A kinetic and nuclear magnetic resonance study of methylated pyrimidine nucleosides

JEAN CADET, LUCIENNE VOITURIEZ, FRANK E. HRUSKA, LOU-SING KAN, FRANK A. A. M. DE LEEUW, and CORNELIS ALTONA. Can. J. Chem. 63, 2861Chem. 63, (1985.We describe the preparation of the six configurationally distinct cyclobutane-type photodimers generated by the acetonesensitized uv irradiation of thymidine in aqueous solution. Also prepared as minor photoproducts are the 5R and 5 S diastereoisomers of 5,6-dihydrothymidine, and two novel molecules, the 5R and 5.3 diastereoisomers of 5-acetonyl-5,6-dihydrothymidine. The purification of the ten molecules by chromatographic techniques (hplc, tlc) is described, along with their extensive characterization by uv, ir, cd, FAB-ms and 'H nmr. The proton chemical shifts and coupling constants are discussed in terms of the geometry of the pyrimidine, cyclobutane, and sugar rings. Les six diastCrCoisomkres possibles de la cyclobutidithymidine ont CtC prCparCs par photosensibilisation de la thymidine B la lumikre du proche ultra-violet en utilisant I'acetone. Les diastCrCoisomkres 5R et 5.3 de la dihydro-5,6 thymidine et deux nouveaux photoproduits, les formes 5R et 5 S de I'acCtonyl-5 dihydro-5,6 thymidine ont aussi CtC isolts. L'identification de ces photoproduits a fait appel B diverses techniques spectroscopiques: uv, ir, dichroi'sme circulaire, spectromktrie de masse par bombardement avec des atomes rapides et rmn 'H. Les valeurs des paramktres de rmn (deplacements chimiques, constantes de couplage) sont discutCes en termes de stCrCochimie des cycles pyrimidiniques, cyclobutyles et osidiques. IntroductionThe cyclobutane-type of photoproduct formed from adjacent thymine bases is the most thoroughly studied of the lesions induced by uv irradiation of DNA (1). The biological significance of these thymine photodimers is evidenced by the existence of mechanisms for their removal (2). Several studies reveal that the presence of the dimers leads to distortions in nucleic acid structure (3-7) that could play a role in the recognition by the enzymes of the repair system and may account for the altered specificity of, for example, restriction enzymes which employ DNA as a substrate (8). The numerous studies of the photodimerized thymine bases, Thy()Thy (R = H; Fig. I), have provided valuable photochemical and structural information (I), but relatively fewer data are available for the corresponding thymidine derivatives, dThd()dThd (R = 2-deoxy-P-D-ribose), which are the molecules of main interest in the present work. Wulff and Fraenkel (9) originally listed four isomeric forms of Thy()Thy. Actually, six configurationalIy-distinct forms are possible, since the trans-syn (ts) and cis-anti (ca) isomers exist as enantiomeric pairs ts 1, ts2 and c a l , ca2 whereas the cis-syn (cs) and trans-anti (ta) isomers exist as single (rneso) molecules. Similarly, six dThd()dThd are possible and are denoted CS, TS1, etc. according to the geometry of the Thy()Thy fragment (Fig. 1).

Section: Sugar Conformationmentioning

confidence: 83%

Characterization of thymidine ultraviolet photoproducts. Cyclobutane dimers and 5,6-dihydrothymidines

Cadet¹,

Voituriez²,

Hruska³

et al. 1985

“…The calculated values of %g- (Table 5) are interesting in the light of data for ribosides and other 2'-deoxyribosides (41,46,47). In both the ribose and deoxyribose series, the g-con- formation is the least likely, but g-is more completely suppressed in the ribosides.…”

Section: C4'<5'mentioning

confidence: 87%

A conformational study of the adducts of 2′-deoxythymidine and 2,2,6,6-tetramethyl-1,4-piperidone-N-oxyl by ¹H and ¹³C nuclear magnetic resonance

Hruska¹,

Berger²,

Cadet³

et al. 1985

CADET, and MIECZY~LAW REMIN. Can. J. Chem. 63, 15 (1985). y-Irradiation of oxygen-free, aqueous solutions of 2'-deoxythymidine in the presence of the organic nitroxide free radical, 2,2,6,6-tetramethyl-1,4-piperidone-N-oxyl (TAN), leads to a complex mixture of products in which the TAN moiety is linked to the C5 or C6 position of a 5,6-saturated thymine ring. Extensive 'H and '?c nmr data are provided for the eight TAN-dT adducts which are produced in the largest amounts. The results show that the conformational properties of the sugar moiety are dependent on the point of attachment of the TAN group and the configuration of the saturated thymine ring.

“…To obtain i2dT and e2dT, dT was converted to its 3'-acyl derivative by standard procedures (18) and then to the 23'-anhydronucleoside following Secrist (19), as described in earlier work (20). Reflux of the latter derivative (1 rnmol) in 20 rnL of rnethanolic sodium isopropoxide or sodium ethoxide afforded the unprotected i2dT or e2dT.…”

Section: Methodsmentioning

confidence: 99%

“…Following neutralization with IRC-50 resin, the three nucleosides were purified by silica gel chromatography. Compounds m2dT and m4dT were preparedearlier as described (20).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Carcinogenic alkylation of nucleic acid bases. Solid state and solution studies of O²-isopropyl-2′-deoxythymidine

Birnbaum¹,

Sadana²,

Razi³

et al. 1988

. Can. J. Chem. 66, 1628 (1988). 0~-1so~ro~yl-2'-deoxythy~idine (i2dT) crystallizes in the tetragonal space group P4,2,2, and the cell dimensions are a = b = 8.7667(2), c = 37.1943(12) A. X-ray intensity data were measured with a diffractometer, and the structure was solved by direct methods. Least-squares refinement, which included all hydrogen atoms, converged at R = 0.036 for 1780 observed reflections. In analogy with other 0-alkylated bases, the exocyclic 0 2 4 8 bond is syn-periplanar to the C2-N3 bond in the pyrimidine ring. Angular distortions in the base can be correlated with those observed in 04-alkylated pyrimidines and 06-alkylated guanines. The conformation of the glycosyl bond is anti with XCN = 27. lo. The furanose ring adopts a C2' endo pucker and the conformation about C 4 ' 4 5 ' is gauche+. 'H nrnr data show that these conformations are also preferred in solution. [Traduit par la revue]