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Various structural analogues of cytosine and uracil nucleosides were tested as potential inducers of the nucleoside catabolizing (cyt) enzymes in Salmonella typhimurium. Some analogues, e.g. 5'-O-alkyl cytidines and uridines, resistant to catabolic enzymes, were as effective as the natural inducers cytidine and uridine; but etherification of one of the cis 2' or 3'hydroxyls fully abolished activity, pointing to a requirement of an intact ribose cis-glycol system for activity. A uridine analogue in the syn conformation, 6-methyluridine, a good substrate for uridine phosphorylase, was inactive as an inducer. The behavior of various other analogues, in relation to their structure, conformation and substrate properties, indicated the absence of any correlation between inducing activity and substrate susceptibility. The overall findings are consistent with conclusions derived from genetic experiments. The active analogues apparently act via similar pathways, and probably affect the same regulatory mechanism(s) as the natural inducers.
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The differential tissue uptake and blood clearance of [2-14C]-5-ethyl-1-(2'-deoxy-beta-D-ribofuranosyl)uracil [2-14C]-5-EtUdR) in BDF1 mice bearing Lewis Lung carcinomas has been investigated. The kidney, gall bladder with contents and GIT exhibited the greatest concentration of radioactivity relative to the tumor up to 30 min after i.v. injection of [2-14C]-5-EtUdR. Blood, spleen, liver and muscle exhibited a lower concentration of radioactivity than the former group. Radioactivity levels in the stomach and skin were similar to that of the tumor. The long bone had the lowest radioactivity level of all the tissues examined. During the 1-3 h period following injection, the tumor contained more radioactivity than most other tissues with the exception of the gall bladder and contents, GIT and kidney. Packed erythrocytes contained 62-78% of the radioactivity in the whole blood. Clearance of injected radioactivity from whole blood followed two-compartment kinetics. Elimination was mainly renal, although some biliary excretion of injected radioactivity was also observed.
The tritium-labelled acyclonucleoside, N-[2-(hydroxyethoxy)methyl]-5-[3H]methyluracil (3H-3), was synthesized for evaluation as a tumor diagnostic agent. 5-[3H]-Methyluracil, 3H-1, was converted to the 2,4-bis-trimethylsilyl intermediate which was coupled with 2-acetoxyethoxymethyl bromide to afford 1-[(2-acetoxyethoxy)methyl-5-[3H]methyluracil (3H-2). Treatment of 3H-2 with sodium methoxide in methanol afforded 3H-3 (specific activity 188 MBq mmol-1. The tissue distribution of 3H-3 was examined in male BDF1 mice bearing Lewis Lung (LL) carcinomas. Long bone exhibited the highest tumor: tissue ratios. The kidney contained the highest radioactivity level relative to the tumor. This suggested a major urinary route of excretion. The major radioactive blood component (89.21%) was found to have a biological half-life of 0.19 min. The title compound is unsuitable for use as a diagnostic agent for LL carcinoma because of low tumor uptake and rapid urinary elimination of injected radioactivity from the body.
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Vibrational circular dichroism (VCD) spectra were measured in the C = O stretching region for poly(U)*poly(A).poly(U), poly(dT)*poly(dA).poly(dT), and poly(U)*poly(dA). poly(dT). These VCD spectra of the triple-helical structure were dramatically different from those of the corresponding duplexes. The VCD indicates that a very similar base-pair structure is present in these triplexes. The same sign pattern was found for poly(C+)*poly(I).poly(C), which implies a generality of structure than can result from the steric constraint of the triple helix conformation. By contrast, the corresponding duplexes are quite different in terms of their VCD. The transitions between triplex, duplex, and single-stranded forms were studied as a function of temperature and interpreted using factor analysis. The relative stabilities of the triplexes lie in the order RNA > DNA > hybrid. Nondegenerate dipole-coupling calculations for a U*A.U oligomer were carried out for the C = O stretching modes to model the spectral changes observed. The experimental absorbance spectra indicate that the bases have nonequivalent H-bonds which can be achieved if a reverse Hoogsteen base-pairing scheme is assumed. The computational VCD results with such a scheme were in better qualitative agreement with experiment than those using the expected Hoogsteen base-pairing scheme.
The detailed conformational features and dynamics of heterodinucleoside monophosphates ApU, ApC, GpU, GpC, UpA, CpA, UpG, and CpG have been studied in aqueous solution by high field nuclear magnetic resonance (NMR) spectroscopy. Analysis of the resultant NMR parameters leads to a number of discernible trends throughout the series. Thus the ribose rings of the dimers exist as equilibrium mixtures of C(2')-endo(2E) in equilibrium C(3')-endo(3E) conformers with a proclivity for the 3E pucker in most cases; the C(4')-C(5') bonds of both nucleotidyl units show significant preference (74-96%) for a gg conformation and the dominant conformer (85-89%) about C(5')-O(5') is g'g'. Orientation about the C(3')-O(3') bond is coupled to the ribose conformational equilibrium and the system exists with a bias for the 3Eg- coupled conformation in which the H(3')-C(3')-O(3')-P dihedral angle occupies the narrow range of 33-35 degrees. Dimerization, on the average, causes about 10% increase in gg and g'g' populations and the g-domain becomes increasingly populated about the C(3')-O(3') bond. The ribose equilibrium 2E in equilibrium 3E shifts in favor of 3E upon dimerization, the effect being very conspicuous for the pu-py series (similar to 40 yields 60%) and less noticeable for the py-pu systems (similar to 47 yields 58%), clearly suggesting a correlation between sequence and ribose conformational equilibrium. The temperature and dimerization data for the heterodinucleoside monophosphates show that the transition 2E yields 3E is directly related to XCN changes induced by dimerization and stacking. Analysis of the ribose coupling data shows that the percentage populations of stacked species vary from dimer to dimer with GpC displaying a maximum of 45% stacked population and UpG about 10%. However, in general, the pu-py dimers show a higher preference (27-45%) for stacked conformations than py-pu dimers (10-25%). It is proposed that the pronounced deshielding of H(5') of the 5'-nucleotidyl units upon dimerization is associated with the presence of right-handed stacks (g-g-), whereas the chemical shift trends of H(5') and H(5') of 3'-nucleotidyl units are due to the presence of left-handed stacks (g+g+) in all the dimers. In pu-py dimers, the population of the g-g- species is found to be greater than that of g+g+. Also the population of g-g- stacks in pu-py dimers is generally greater than in their corresponding matched py-pu dimers. Thus the base sequence has not only an explicit effect on the overall populations of stacked species, but also on the handedness of the stacks. The present results further confirm the interdependence of conformational bonds throughout the nucleotidyl framework.
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