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

Abstract

. 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]

An NMR study of dinucleoside monophosphates with an O4-ethylated thymine. d(e4TpT) and d(Tpe4T)

“…The H6 and 5-CH3 protons were assigned on the basis of the observed deshielding effect (0.22 ppm and 0.10 ppm, respectively) due to 04-alkylation at the monomer lever (7,8,12,13 Fig. 2).…”

“…0 -Alkylation of guanine and thymine effects an alteration in their hydrogen bonding capacity that forms the basis for interpretation of the misincorporations observed during transcription and replication (2)(3)(4). Information about the electronic and geometrical changes resulting from 0-alkylation has been provided by the X-ray crystallographic studies of 04-methyluridine (m4U) ( 3 , 04-methylthymidine (m4dT) (6), 04-ethylthymidine (e4dT) (7), and 02-isopropylthymidine (i2dT) (8), as well as for 'presented at the 5th Conversation in Biomolecular Stereodynamics, Albany, NY, June 2-6, 1987 and the 70th Canadian Chemical Conference, QuCbec, P.Q., June 7-11, 1987.…”

“…several 06-alkylated purine nucleosides and analogues (9-1 1): 'H and 13C NMR data have been reported for a large number of 0-alkylated nucleosides (8,(12)(13)(14). More relevant data about the changes produced in DNA structure are now being provided by NMR investigations of oligodeoxynucleotides, but these are limited to a few recent studies (15,16).…”

Comparison of polymerase insertion and extension kinetics of a series of O2-alkyldeoxythymidine triphosphates and O4-methyldeoxythymidine triphosphate

“…Recent NMR and X-ray crystallographic studies of the nucleoside OMsopropyl-dT indicate a conformation similar to that of 04-ethyl-dT (Lafortune, 1986;Birnbaum et al, 1988). However, preliminary modeling studies of the C^-alkyl-dT series in the M13 DNA sequence and poly[d(A-T)] (E. Loechler, personal communication) suggest an unusual hydrophobic pocket resulting from the branched isopropyl group extending to the opposite A and interacting with the C2 of A.…”

Synthesis and properties of DNA oligomers containing an O4-ethylated thymine. d(e4TpA), d(Ape4T), d(Ape4TpA), and d(Tpe4TpT)

“…-On the other hand, the formation of the alkyltriesters does not lead to misincorporation of bases, though their presence has been shown to inhibit in vitro replication by E. coli DNA polymerase I (2). Some insight into the action of these agents is provided by the structural information obtained at the monomer level by X-ray crystallographic (3)(4)(5)(6)(7)(8) and NMR (9, 10) investigations of 0-alkylated nucleosides. More useful are the structural data for oligomer duplexes are limited (11,12):…”