- HETEROCYCLIC GTP CYCLOHYDROLASE 1 INHIBITORS FOR THE TREATMENT OF PAIN
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The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).
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Page/Page column 85
(2011/04/19)
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- Synthesis of 8-amino and 8-substituted amino derivatives of acyclic purine nucleoside and nucleotide analogs. Alkylation of 8-substituted purine bases
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Two synthetic approaches were used for preparation of 8-amino-, 8-methylamino-, and 8-dimethylaminoadenine and -guanine analogs of PME and HPMP series: (a) direct modification of 8-bromopurine acyclic nucleotide analogs at the 8-position of the base, (b) alkylation of 8-modified purine bases with alkylation agents.
- Janeba,Holy
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p. 1103 - 1106
(2007/10/03)
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- Analysis of peroxynitrite reactions with guanine, xanthine, and adenine nucleosides by high-pressure liquid chromatography with electrochemical detection: C8-nitration and -oxidation
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Peroxynitrite, the reaction product of nitric oxide and superoxide anion, and a powerful oxidant, was found to nitrate as well as oxidize adenine, guanine, and xanthine nucleosides. A highly sensitive reverse-phase HPLC method with a dual-mode electrochemical detector, which reduces the nitro product at the first electrode and detects the reduced product by oxidation at the second electrode, was applied to detect femtomole levels of 8-nitroguanine and 8-nitroxanthine. This method was used to separate and identify the products of nitration and oxidation from the reactions of nucleosides with peroxynitrite. Peroxynitrite nitrates deoxyguanosine at neutral pH to give the very unstable 8-nitrodeoxyguanosine, in addition to 8-nitroguanine. 8-Nitrodeoxyguanosine, with a half-life of ～10 min at room temperature and ≤3 min at 37 °C, hydrolyzes at pH 7 to 8-nitroguanine. A decrease in the reaction pH resulted in a decrease in the level of C8-nitration. Peroxynitrite also oxidizes deoxyguanosine in a pH-dependent manner, to give 8-oxodeoxyguanosine with a maximum yield (0.5-0.7%) at pH 5. Guanosine and xanthosine exhibit reactivity similar to that of deoxyguanosine toward peroxynitrite at neutral pH, producing only the corresponding 8-nitronucleosides as well as 8-nitroguanine and 8-nitroxanthine, respectively. 8-Nitroguanosine at pH 7, with a half-life of several weeks at 5 °C and 5 h at 37 °C, was much more stable than 8-nitrodeoxyguanosine. C8-nitration was confirmed by dithionite reduction to the corresponding amino nucleosides, which cochromatographed with synthesized 8-amino nucleoside standards. In contrast to guanine nucleosides, adenine nucleosides undergo peroxynitrite-mediated C8 oxidation even at neutral pH to give the corresponding 8-oxoadenine nucleosides in ～0.3% yield. Adenine nitration, though minor compared to C8-oxidation, appears to occur at both C2 and C8 positions of the adenine ring. Lowering the reaction pH from 7 to 5 results in 2.4- and 2.2-fold increases in the yields of 8-oxo-dA and 8-oxo-Ado, respectively, but the level of nitration is not altered.
- Sodum, Rama S.,Fiala, Emerich S.
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p. 438 - 450
(2007/10/03)
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- 8-Nitroxanthine, an adduct derived from 2′-deoxyguanosine or DNA reaction with nitryl chloride
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Activated phagocytic cells generate reactive nitrogen species, including nitryl chloride and peroxynitrite, for host defense against invading pathogens. It has been proposed that these reactive nitrogen species may cause DNA damage and thus contribute to the multistage carcinogenesis process associated with chronic infections and inflammation. Previous studies showed that peroxynitrite reacted with guanine, 2′-deoxyguanosine, or DNA forming 8-nitroguanine. We herein report formation of 8-nitroxanthine as the major nitration product in reactions of 2′-deoxyguanosine or calf thymus DNA with nitryl chloride produced by mixing nitrite with hypochlorous acid, and 8-nitroguanine was a minor product in these reactions. 8-Nitroxanthine was characterized by its NMR and laser desorption ionization mass spectra and by deamination of 8-nitroguanine. Formation of 8-nitroxanthine was also detected by xanthine reaction with various reactive nitrogen species, including nitryl chloride, peroxynitrite, nitronium tetrafluoroborate, and heated nitric and nitrous acid. The identity of 8-nitroxanthine in nitryl chloride-treated dG and DNA was confirmed by co-injection with synthetic 8-nitroxanthine and by its reduction to 8-aminoxanthine. Levels of 8-nitroxanthine and 8-nitroguanine in these reactions were quantified by reversed-phase HPLC with photodiode array detection. Once formed, 8-nitroxanthine was spontaneously removed from DNA with a half-life of 2 h at 37 °C and pH 7.4. Therefore, 8-nitroxanthine might be an important DNA lesion derived from reactive nitrogen species in vivo.
