8-Chloroguanosine: solid-state and solution conformations and their biological implications

Abstract

The three-dimensional structure of 8-chloroguanosine dihydrate was determined by X-ray crystallography. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), and the cell dimensions are a = 4.871 (1) A, b = 12.040 (1) A, and c = 24.506 (1) A. The structure was determined by direct methods, and least-squares refinement, which included all hydrogen atoms, converged at R = 0.031 for 1599 observed reflections. The conformation about the glycosidic bond is syn with chi CN = -131.1 degrees. The ribose ring has a C(2')-endo/C-(1')-exo (2T1) pucker, and the gauche+ conformation of the -CH2OH side chain is stabilized by an intramolecular O-(5')-H...N(3) hydrogen bond. Conformational analysis by means of 1H NMR spectroscopy showed that, in dimethyl sulfoxide, the sugar ring exhibits a marked preference for the C(2')-endo conformation (approximately 70%) and a conformation about the glycosidic bond predominantly syn (approximately 90%), hence similar to that in the solid state. However, the conformation of the exocyclic 5'-CH2OH group exhibits only a moderate preference for the gauche+ rotamer (approximately 40%), presumably due to the inability to form the intramolecular hydrogen bond to N(3) in a polar medium. The conformational features are examined in relation to the behavior of 8-substituted purine nucleosides in several enzymatic systems, with due account taken of the steric bulk and electronegativities of the 8-substituents.

8‐Chloro‐dGTP, a hypochlorous acid‐modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog

“…We have previously reported that the oxidized purine nucleotides, 2‐OH‐dATP, 8‐OH‐dATP, and 8‐OH‐dGTP, and 2‐OH‐ATP, which have the syn ‐conformation, are all good substrates for hMTH1 [7,9]. Therefore, our present result that 8‐Cl‐dGTP, which may adopt the syn ‐conformation [10], is efficiently hydrolyzed by hMTH1 is compatible with this finding. Bessman et al have reported that 8‐Br‐dATP and 8‐Br‐dGTP are hydrolyzed by the Escherichia coli Mut T protein at a higher rate than unmodified dATP and dGTP [11].…”

Fluorescence Properties of 8‐(2‐Pyridyl)guanine “2PyG” as Compared to 2‐Aminopurine in DNA

“…Derivatization of the 8-position can generate fluorescent products [12-15, 17, 31] with emission properties that are sensitive to nucleic acid conformation. [17,18] While the addition of bulky groups to the 8-position of guanosine can shift the conformational equilibrium of the glycosidic bond from anti to syn, [32][33][34] DNA folding can force 8-modified guanosines to adopt anti conformations with relatively small energetic penalties to DNA folding (DDG 1 kcal mol À1 ). [34] Polymorphic G-quadruplex structures derived from the human telomeric repeat (hTelo) and cKit promoter (cKit) provide highly demanding model systems to evaluate internal fluorescent probes for their potential impact on the folding and stability of nucleic acids.…”

Biotechnology of Nucleic Acid Constituents - State of the Art and Perspectives

“…Such behavior of these related nucleosides may be explained by the strong preference of the latter for the syn-conformation about the glycosidic bond in contrast to the 2'-deoxy counterpart, which is in the syn anti equilibrium, accompanied by the different contribution of the bulky methyl group in the reaction. Note that 6-methyluracil was not a substrate in the reverse, synthetic reaction in the presence of an excess of the corresponding sugar 1-phosphates [25,26]. It was also found that neither 6-methyl-2'-deoxy-L-uridine nor L-thymidine undergo any change in the growing culture of E. coli and by the action of cell-free-extracts of E. coli both in the presence and the absence of ATP and the 2-deoxy-D-ribofuranose-1-O-phosphate (2'd-RP) [25].…”

“…It was suggested that the syn anti equilibrium of base about the glycosidic bond is driven by these substituents almost exclusively toward the former giving rise to the inactivity of the analogs vs the natural substrates that are conformationally rather flexible [13,26]. Indeed, the C8 amino group does not prevent the population of any conformation about the glycosidic bond and, as a consequence, 8-amino-adenosine and -guanosine are substrates of the phosphorolysis reaction; 8-aminoadenine was found to be a good ribosyl acceptor with guanosine as donor [13].…”