Relationship between the mutagenic and base-stacking properties of halogenated uracil derivatives: The crystal structures of 5-chloro- and 5-bromouracil

Abstract

Three-dimensional X-ray diffraction data were used to determine the crystal structures of 5-chlorouracil and 5-bromouracil, two mutagenic pyrimidine analogs that can substitute for thymine in DNA. Crystals of the two compounds are nearly isostructural. The space group is P2 1 c , with a = 8.450(6), b = 6.842(3), c = 11.072(16) a ̊ , β = 123.53(19)° for 5-chlorouracil, and a = 8.598(3), b = 6.886(1), c = 11.417(5) a ̊ , β = 123.93(3)° for 5-bromouracil. Intensity data were collected with an automated diffractometer. The structures were refined by full-matrix least-squares to R = 0.058 for 5-chlorouracil and R = 0.027 for 5-bromouracil. The analogs form planar, hydrogen-bonded ribbons that are nearly identical to those found in the crystal structure of thymine monohydrate. As in many other structures of 5-halogenated uracil derivatives, the bases assume a stacking pattern that permits intimate contacts between the halogen substituents and the pyrimidine rings of adjacent bases. This stacking pattern involves halogen contacts that are significantly shorter than normal van der Waals interactions. The crystallographic results provide additional evidence that halogen substituents influence the stacking patterns of uracil derivatives, while exerting little direct effect on the hydrogen-bonding properties. The observed stacking patterns are consistent with the hypothesis that altered stacking interactions may account for the mis-pairing between 5-halogenated uracil bases and guanine residues within double-helical nucleic acids.