The glycosylation of 3,4-dicyano-2-[(ethoxymethylene)amino]pyrrole (7) with 2-deoxy-2-fluoro-alpha-D-erythro-pentofuranosyl bromide (2) furnished an anomeric mixture of nucleosides (8a,b). This mixture was separated, and the individual anomers were treated with methanolic ammonia to effect a concomitant deblocking and ring closure. This furnished both anomers of 2'-deoxy-2'-fluoro-ara-toyocamycin (9a,b). The cyano moiety of 9b was converted to the carboxamide moiety to furnish 2'-deoxy-2'-fluoro-ara-sangivamycin (10) and to the thiocarboxamide moiety to furnish 2'-deoxy-2'-fluoro-ara-thiosangivamycin (11). The target compounds 10 and 11 showed similar antiproliferative activity against L1210 cells in vitro, with IC50's of 3 and 5 microM. Antiviral evaluation revealed a somewhat different pattern of activity. All analogs, both alpha and beta anomers, were active against human cytomegalovirus (HCMV), albeit the beta anomers were most active. The beta anomers also were active against herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus (HIV). Compound 10 was most active in the series, ca. 10-fold more potent than 11; IC50's for 10 ranged from 4 to 25 nM for HCMV, HIV, and varicella zoster virus (VZV) and from 30 to 500 nM for HSV-1. Even though compound 10 was cytotoxic, which will probably preclude its use as an antiviral drug (IC50's = 0.2-5.5 microM), the difference between cytotoxicity and activity against HCMV, HIV, and VZV was sufficient to indicate specific activity against a viral target.
The syntheses of the imidazole alkaloid casimiroedine (7), a natural product isolated from the seeds of the Mexican fruit "Zapote blanco," and its hydrolysis product casimidine (6) have been accomplished. The key step in the synthesis of casimiroedine (7) involves the formation of the peptide linkage between irans-cinnamic acid and casimidine. The unambiguous synthesis of 7 established the stereochemistry of the cinnamoyl moiety as trans. This assignment was corroborated by the synthesis of cis-casimiroedine ( 8) and spectral evidence. Chemical investigations conducted on the seeds of the fruit of the tree Casimiroa edulis La Llave et Lejarza have shown them to contain a variety of constituents. 2-4 The principal constituent, the alkaloid casimiroedine (7), was found to be the cinnamic acid amide of casimidine ( 6).6 Degradation studies6 on casimidine confirmed the presence of A-methylhistamine and a carbohydrate fragment. An X-ray analysis7•8 firmly established the structure of the carbohydrate as /S-D-glucose and of casimidine as 4-[2-(methylamino)ethyl]-l-(/3-D-glucopyranosyl)imidazole. These studies provided the basic structure of casimiroedine (7) and left one question unanswered, whether casimiroedine was the cisor trans-cinnamic acid amide of 6. This final question has now been resolved by the total synthesis of casimiroedine.113 Results and DiscussionChemical Synthesis. The chloromercury derivative9 (2) of 4-(2-chloroethyl)imidazole hydrochloride10•11 (1) (Scheme I) was glycosylated with 2,3,4,6-tetra-O-acetyl--D-glucosyl bromide12 (3) to provide 4 as a thick syrup.(1) (a) This investigation was supported in part by Research Contract No. C72-3710 with the
A series of 2,4,6-trisubstituted-5-nitropyrimidines have been prepared and evaluated for inhibition of proliferation of L1210 and H.Ep.2 cells in vitro. The most potent compound was 6-(dibromomethyl)-2-methoxy-4-morpholino-5-nitropyrimidine (11) (L1210, IC50 = 0.32 microM; H.Ep.2, IC50 = 1.6 microM). Of the 6-substituents incorporated, only CHBr2, CH2Br, and CHO were compatible with antiproliferative activity, while a wider variety of 4-substituents were tolerated. At concentrations near the IC50 for antiproliferative activity, a delayed resumption of cell proliferation in L1210 cultures indicated that the activity of the compounds was short-lived and suggested they might act by an alkylation mechanism.
Aus den Cyclo‐5‐diazouridin (I) erhält man bei der Hydrolyse unter Ringkontraktion das Triazol‐carbonamid (II), wobei der Reaktionsablauf aufgrund der Umsetzung mit der entsprechenden lgO‐markierten Verbindung sichergestellt werden kann.
The effects of certain substituents and solvents on the circular dichroism (CD) spectra are reported for a number of guanine nucleoside derivatives from 320 to 200 nm. Both theoretical and empirical analyses of the data suggest that the anti conformation predominates in aqueous solution, but that the syn conformation is preferred in alcoholic solvents, at low pH in water, and when the heterocycle carries a large substituent on carbon 8 of the imidazole ring. Theoretical optical calculations based on the bond-bond coupled oscillator theory are included to check the validity of the theory with experimental data. The interaction of guanine nucleoside derivatives with actinomycin is also reported and the data suggest that the anti conformation is necessary for complex formation.A fundamental aspect of the conformational analyses of nucleic acids and their fragments concerns the allowed conformational states of the individual nucleotide or nucleoside monomers.In particular the relative position of the sugar and the base about the glycosidic bond, as described by the torsion angle, <£CN, has received a great deal of attention.1-4 Steric considerations lead to two extreme conformations as demonstrated by 1 and 5 in Figure 1, which are designated anti and syn, respectively. Crystallographic studies have pointed to the almost exclusive presence of the anti conformation.5 A number of exceptions, however, are known: deoxyguanosine, which is syn in a mixed crystal with 5-bromodeoxycytidine;6 3',5' cyclic AMP, which can exist simultaneously in the anti and syn conformations in the same crystal structure;7 8bromoguanosine;8 8-bromoadenosine;8 and 3'-0-acetyladenosine.9 Several independent calculations using (1) A.
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