-10 and (Z)-5- (Z)-10 were synthesized by Wittig reaction of the carbonyl compounds and the corresponding triphenylphosphonium salts and subsequent separation of the stereoisomers. Depending on the time of reaction, catalytic hydrogenation of the ethenyl isomers (E)-5- (E)-10 led to the pyridone-substituted ethylene compounds 11–16 as well as to the piperidone-substituted ethylene compounds 17–22. The 5α-reductase inhibitory properties were determined using rat ventral prostate, as well as human BPH and prostate cancer as source, 1β,2β-[ 3H]testosterone as substrate and a HPLC procedure for the separation of dihydrotestosterone (DHT). Tested at a concentration of 100 μM, the inhibition values of 1–22 ranged from 0–99%. Significant differences were observed between rat and human enzyme. The most active compound was N,N-diisopropyl-4-[2-(1-methyl-2-oxo-piperidine-5-yl)ethylene]benzamide 17 (IC 50: 13 μM).

Ortho-Aryloxylation of N-substituted benzamides: a new oxidizing process induced by the copper(II)/trimethylamine N-oxide system

The oxidation of N-(2-hydroxy-4-nitrophenyl)benzamide 1 by the CuII/trimethylamine N-oxide couple has been studied. Under experimental conditions where the concentration quotient, α=[1]/[Cu], of starting benzamide to copper is maintained as low as possible, the benzamide is ortho-hydroxylated into the corresponding salicylamide with 88% yield of isolated product. On the other hand, when α is kept as high as possible, a new oxidation process leads to an oxidative cascade: the benzamide is ortho-aryloxylated by the phenolic group of a second molecule of itself to afford a 2-aryloxy-N-(2-hydroxy-4-nitrophenyl)benzamide, which in turn can undergo another ortho-aryloxylation. In intermediate conditions both processes are in competition, thus providing composite compounds such as a 6-aryloxy-2-hydroxy-N-(2-hydroxy-4-nitrophenyl)benzamide. Transitory formation of, respectively, CuIII-OH and CuIII-OAr complexes is suggested to be responsible for these ortho-selective oxidizing processes. Finally, these results show that the 2-(N-amido)-5-nitrophenol group (which is the copper ligand) is a good mediator for the oxidation of a covalently linked aromatic nucleus by the CuII/TMAO system.

Carbon–carbon bond formation by intramolecular 1,4-dipolar cycloaddition: heterocyclic betaines generated in situ from amides and N-substituted amides

Reaction of benzamides and N-substituted benzamides with appropriate o-alkenyl and -alkynyl side-chains and (chlorocarbonyl)phenyl ketene gives transient anhydro-1,3-oxazinium hydroxides which readily undergo intramolecular 1,4-dipolar cycloaddition; loss of CO2 from these 1:1-cycloadducts, isolable with N-substituted systems and alkenyl side-chains, gives chromeno[4,3-b]pyridin-2-ones.

SENSITIZED PHOTOLYSIS OF BENZOYL AZIDE. A NITRENE SINGLET-TRIPLET EQUILIBRIUM

Abstract The acetophenone-sensitized photolyses of benzoyl azide in cis-and trans-1,4-dimethylcyclohexanes gave the N-substituted benzamides stereospecifically. The photolyses in 2,3-dimethylbutane showed the same insertion regioselectivity ratio toward the C–H bonds as that of singlet benzoylnitrene in the direct photolysis. These facts indicate the existence of the singlet nitrene despite the triplet photosensitization and provide a chemical evidence for the establishment of a singlet-triplet equilibrium for benzoylnitrene.

Torsional angles in N-substituted benzamides and related compounds by carbon-13 N.M.R. chemical shifts

The torsional angles in 30 N-substituted benzamides and related compounds have been estimated by the use of the 13C substituent chemical shifts of the meta and para carbon atoms. Steric interaction between the N-substituted groups and the ortho hydrogen atoms of the benzene ring is the major determinant of non-planarity in these systems. A linear relationship between steric substituent constants of the N-substituted groups of some benzamides and the torsional angles is proposed. Dynamic processes involving rotation about the C-N bond, nitrogen inversion and ring inversion contribute a dynamic steric effect to the overall steric interaction. The preferred conformations of some N-substituted groups is also discussed.

