- USE OF A DHODH INHIBITOR IN COMBINATION WITH AN INHIBITOR OF PYRIMIDINE SALVAGE
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Compounds and methods are provided for the treatment of pathogenic virus infections or cancer. The formulations combine an inhibitor of de novo pyrimidine synthesis, and an inhibitor of a pyrimidine salvage pathway enzyme.
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Paragraph 00206
(2017/07/31)
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- Synthesis and Oxidative Cleavage of Oxazinocarbazoles: Atropselective Access to Medium-Sized Rings
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Polycyclic systems can be converted into medium-sized-ring-containing compounds through the controlled oxidative cleavage of internal double bonds. This approach is particularly accessible in systems that contain a suitably substituted indole ring. Here, a robust approach to the synthesis of the understudied oxazinocarbazole system is reported. After regioselective incorporation of a carbonyl functional group, m-chloroperoxybenzoic acid (MCPBA) is used to cleave the indole 2,3-double bond that this system contains. This results in a competition between two processes, oxidative cleavage of the double bond and a pinacol-type rearrangement, both of which occur with very high diastereoselectivity. The balance between the two processes is studied as a function of the substrate structure. Extensive use of X-ray crystallographic analysis of the products enables detailed mechanistic conclusions to be drawn.
- Liu, Gu,Lancefield, Christopher S.,Lorion, Magali M.,Slawin, Alexandra M. Z.,Westwood, Nicholas J.
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p. 2808 - 2814
(2015/02/19)
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- A novel CAN-SiO2-mediated one-pot oxidation of 1-keto-1,2,3,4-tetrahydrocarbazoles to carbazoloquinones: Efficient syntheses of murrayaquinone A and koeniginequinone A
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One-pot oxidations of substituted 1-keto-1,2,3,4-tetrahydrocarbazoles (1) to carbazole-1,4-quinones (2) are efficiently carried out by CAN-SiO 2-mediated reaction. This generalized protocol was successfully extended to the synthesis of two naturally occurring carbazoloquinones: murrayaquinone A (2b) and koeniginequinone A (2g). A plausible mechanism for this novel reaction involves formation of a 9-hydroxy-2,3,4,9-tetrahydro-1H- carbazole-1-one followed by rearrangement to 1-hydroxycarbazole derivatives, which are further oxidized by cerium (IV) to carbazoloquinones.
- Chakraborty, Suchandra,Chattopadhyay, Gautam,Saha, Chandan
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scheme or table
p. 331 - 338
(2011/06/19)
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- Substituted tetrahydrocarbazoles with potent activity against human papillomaviruses
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The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.
- Gudmundsson, Kristjan S.,Sebahar, Paul R.,Richardson, Leah D'Aurora,Catalano, John G.,Boggs, Sharon D.,Spaltenstein, Andrew,Sethna, Phiroze B.,Brown, Kevin W.,Harvey, Robert,Romines, Karen R.
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scheme or table
p. 3489 - 3492
(2010/03/31)
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- Conformationally restrained carbazolone-containing α,γ-diketo acids as inhibitors of HIV integrase
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Since α,γ-diketo acid (DKA) compounds were identified as potent and selective inhibitors for HIV integrase, numerous structural modification studies have been carried out to search for a clinical candidate as a supplement for the highly active antiretroviral therapy regimen. Due to the lack of structural information on inhibitor-integrase interactions, a comprehensive structure-activity relationship study is necessary. Most of the reported modification studies on the key α,γ-diketo acid pharmacophore focused on substituting the carboxylate moiety with its bioisosteres or other electron-pair bearing heterocycles. We were interested in studying the conformation and geometry of the central diketo moiety. A series of carbazolone-containing α,γ-diketo acids were designed and synthesized by applying conformational restraint onto the open-chain form of the diketo acid. These compounds showed anti-integrase activity in the low micromolar range, and integrase assay results indicated that the geometry of the diketo acid moiety is crucial to potency. Carbazol-1-one containing DKA analogs (7-8) showed a 2- to 3-fold increase in activity compared with those of carbazol-4-one containing DKA analogs (5 and 6). Alkylation of carbazol-4-one DKA nitrogen (6a-c) led to a loss of activity, suggesting this nitrogen atom may directly interact with the active site of integrase. The halogens (7b-d) and para-fluorobenzyl substituents (8a-d) on carbazol-1-one ring had little effect on potency.
- Li, Xingnan,Vince, Robert
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p. 2942 - 2955
(2007/10/03)
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- TETRAHYDROCARBAZOLE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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The present invention relates to novel compounds of formula (I), that are useful in the treatment of human papillomaviruses, and also to the methods for the making and use of such compounds.
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- TETRAHYDROCARBAZOLE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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The present invention relates to novel compounds of formula (I) that are useful in the treatment of human papillomaviruses, and also to the methods for the making and use of such compounds.
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- The reaction studies of α-chloroformylarylhydrazines with thiols, thioureas and α-cyclodiketones
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The reactions of α-chloroformylarylhydrazines 1 with various types of mercaptan, thiourea and α-cyclodiketone have been studied intensively. 1-Arylhydrazinecarbothioates 2 were obtained via thioesterization when α-chloroformylarylhydrazines reacted with thiols. On the other hand, compounds 3 were obtained when α-chloroformylarylhydrazines reacted with thio-containing heterocyclic compounds, which suggested a totally different mechanism in these types of reactions. Further studies on the reaction of α-chloroformylarylhydrazines 1 with thiourea compounds confirmed a novel cyclization and de-cyclization mechanism, which led to give 2-arylhydrazinecarboximidamides 5 and 1,3,4-thiadiazolin-5-ones 6. In addition, various 1,3,4-oxadiazines 9 were obtained by reacting α-chloroformylarylhydrazines with α-cyclodiketones, showing ring cyclization was involved in this type of reaction.
- Kuo, Wen-Fa,Wu, Ming-Shyue,Chiu, Chun-Yen,Yeh, Mou-Yung
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p. 215 - 228
(2007/10/03)
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