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Chemical Compound Review

Drewamine     morpholine

Synonyms: morpholin, MORPHOLINE, Tetrahydro-1,4, SureCN986, PubChem15002, ...
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Disease relevance of morpholine

  • Male CD-1 mice were exposed to approximately 20 ppm nitrogen dioxide (NO2) for 5-6 hours, to 1 g morpholine/kg body weight by gavage, or to both [1].
  • Degradation of morpholine by an environmental Mycobacterium strain involves a cytochrome P-450 [2].
  • Other independent approaches that did not start from bafilomycin have led to the discovery of a different class of V-ATPase inhibitors, among which 4-(2,6-dichlorobenzoyl)amino-2-trifluoromethyl(benzoimidazol-1-yl)acetyl morpholine (FR177995) was the most effective in preventing bone resorption in an ovariectomized rat model of osteoporosis [3].
  • We compared the anti-proliferative properties of 4-benzylphenoxy-N ethyl morpholine (morpho-BPE) and trifluopromazine (TFP) on both the human breast cancer cell lines, MCF7, and its tamoxifen-resistant variant RTx6 [4].
  • For AM281, in which the terminal group of the 3-substituent is a morpholine ring, dehydration of the first two metabolites yielded a single third metabolite due to only one possible position for the carbon-carbon double bond on the morpholinyl ring [5].

High impact information on morpholine

  • Groups of three to four mice were gavaged with aqueous solutions of 2 milligrams of morpholine, after which they were exposed to nitrogen dioxide in inhalation chambers at concentrations of 0.2 to 50 parts per million for up to 4 hours [6].
  • A pH- dependent induction period observed during the nitrosation of morpholine in the presence of ascorbate and excess nitrite was accounted for by the kinetics of the reactions [7].
  • Loss-of-function assays with morpholine-substituted antisense oligonucleotides show that SpGsc is required for endoderm and pigment cell differentiation and for gastrulation [8].
  • Rate constants for reaction of morpholine, phosphate, and bicarbonate with N2O3 relative to N2O3 hydrolysis at pH 8.9 were determined to be (3.7 +/- 0.2) x 10(4) M-1, (4.0 +/- 0.9) x 10(2) M-1, and (9.3 +/- 1.5) x 10(2) M-1, respectively [9].
  • Rate data for the oxidation addition of Me-4-C(6)H(4)Cl to [Pd(NHC)(2)] compared to that obtained for the [Pd(NHC)(2)]-catalyzed coupling of morpholine with 4-chlorotoluene are consistent with a rate-determining oxidative addition in the catalytic amination reaction [10].

Chemical compound and disease context of morpholine


Biological context of morpholine

  • Deamination rate constants for cytosine and guanine in all types of DNA were lower than the morpholine nitrosation rate constant by a factor of approximately 10(3)-10(4) [16].
  • EXPERIMENTAL DESIGN: AVI-4126 administration in athymic mice bearing s.c. PC-3 xenografts was carried out to determine the bioavailability, tolerance, antitumor activity, and histological changes induced by targeted inhibition of c-Myc expression using a specific morpholine antisense oligomer [17].
  • The nitrobenzyl carbamates were not activated after a one-electron reduction; however, the morpholine and the ether adducts of these agents were observed after catalytic hydrogenation [18].
  • A series of 7-alkanoyl-substituted hydromorphone derivatives were prepared by acylation of the morpholine enamines [19].
  • o- and p-nitrobenzyl chlorides and carbamates were chemically and electrochemically reduced in the presence and absence of the nucleophile morpholine; activation of these compounds by reduction was required to produce an intermediate capable of alkylation [18].

