In view of the selective anti-HIV activity of 2',3'-dideoxy-3'-fluoro-5-chlorouridine (11), a series of eight 2',3'-dideoxy-5-chloropyrimidines were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus type 1 (HIV-1) replication in MT-4 cells. A marked improvement in selectivity was noted for the 5-chlorouracil derivatives of 2,3-dideoxyribofuranose, 3-azido-2,3-dideoxyribofuranose, and 3-fluoro-2,3-dideoxyribofuranose, mainly due to decreased toxicity of the compounds for the host cells. While chlorination of 2',3'-dideoxycytidine removed the anti-HIV activity, introduction of a chlorine at the C-5 position of 3'-fluoro-, 3'-azido- or 2',3'-didehydro-2',3'-dideoxycytidine led to reduced cytotoxicity with only slightly reduced anti-HIV activity. X-ray analysis showed compound 11 to have two molecules in the asymmetric unit with chi = -168.8 (3) degrees and -131.3 (3) degrees and P = 179 (1) degree and 163 (1) degree, respectively; thus revealing no close resemblance to 3'-azido-3'-deoxythymidine (AZT).
A comparison between the cdi1formation al parameters of eleven active and inactive anti-HIV· 2',3'-dideoxyp yrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles X in the anti range, have pseudorotatio n phase angles Pwell distributed over both N (C3 '-endo) and S (C2'-endo and C3' -exo) type sugar conformation s and have both +sc and ap C4' -C5' conformations . This means that solid state conformation s characterized by P, X and "y do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirica l quantum chemical AM1 method. Calculations of C3'-X3' bond polarities indicate that anti-HIV activity in C3'-substitute d nucleoside analogues is consistent with the presence of a positive C3'-X3' bond polarity. Exploration of the conformationa l space of X vs. "y for C3'-endo, C2'-endo and C3'-exo sugar puckering modes using the same AM1 method, reveals that although the C3'-endo (P = 10°) region is about 2 kcal rnol" lower than the C2'-endo region (P = 170°),the C2'-endo sugar puckering mode is the most accessible one due to the conformationa l flexibility about the minima. Our results also suggest that as P increases from 10°, through 170°,to 210°, the preferred range for v dramatically shifts from almost exclusively
1-(2,3-Dideoxy-3-fluoro-beta-D-erythro-pentofuranosyl)thymine, C10H13FN2O4, Mr = 244.22, monoclinic, P21, a = 6.408 (14), b = 18.716 (26), c = 9.329 (7) A, beta = 98.4 (1) degrees, V = 1107 (3) A3, Z = 4, Dm = 1.46, Dx = 1.465 Mg m-3, graphite-monochromated Mo K alpha radiation, lambda = 0.71073 A, mu = 0.1169 mm-1, F(000) = 512, T = 298 K, final R = 0.035 for 1425 unique observed reflections. The asymmetric unit contains two molecules (A and B). For molecule A: the N-glycosidic torsion angle chi has a value of -138.4 (5) degrees in the anti range; the sugar pucker is 2E with P = 164 (1) degrees and psi m = 36 (1) degrees and the C4'--C5' conformation is +sc with gamma = 50.2 (7) degrees. For molecule B: the N-glycosidic torsion angle chi has a value of -159.6 (5) degrees in the anti range; the sugar pucker is 2T3 with P = 169 (1) degrees and psi m = 32 (1) degrees and the C4'--C5' conformation is + sc with gamma = 52.8 (7) degrees. The conformational parameters are in accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature [Pure Appl. Chem. (1983), 55, 1273-1280] guidelines. Base-pair formation occurs between the two molecules A and B.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.