Synthesis, structure, and biological activity of certain 2-deoxy-.beta.-D-ribo-hexopyranosyl nucleosides and nucleotides

Abstract

2-Deoxy-beta-D-ribo-hexopyranosyl nucleosides with adenine (2), hypoxanthine (17), guanine (23), cytosine (13), and uracil (7) as the aglycon were synthesized by the Lewis-acid catalyzed condensation of an appropriate trimethylsilylated heterocyclic base and 2-deoxy-1,3,4,6-tetrakis-O-(4-nitrobenzoyl)-beta-D-ribo-hexopyranose+ ++ (5) to provide the desired beta anomers in good yield. When the synthesis of 7 via an SN2 displacement was attempted by reaction between silylated uracil and 2-deoxy-3,4,6-tris-O-(4-nitrobenzoyl)-alpha-D-ribo-hexopyranosyl bromide (8), the major product, 1-(2-deoxy-3,4,6-tris-O-(4-nitrobenzoyl)-alpha-D-ribo-hexopyranosyl)-2,4 - pyrimidinedione (9), had retained the alpha configuration at the anomeric carbon. The structures of both anomers of 1-(2-deoxy-D-ribo-hexopyranosyl)-2,4-pyrimidinedione were assigned by single-crystal X-ray methods. The anomeric configuration and conformation of other nucleosides were determined by proton magnetic resonance analysis of the 4-nitrobenzoylated nucleosides. Nucleoside 6'-monophosphates of 7, 13, and 2 and the 4',6'-cyclic monophosphate of 2 were also prepared. All 2'-deoxy-D-ribo-hexopyranosyl nucleosides and 6'-monophosphate derivatives were tested in vitro for antiviral and antitumor activity. The guanosine analogue 23 was moderately active against HSV-2 virus. The UMP analogue, 1-(2-deoxy-6-O-phosphono-beta-D-ribo-hexopyranosyl) -2,4-pyrimidinedione (28), demonstrated moderate activity against HSV-2 and parainfluenza 3 virus and was also active against L1210 (ID50 = 39 microM) and P388 (ID50 = 33 microM) leukemic cell lines. Two compounds, 6-amino-9-(2-deoxy-beta-D-ribo-hexopyranosyl)purine (2) and 9-(2-deoxy-beta-D-ribo-hexopyranosyl)-2,6-diaminopurine (24), were substrates for adenosine deaminase (EC 3.5.4.4) with Km values of 57 and 90 microM, respectively. 6-Amino-7-(2-deoxy-beta-D-ribo-hexopyranosyl)purine, 18, was a competitive inhibitor of ADase (Ki = 0.1 mM).

A synthetic cyclitol-nucleoside conjugate polyphosphate is a highly potent second messenger mimic

“…However, no reaction was observed when DMF alone was used as a solvent. Subsequent coupling of 35 via its pent-4-ene orthoester group with silylated 6-chloropurine51 in the presence of an activator under anhydrous conditions gave compound 14 in good yield 43 b . The trans -isopropylidene group was then selectively removed by treatment with ethylene glycol and p -toluenesulfonic acid in dichloromethane for no longer than 20 minutes to give compound 13 in almost quantitative yield.…”

New Approaches toward Ferrocene–Guanine Conjugates: Synthesis and Electrochemical Behavior

“…The direct modification of nucleobases by nucleophilic aromatic substitution and successive hydrolysis allows in many cases the synthesis of the desired derivatives. 19 The chloro derivatives 2 and 8 were reacted with 1a in the presence of a catalytic amount of In(OTf) 3 . While 8 was insoluble in many of the solvents tested, 2 smoothly reacted with ferrocene 1a, affording the desired compound 3a in moderate yield.…”

“…The hydrolysis of 3a into 4a occurred by following the standard procedure in the literature. 19 However, the synthesis of 9-ferrocenylguanine was attempted under various conditions, using ammonia or ammonia equivalents (Scheme 1). In addition, Buchwald−Hartwig methodologies were briefly considered, but no results were obtained.…”

Polyphosphates and Pyrophosphates of Hexopyranoses as Allosteric Effectors of Human Hemoglobin: Synthesis, Molecular Recognition, and Effect on Oxygen Release

“…However, we were interested in checking the reactivity of the unprotected hydroxymethyl group under the neutral reaction conditions described, and not in pyridine, where formation of 4,6-cyclic phosphates of carbohydrates from their 6-monophosphorylated precursors has been described. [38] Preliminary results showed mainly the formation of two products, one that possibly contains the 3,4-pyrophosphate, and another that contains the 4,6-cyclic phosphate along with the 2,3-pyrophosphate. We checked the formation of cyclic phosphate by the heteronuclear coupling constant observed for C-6 in 13 C NMR spectra.…”