- Chen, Hauh-Jyun Candy,Chen, Yuan-Mao,Wang, Tze-Fan,Wang, Kuang-Sian,Shiea, Jentaie
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p. 536 - 546
(2007/10/03)
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- Formation and reactions of N7-aminoguanosine and derivatives
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Arylamines are mutagens and carcinogens and are thought to initiate tumors by forming adducts with DNA. The major adducts are C8-guanyl, and we have previously suggested a role for guanyl-N7 intermediates in the formation process. N7-Aminoguanosine (Guo) was synthesized and characterized, with the position of the NH2 at N7 established by two- dimensional rotating frame Overhauser enhancement NMR spectroscopy. In DMF, N7-NH2Guo formed C8-NH2Guo and the cyclic product C8:5'-O-cycloGuo. In aqueous media, these products were formed along with 8-oxo-7,8-dihydroGuo, N7-NH2guanine, and a product characterized as a purine 8,9-ring-opened derivative (N-aminoformamidopyrimidine). The rate of aqueous decomposition of N7-NH2Guo increased with pH, with a t( 1/2 ) of 10 h at pH 7 and a t( 1/2 ) of 2 h at pH 9. The rate of migration of NH2 from N7 to C8 is fast enough to explain the formation of C8-NH2Guo from the reaction of 2,4- dinitrophenoxyamine with Guo but not the formation of C8-(arylamino)Guo in the reaction of Guo with aryl hydroxylamine esters; however, the fluorenyl moiety may facilitate the proposed rearrangement by stabilizing an incipient negative charge in the transfer. In the reaction of Guo with N-hydroxy-2- aminofluorene and acetylsalicylic acid, a peak with the mass spectrum expected for N7-(2-aminofluorenyl)Guo was detected early in the reaction and was distinguished from C8-(2-aminofluorenyl)Guo. NMR experiments with [8- 13C]Guo also provided some additional support for transient formation of N7-(2-aminofluorenyl)Guo. We conclude that a guanyl-N7 intermediate is reasonable in the reaction of activated arylamines with nucleic acids, although an exact rate of transfer of an N7-arylamine group to the C8 position has not yet been quantified. The results provide an explanation for the numerous products associated with modification of DNA by activated arylamines. However, the contribution of 'direct' reaction at the guanine C8 atom cannot be excluded.
- Guengerich, F. Peter,Mundkowski, Ralf G.,Voehler, Markus,Kadlubar, Fred F.
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p. 906 - 916
(2007/10/03)
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- Reactions of Benzenediazonium Ions with Guanine and Its Derivatives
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Guanine reacts with several benzenediazonium ions rapidly in aqueous solution at pH 10.5 to form 8-(arylazo)guanines in good yield.The reaction of guanine with 4-bromobenzenediazonium ion forms ε-guanine about 50-fold more rapidly than the reaction of adenine with this ion to yield 6-purine under these experimental conditions.Guanosine reacts much more slowly than guanine with the benzenediazonium ions in aqueous solution at pH 8.5 or 10.5 to give 8-arylguanosines.The structures of these products were established by their spectroscopic properties and by their quantitative conversion to 8-arylguanines. 5'-Guanylic acid also reacts quite slowly with the benzenediazonium ions in aqueous solution at pH 10.5.Only the compounds with strong electron-withdrawing groups yield N-2 triazenes at ambient temperature.No 8-aryl or 8-arylazo compounds are formed with 5'-guanylic acid at this temperature.However, 4-bromo- and 4-sulfobenzenediazonium ions react with 5'-guanylic acid at higher temperatures to yield the 8-aryl-5'-guanylic acids in low yield.The structures of these products were proven by hydrolysis to 8-arylguanines.The 8-arylguanosines and the 8-aryl-5'-guanylic acids are formed via free-radical phenylation reactions.The factors governing the reactivity of the adenines and the guanines are discussed.
- Hung, Ming-Hong,Stock, Leon M.
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p. 448 - 453
(2007/10/02)
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