Anatomical context of morpholine

  • Nitrite (150 microM) incubated with morpholine in cell-free medium did not form NMOR nor did cells plus morpholine and NO2-. The rate of NMOR formation in the J774.1 cell line was highest in the middle incubation period (24-36 h) although [NO2-] was highest in the final incubation period (48-72 h) [20].
  • A combination of the cytosols from macrophages treated with LPS alone and IFN-gamma alone did not nitrosate morpholine as rapidly as the cytosol of macrophages treated with both compounds together [21].
  • Lack of differential sensitivity of normal hematopoietic stem cells and murine lymphoblastic leukemic cells to a lysosomotropic agent, N-dodecyl morpholine [22].
  • Compounds 5 and 6 showed both alpha-stimulating and alpha-blocking activity on rat vas deferens, the effect depending on the concentration employed; on the same isolated tissue, N-isopropyl derivative 7 and the morpholine analogues 8-10 exhibited only alpha-blocking activity [23].
  • Thirty-eight strains of microorganisms isolated from infected human trachea, urine, blood and faeces were examined for their ability to form N-nitrosomorpholine from morpholine and nitrite at pH 7.25 [24].

Associations of morpholine with other chemical compounds


Gene context of morpholine

  • The Saccharomyces cerevisiae ERG24 gene, encoding sterol delta 14 reductase (Erg24p), was cloned by selecting strains carrying sequences on a 2 mu-based vector for resistance to the morpholine fungicide, fenpropimorph (Fp) [29].
  • The morpholine-resistant phenotype of the suppressor was used to identify the suppressor as a mutation in the ELO3 gene [30].
  • Treatment of Saccharomyces cerevisiae with the morpholine fungicide fenpropimorph was examined using both a wild-type and a mutant strain (erg2) defective in sterol delta 8-->7-isomerase [31].
  • The short duration of action of this MAO inhibitor containing a morpholine ring moiety is due to the complete reversibility (probably by metabolism of the inhibitory molecular species) of MAO-A inhibition [32].
  • Crystal structures for these compounds bound to toxin B pentamer revealed a conserved binding mode for the MNPG moiety, with multiple binding modes adopted by the attached morpholine derivatives [33].