The effect of side chain conformation on the carbon-13 substituent chemical shifts of N-substituted benzamides

The carbon-13 substituent chemical shifts of the ipso and carbonyl atoms in the para-substituted series Z-C6H4CONY2 (where Y = Me, Pri, Ph) have been measured at low dilution in (D)chloroform, and dimethyl sulfoxide. The DSP equation has been shown to hold for varying side chain conformations with high precision when the same resonance substituent parameter is used. Analysis of these data by the DSP equation indicates that the 'reverse substituent chemical shift effect' for the carbonyl atom is substantially due to a localized polarization of the π-electron system of the amide side chain. The ratio of localized to extended π-polarization of the β position of the amide side chain has been estimated. It is suggested that the effective dielectric constant term for the transmission of field effects by the cavity model varies with side chain conformation. The Cl substituent shifts have been discussed in terms of the shift-charge ratio. A variable-temperature study of the DSP parameters indicates an insignificant temperature effect provided rotation around the benzene ring to amide side chain bond is rapid.

Photoelimination in n-substituted benzamides

Photoelimination in n-substituted benzamides

Electron spin resonance studies of reduction by solvated electrons in liquid ammonia. Part 5.—Aromatic amides and thioamides

The radical-anions ArCONH–2· or -dianions ArCONH2–· of a series of ring- and N-substituted benzamides, thiobenzamides and nicotinamides have been characterized at temperatures near 200 K by electron spin resonance spectroscopy utilizing a low-temperature modification of the rapid-flow reduction technique incorporating e–amn as reductant. Most of the radicals are of the dianion type and display restricted rotation about the bond from the ring to the substituent. Assignments of coupling constants have been made by comparison with spin densities calculated by simple MO methods.

Synthesis and Anti-Inflammatory Activity of Fluorinated Benzamides

Six fluorine-containing N-substituted benzamides were synthesized, and their physical constants were determined. Their acute toxicity was determined, and LD50 values are given. The compounds were screened for anti-inflammatory activity using a modification of the rat-paw edema method. None of the compounds showed activity comparable to hydrocortisone acetate or indomethacin. However, two of the compounds showed sufficient activity to warrant further study.

Protonation equilibria of amides and related compounds. Part III. ? and ? + Correlations in some N-substituted benzamides

The protonation equilibria in aqueous sulphuric acid of eight ring-substituted N-(2,2,2-trifluoroethyl)benzamides and eight similarly substituted N-ethylbenzamides, have been studied. The basicities of the former set are correlated best by σ+, and of the latter by σ, substituent constants. The amides studied follow the acidity function, HA, reasonably well, so that no separate acidity function for secondary amides is required.

<i>In vitro</i> Antimicrobial Activity of Some Synthetic Isoindolinone and Isoquinolinone Derivatives

A total of six N-substituted benzamides, eight isoindolinone derivatives and six isoquinolinone analogs have been screened against five Gram positive and twelve Gram negative bacteria as well as four human fungal pathogens. From the antimicrobial screening, it is evident that 2-iodo-N-subustituted tetrahydro-1-oxo isoquinoline-3-carboxylic acids showed very prominent activity at a concentration 200 µg/disc, while the N-subtituted-3-alkyl isoindolin-1-one acetates showed weak to moderate activity. At the same time, 2-iodo-N-subustituted benzamides revealed very poor activity.
 
 Key words: 2-iodo-N-substituted benzamide, Isoindolinone, Isoquinolinone, Antimicrobial assay, Disc diffusion.
 
 Dhaka Univ. J. Pharm. Sci. Vol.5(1-2) 2006
 
 The full text is of this article is available at the Dhaka Univ. J. Pharm. Sci. website