N-hydroxy-imides. Part II. Derivatives of homophthalic and phthalic acids

Ames, D. E.; Grey, T. F.

doi:10.1039/jr9550003518

Cited by 30 publications

(7 citation statements)

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“…However, the pH at the transition between high and low inhibitory potency is similar to the reported second p K a (7.62) for 2,4-diketo-4-(naphth-2-yl)butanoic acid 13 and could suggest that these compounds were binding in a doubly ionized state. This is in apparent contrast with the hydroxyimides series which literature data suggests would be unlikely to be significantly singly ionized under the assay conditions (reported p K a s for 13 are 8.0 and 11.9) . For compound stability reasons we were not able to undertake the pH activity profiling of inhibitors from the N -hydroxyimide series, or measure the p K a values of representative compounds from the two series ourselves under comparable, and preferably more physiological, conditions.…”

Section: Resultsmentioning

confidence: 90%

“…This is in apparent contrast with the hydroxyimides series which literature data suggests would be unlikely to be significantly singly ionized under the assay conditions (reported pK a s for 13 are 8.0 and 11.9). 14 For compound stability reasons we were not able to undertake the pH activity profiling of inhibitors from the N-hydroxyimide series, or measure the pK a values of representative compounds from the two series ourselves under comparable, and preferably more physiological, conditions. However, we have observed by 1 H NMR that 13 was present as an equilibrium mixture of keto and enol forms in buffered aqueous solution, and that the equilibrium shifted significantly in favor of the enol tautomer on the addition of 50 mM Mg 2+ .…”

Section: Resultsmentioning

confidence: 99%

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Use of a Pharmacophore Model To Discover a New Class of Influenza Endonuclease Inhibitors

et al. 2003

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Data from both our own and literature studies of the biochemistry and inhibition of influenza virus endonuclease was combined with data on the mechanism of action and the likely active site mechanism to propose a pharmacophore. The pharmacophore was used to design a novel structural class of inhibitors, some of which were found to have activities similar to that of known influenza endonuclease inhibitors and were also antiviral in cell culture.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Use of a Pharmacophore Model To Discover a New Class of Influenza Endonuclease Inhibitors

et al. 2003

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“…Despite extensive use and interest in the phthalimide derivatives, their electronic spectra have not been fully clarified. − From studies of the photophysical and photochemical properties, , it has been suggested that the lowest excited singlet state of N -alkylated phthalimides is an nπ* state, but this has never been unambiguously proven. For the higher energy transitions, reliable experimental assignments are missing.…”

Section: Introductionmentioning

confidence: 99%

Excited States of the Phthalimide Chromophore and Their Exciton Couplings: A Tool for Stereochemical Assignments

et al. 1998

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The electronically excited states of the phthalimide chromophore have been studied by means of linear dichroism (LD) of samples partially oriented in poly(vinyl alcohol) films, magnetic circular dichroism (MCD), and circular dichroism (CD) spectroscopy. On the basis of the LD measurements, the low-energy tail (340−320 nm) of the first absorption band is assigned to an out-of-plane polarized n→π* transition (I). At higher energy, the electronic spectrum is resolved into contributions from five π→π* transitions: II (300 nm, long-axis polarized), III (275 nm, short-axis polarized), IV (235 nm, short-axis polarized), V (220 nm, long-axis polarized), and VI (∼210 nm, short-axis polarized). The results from semiempirical (INDO/S-CI) and ab initio (CIS/6-31+G(d)) MO calculations compare well with the proposed assignments of the excited states. Degenerate exciton interaction between electric-dipole-allowed transitions of two phthalimide chromophores is observed in the electronic absorption spectra of the achiral bis-phthalimides 2a−c and in the CD spectrum of the chiral bis-phthalimide 3a. For the latter compound, the solid-state geometry has been determined by X-ray diffraction analysis. Good agreement between experimental and computed CD spectra confirms that the coupled-oscillator exciton model provides the basis for a reliable nonempirical method for the assignment of absolute configuration for this class of compounds. Nondegenerate exciton coupling between phthalimide and benzoate or phenyl chromophores is born out in the CD spectra of homochiral molecules 3c and 3d with the rigid cyclohexane skeleton. Finally, the exciton coupling method is used to make stereochemical assignments for the acyclic, conformationally flexible derivatives 4a−c and 5b.

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“… NHPI ( 3H ), p K a = 6.1; , Me 2 NOH, p K a = 8.80; , Me 2 CNOH and E t 2 CNOH, p K a = 12.4 and 12.6, respectively, where the last three compounds must be seen as surrogates for 1bH and 2H .…”

Section: Referencesmentioning

confidence: 99%

Mechanisms of Reaction of Aminoxyl (Nitroxide), Iminoxyl, and Imidoxyl Radicals with Alkenes and Evidence that in the Presence of Lead Tetraacetate, N-Hydroxyphthalimide Reacts with Alkenes by Both Radical and Nonradical Mechanisms

2005

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1,2-dideuterio-cyclohexene, 1,2-dideuterio-cyclooctene, and trans-3,4-dideuterio-hex-3-ene were reacted with three >NO* radicals: 4-hydroxyTempo, di-tert-butyliminoxyl, both used as the actual radicals, and phthalimide-N-oxyl (PINO) generated from N-hydroxyphthalimide (NHPI) by its reaction with tert-alkoxyl radicals (t-RO*) and with lead tetraacetate. In all cases, except the NHPI/Pb(OAc)4 system, only mono >NO-substituted alkenes were produced. The 2H NMR spectra imply that 88-92% of monoadducts were formed by the initial abstraction of an allylic H-atom, followed by capture of the allylic radical by a second >NO*, while the remaining 12-8% appear to be formed by an initial addition of >NO* to the double bond followed by H-atom abstraction by a second >NO*. A substantial and sometimes the major product formed with the NHPI/Pb(OAc)4 system has two PINO moieties added across the double bond. Since such diadducts are not formed with the NHPI/t-RO* system, a heterolytic mechanism is proposed, analogous to that known for the Pb(OAc)4-induced acetoxylation of alkenes. A detailed analysis of the NHPI/Pb(OAc)4/alkene products indicates that monosubstitution occurs by both homolytic and heterolytic processes.

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N-hydroxy-imides. Part II. Derivatives of homophthalic and phthalic acids

Cited by 30 publications

References 0 publications

Use of a Pharmacophore Model To Discover a New Class of Influenza Endonuclease Inhibitors

Use of a Pharmacophore Model To Discover a New Class of Influenza Endonuclease Inhibitors

Excited States of the Phthalimide Chromophore and Their Exciton Couplings: A Tool for Stereochemical Assignments

Mechanisms of Reaction of Aminoxyl (Nitroxide), Iminoxyl, and Imidoxyl Radicals with Alkenes and Evidence that in the Presence of Lead Tetraacetate, N-Hydroxyphthalimide Reacts with Alkenes by Both Radical and Nonradical Mechanisms

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