Analytical, diagnostic and therapeutic context of morpholine


  1. In vivo formation of N-nitrosomorpholine in CD-1 mice exposed by inhalation to nitrogen dioxide and by gavage to morpholine. Van Stee, E.W., Sloane, R.A., Simmons, J.E., Brunnemann, K.D. J. Natl. Cancer Inst. (1983) [Pubmed]
  2. Degradation of morpholine by an environmental Mycobacterium strain involves a cytochrome P-450. Poupin, P., Truffaut, N., Combourieu, B., Besse, P., Sancelme, M., Veschambre, H., Delort, A.M. Appl. Environ. Microbiol. (1998) [Pubmed]
  3. Selective inhibition of osteoclast vacuolar H(+)-ATPase. Farina, C., Gagliardi, S. Curr. Pharm. Des. (2002) [Pubmed]
  4. The anti-proliferative properties of 4-benzylphenoxy ethanamine derivatives are mediated by the anti-estrogen binding site (ABS), whereas the anti-estrogenic effects of trifluopromazine are not. Poirot, M., Garnier, M., Bayard, F., Riviere, I., Traore, M., Wilson, M., Fargin, A., Faye, J.C. Biochem. Pharmacol. (1990) [Pubmed]
  5. In vitro metabolism of diarylpyrazoles, a novel group of cannabinoid receptor ligands. Zhang, Q., Ma, P., Wang, W., Cole, R.B., Wang, G. Drug Metab. Dispos. (2005) [Pubmed]
  6. Role of nitrogen dioxide in the biosynthesis of nitraosamines in mice. Iqbal, Z.M., Dahl, K., Epstein, S.S. Science (1980) [Pubmed]
  7. Reaction of nitrite with ascorbate and its relation to nitrosamine formation. Archer, M.C., Tannenbaum, S.R., Fan, T.Y., Weisman, M. J. Natl. Cancer Inst. (1975) [Pubmed]
  8. Sea urchin goosecoid function links fate specification along the animal-vegetal and oral-aboral embryonic axes. Angerer, L.M., Oleksyn, D.W., Levine, A.M., Li, X., Klein, W.H., Angerer, R.C. Development (2001) [Pubmed]
  9. Bicarbonate inhibits N-nitrosation in oxygenated nitric oxide solutions. Caulfield, J.L., Singh, S.P., Wishnok, J.S., Deen, W.M., Tannenbaum, S.R. J. Biol. Chem. (1996) [Pubmed]
  10. Synthetic, structural, and mechanistic studies on the oxidative addition of aromatic chlorides to a palladium (N-heterocyclic carbene) complex: relevance to catalytic amination. Lewis, A.K., Caddick, S., Cloke, F.G., Billingham, N.C., Hitchcock, P.B., Leonard, J. J. Am. Chem. Soc. (2003) [Pubmed]
  11. Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine. Mirvish, S.S., Pelfrene, A.F., Garcia, H., Shubik, P. Cancer Lett. (1976) [Pubmed]
  12. Molecular cloning, nucleotide sequencing and expression of genes encoding a cytochrome P450 system involved in secondary amine utilization in Mycobacterium sp. strain RP1. Trigui, M., Pulvin, S., Truffaut, N., Thomas, D., Poupin, P. Res. Microbiol. (2004) [Pubmed]
  13. The relative efficacy of 0.1% and 0.2% delmopinol mouthrinses in inhibiting the development of supragingival dental plaque and gingivitis in man. Abbott, D.M., Gunsolley, J.C., Koertge, T.E., Payne, E.L. J. Periodontol. (1994) [Pubmed]
  14. Experimental models for the biological detection of N-nitroso compounds formed from amines and nitrite. Baumeister, M. Toxicol. Lett. (1982) [Pubmed]
  15. Thiomorpholine and morpholine oxidation by a cytochrome P450 in Mycobacterium aurum MO1. Evidence of the intermediates by in situ 1H NMR. Combourieu, B., Poupin, P., Besse, P., Sancelme, M., Veschambre, H., Truffaut, N., Delort, A.M. Biodegradation (1998) [Pubmed]
  16. Nitric oxide-induced deamination of cytosine and guanine in deoxynucleosides and oligonucleotides. Caulfield, J.L., Wishnok, J.S., Tannenbaum, S.R. J. Biol. Chem. (1998) [Pubmed]
  17. Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans. Iversen, P.L., Arora, V., Acker, A.J., Mason, D.H., Devi, G.R. Clin. Cancer Res. (2003) [Pubmed]
  18. Nitrobenzyl derivatives as bioreductive alkylating agents: evidence for the reductive formation of a reactive intermediate. Kirkpatrick, D.L., Johnson, K.E., Sartorelli, A.C. J. Med. Chem. (1986) [Pubmed]
  19. Novel opiates and antagonists. 4. 7-Alkanoylhydromorphones. Quick, J., Herlihy, P., Razdan, R.K., Howes, J.F. J. Med. Chem. (1982) [Pubmed]
