6-Oxa isosteres of uracil and thymine

Masingale, Robert E.; Bryant, Sarah R.; Skinner, Charles G.; Nash, James; Kruse, Paul F.

doi:10.1021/jm00301a040

Cited by 5 publications

(13 citation statements)

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“…The synthetic 6-oxa analogue is an isoster of 5,6-dihydrouracil and has been shown to be an apparent competitive antagonist of uracil in bacterial systems. [11] Whereas the first substitution directly alters an H-bond acceptor site of the uracil base, the second analogue is composed of a different heterocyclic ring system with unchanged H-bond donor and acceptor functionalities. The modifications introduced in 2 and 3 are shown to have a marked effect on the association modes of the nucleoside.…”

Section: Introductionmentioning

confidence: 99%

NMR Studies on the Self-Association of Uridine and Uridine Analogues

1998

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Association constants for the dimerization of acylated uridine and two analogues, 4-thiouridine and 6-oxadihydrouridine, have been determined in chloroform solution. At 293 K, self-association constants K were found to decrease in the order uridine b 6-oxadihydrouridine b 4-thiouridine. Lowtemperature 1D and 2D NMR measurements in a deuterated freon mixture allowed the unambiguous assignment of the different dimeric species formed. For homodimers of uridine, the 2-and 4-carbonyl groups act as H-bond acceptors with equal frequency, whereas for the 6-oxa analogue the 2-carbonyl is strongly favored over the 4-carbonyl group. No hydrogen bonding of the 4-S atom is observed in the 4-thio analogue. In agreement with the more negative atomic charge on the O4 oxygen predicted from ab initio calculations, 1 H chemical shifts of the H-bonded proton in uridine dimers indicate a stronger hydrogen bond in the 4-as compared to the 2-position.

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Section: Introductionmentioning

confidence: 99%

NMR Studies on the Self-Association of Uridine and Uridine Analogues

1998

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“…It had previously been reported3 that reaction of 6/7-1.2.4-oxadiazine-3,5(2/7,4/7)-dione (1) with methyl iodide in aqueous ethanol in the presence of sodium hydroxide afforded 4-methyl-6/7-l,2,4-oxadiazine-3,5(2/7,4/7)-dione (5). However, when we repeated the above alkylation, using the same conditions, we obtained 2-methyl-6/7-l,-2.4-oxadiazine-3,5(2/7,4Z7)-dione (6a).…”

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confidence: 95%

“…Long, Phoebe Dea, Roland K. Robins, and Thomas R. Matthews ICN Pharmaceuticals, Inc., Nucleic Acid Research Institute, Irvine, California 92715. Received May 5,1976 Treatment of 6/7-l,2,4-oxadiazin-3(2//)-one-5(4/f)-thione (2) with hydroxylamine, hydrazine, methylamine, or benzylamine afforded the corresponding N5-substituted 5-amino-6//-l,2,4-oxadiazin-3(2/7)-ones 3c-f. Refluxing a dioxane solution of 6/7-1,2,4-oxadiazine-3,5(2/7,4//)-dione (1) with benzylamine or aminodiphenylmethane and hexamethyldisilazane in the presence of ammonium sulfate gave 5-benzylamino-6/7-l,2,4-oxadiazin-3(2/7)-one (3f) and the corresponding 5-diphenylmethylamino derivative 3g. Reaction of 1 with methyl iodide, benzyl chloride, dihydropyran, dihydrofuran, or benzyloxycarbonyl chloride afforded the corresponding 2-substituted 677-1,2,4oxadiazine-3,5(2/7,4/7)-diones 6a-e.…”

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confidence: 99%

“…The degree of in vitro activity and the presence of antibacterial activity in the urine of animals given 5-amino-6/7-l,2,4-oxadiazin-3(277)-one (3a) by oral route of administration prompted selection of this compound for further study. 2,5(2/7,4/7)-dione (1) has been shown to significantly inhibit growth in several bacterial systems while not being appreciably inhibitory to mammalian cells.1 Although 1, the 6-oxa analogue of uracil, is actually an isostere of 5,6-dihydrouracil, such that 1 can be considered as 6-oxadihydrouracil, the antibacterial activity of 1 is reversed by uracil and not by 5,6-di-hydrouracil.1 6/7-1,2,4-Oxadiazine-3,5(2/7,4/7)-dione (1) is, therefore, an apparent competitive antagonist of uracil in bacterial systems. This study was undertaken to further investigate the antimicrobial properties of the 6-oxa analogues of other pyrimidines.…”

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confidence: 99%

“…Treatment of 6/7-l,2,4-oxadiazin-3(2/pone-5(4/7)-thione (2)2 in dioxane at room temperature with hydrazine, methylamine, or benzylamine, or reaction of 2 in ethanol at room temperature with hydroxylamine, afforded the corresponding N5-substituted 5-amino-6/7-l,2,4-oxadiazin-3(2/7)-ones 3c-g (Scheme I). 6/7-1,2,4-Oxadiazine-3,5(2/7,4/7)-dione (1) could also be converted to 5-benzylamino-6/7-l,2,4-oxadiazin-3(2/7)-one (3f) by conversion in situ to 3,5-bis(trimethylsilyloxy)-6/7-1,2,4-oxadiazine (4) and subsequent reaction with benzylamine. Thus, refluxing a dioxane solution of 1, hexamethyldisilazane, and benzylamine in the presence of ammonium sulfate afforded 3f in 53% yield.…”

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confidence: 99%

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Synthesis and antimicrobial activity of certain 6H-1,2,4-oxadiazin-3(2H)-ones

Berkowitz¹,

Long²,

Dea³

et al. 1977

J. Med. Chem.

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Treatment of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione (2) with hydroxylamine, hydrazine, methylamine, or benzylamine afforded the corresponding N5-substituted 5-amino-6H-1,2,4-oxadiazin-3(2H)-ones 3c-f. Refluxing a dioxane solution of 6H-1,2,4-oxiazine-3,5(2H,4H)-dione (1) with benzylamine or aminodiphenylmethane and hexamethyldisilazane in the presence of ammonium sulfate gave 5-benzylamino-6H-1,2,4-oxadiazin-3(2H)-one (3f) and the corresponding 5-diphenylmethylamino derivative 3g. Reaction of 1 with methyl iodide, benzyl chloride, dihydropyran, dihydrofuran, or benzyloxycarbonyl chloride afforded the corresponding 2-substituted 6H-1,2,4-oxadiazine-3,5(2H,4H)-diones 6a-e. Reaction of 2-methyl-6H-1,2,4-oxadiazine-3,5(2H,4H)-dione (6a) or the corresponding 2-benzyl derivative 6b with phosphorus pentasulfide in dioxane gave 2-methyl-6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione (8a) and the corresponding 2-benzyl derivative 8b, respectively. Reaction of 8a with ammonia in dioxane afforded 2-methyl-5-amino-6H-1,2,4-oxadiazin-3(2H)-one (9). The degree of in vitro activity and the presence of antibacterial activity in the urine of animals given 5-amino-6H-1,2,4-oxadiazin-3(2H)-one (3a) by oral route of administration prompted selection of this compound for further study.

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