  20. Nitrosation of amines by stimulated macrophages. Miwa, M., Stuehr, D.J., Marletta, M.A., Wishnok, J.S., Tannenbaum, S.R. Carcinogenesis (1987) [Pubmed]
  21. L-arginine-dependent formation of N-nitrosamines by the cytosol of macrophages activated with lipopolysaccharide and interferon-gamma. Ohshima, H., Tsuda, M., Adachi, H., Ogura, T., Sugimura, T., Esumi, H. Carcinogenesis (1991) [Pubmed]
  22. Lack of differential sensitivity of normal hematopoietic stem cells and murine lymphoblastic leukemic cells to a lysosomotropic agent, N-dodecyl morpholine. Lopez, M., Sainteny, F., Kinsky, R., Bony, V. Leukemia (1988) [Pubmed]
  23. Conformational effects on the activity of drugs. 10. Synthesis, conformation, and pharmacological properties of 1-(2,5-dimethoxyphenyl)-2-aminoethanols and their morpholine analogues. Epifani, E., Lapucci, A., Macchia, B., Macchia, F., Tognetti, P., Breschi, M.C., Del Tacca, M., Martinotti, E., Giovannini, L. J. Med. Chem. (1983) [Pubmed]
  24. Screening of microorganisms for nitrosation catalysis at pH 7 and kinetic studies on nitrosamine formation from secondary amines by E. coli strains. Calmels, S., Ohshima, H., Vincent, P., Gounot, A.M., Bartsch, H. Carcinogenesis (1985) [Pubmed]
  25. Synthesis of nitric oxide and nitrosamine by immortalized woodchuck hepatocytes. Liu, R.H., Jacob, J.R., Hotchkiss, J.H., Tennant, B.C. Carcinogenesis (1993) [Pubmed]
  26. Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. Hale, J.J., Mills, S.G., MacCoss, M., Finke, P.E., Cascieri, M.A., Sadowski, S., Ber, E., Chicchi, G.G., Kurtz, M., Metzger, J., Eiermann, G., Tsou, N.N., Tattersall, F.D., Rupniak, N.M., Williams, A.R., Rycroft, W., Hargreaves, R., MacIntyre, D.E. J. Med. Chem. (1998) [Pubmed]
  27. N-(2-hydroxyethyl)doxorubicin from hydrolysis of 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin. Acton, E.M., Tong, G.L., Smith, T.H., Taylor, D.L., Streeter, D.G., Peters, J.H., Gordon, G.R., Filppi, J.A., Wolgemuth, R.L., Giuliani, F.C. J. Med. Chem. (1986) [Pubmed]
  28. Biochemical studies on the catalysis of nitrosation by bacteria. Calmels, S., Ohshima, H., Rosenkranz, H., McCoy, E., Bartsch, H. Carcinogenesis (1987) [Pubmed]
  29. The identification of a gene family in the Saccharomyces cerevisiae ergosterol biosynthesis pathway. Lai, M.H., Bard, M., Pierson, C.A., Alexander, J.F., Goebl, M., Carter, G.T., Kirsch, D.R. Gene (1994) [Pubmed]
  30. A mutation in sphingolipid synthesis suppresses defects in yeast ergosterol metabolism. Valachovic, M., Wilcox, L.I., Sturley, S.L., Bard, M. Lipids (2004) [Pubmed]
  31. Investigation of the role of sterol delta 8-->7-isomerase in the sensitivity of Saccharomyces cerevisiae to fenpropimorph. Kelly, D.E., Rose, M.E., Kelly, S.L. FEMS Microbiol. Lett. (1994) [Pubmed]
  32. From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors. Da Prada, M., Kettler, R., Keller, H.H., Cesura, A.M., Richards, J.G., Saura Marti, J., Muggli-Maniglio, D., Wyss, P.C., Kyburz, E., Imhof, R. J. Neural Transm. Suppl. (1990) [Pubmed]
  33. Anchor-based design of improved cholera toxin and E. coli heat-labile enterotoxin receptor binding antagonists that display multiple binding modes. Pickens, J.C., Merritt, E.A., Ahn, M., Verlinde, C.L., Hol, W.G., Fan, E. Chem. Biol. (2002) [Pubmed]
  34. Separation of morpholine and some of its metabolites by high-performance liquid chromatography. Sohn, O.S., Fiala, E.S., Conaway, C.C., Weisburger, J.H. J. Chromatogr. (1982) [Pubmed]
  35. Determination of morpholine in air by derivatisation with 1-naphthylisothiocyanate and HPLC analysis. Lindahl, R., Wästerby, A., Levin, J.O. The Analyst. (2001) [Pubmed]
  36. Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man. McKillop, D., Hutchison, M., Partridge, E.A., Bushby, N., Cooper, C.M., Clarkson-Jones, J.A., Herron, W., Swaisland, H.C. Xenobiotica (2004) [Pubmed]
  37. Degradation of morpholine by Mycobacterium aurum MO1. Mazure, N., Truffaut, N. Can. J. Microbiol. (1994) [Pubmed]
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