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Biomedical subjects

W D Wilson

Publications and source records attributed to W D Wilson.

At least 199 records · Page 11Linked to original sources
PubMed1984

Stopped-flow kinetic, 1H, and 31P NMR analysis of the intercalation of ethidium with poly d(G-C) X d(G-C).

In a low salt buffer (0.011 M Na+) stopped-flow kinetic results for the SDS driven dissociation of an ethidium-Poly d(G-C) X d(G-C) complex are 8.7, 23, and 58.5 s-1 at 20, 30, and 40 degrees C, respectively. These results predict that in NMR experiments at high field strengths, ethidium should be in slow exchange among polymer binding sites. This has been found to be the case for both 31P (109 MHz) and 1H (imino proton spectra in H2O at 270 MHz) experiments. At higher salt, and/or higher temperature, and/or lower field, the bound and free peaks are no longer resolved in the NMR spectra. Good agreement is obtained between the stopped-flow kinetic results and the coalescence temperature observed in NMR experiments. Imino protons in base pairs on both sides of the intercalated ethidium are shifted approximately one ppm upfield while only the phosphate groups at the intercalation site experience large chemical shifts.

Chemical Phenomena↗
PubMed1984

A new series of reductive amination derivatives of daunorubicin: syntheses, partition coefficients, and DNA binding.

A series of daunorubicin derivatives were prepared by sodium cyanoborohydride reductive amination of daunorubicin with appropriate amines. All derivatives were found to bind quite strongly to DNA and viscosity increases with linear DNA indicated that each formed an intercalation complex. A range of octanol-aqueous buffer partition coefficients was obtained, around the values of daunorubicin and dauxorubicin hydrochloride, by varying the character of the starting amine. All monoamine derivatives had activity against P388 leukemia in mice which was similar to that of daunorubicin. A diamine derivative had reduced activity against P388. Several anthracyclines administered as DNA complexes had similar activity against P388 but significantly reduced toxicity compared to the uncomplexed compounds. For anthracyclines which bind strongly to DNA, optimum activity against P388 leukemia in mice seems to be centered on compounds with octanol-buffer partition coefficients in the range of 0.5-0.8.

Animals↗
PubMed1984

A substituent constant analysis of the interaction of substituted naphthalene monoimides with DNA.

In a continuing analysis of substituent effects in intercalator-DNA interactions, an unsubstituted naphthalene monoimide, with a 3-(dimethylamino)propyl group on the imide nitrogen has been prepared along with 3- and 4-nitro- and 3- and 4-amino-substituted derivatives. These derivatives allow an evaluation of the importance of the Hammett substituent constant and of the substituent position on the binding of naphthalene monoimides to DNA. Viscosity and spectrophotometric analyses indicate that all five compounds bind to DNA by intercalation. The 4-nitro compound gives a smaller viscosity increase and binds only approximately one-third as strongly as the 3-nitro derivative. It is postulated that this difference is due to the significant angle that the 4-nitro group makes with the intercalated monoimide ring system. The 3-NO2 group can assume a coplanar configuration with the monoimide ring system, allowing more favorable interactions with DNA base pairs, larger viscosity increases, and stronger binding to DNA. The binding constants of the 3-substituted monoimides are in the order 2 greater than 4 greater than 1 and, thus, do not follow a substituent constant pattern. The Tm values from thermal melting of DNA, on the other hand, are in the order 2 greater than 1 greater than 4, suggesting that the enthalpy contributions are significantly different for the binding of the three compounds to DNA. van't Hoff plots support this finding and indicate that both enthalpy and entropy contribute significantly to the binding free energy of 1 and 2 while the binding of 4 is primarily an enthalpic process. Plots of Tm and 65 degrees C log K values as a function of substituent constant for 1, 2, and 4 are linear. CPK model building studies suggest that 4 can form a hydrogen bond with the 5' diester oxygen of the sugar-phosphate backbone of DNA in an intercalation complex. This would lead to more favorable energetics of binding but a loss of mobility and/or available binding configurations with a resulting enthalpy-entropy compensation in the binding free energy of 4. This series of compounds dramatically illustrates the steric and hydrogen bonding complexity that can arise in attempts to design drugs to favorably interact with a DNA intercalation site as a potential bioreceptor.

Animals↗
PubMed1983

31P NMR and viscometric studies of the interaction of meso-tetra(4-N-methylpyridyl) porphine and its Ni(II) and Zn(II) derivatives with DNA.

The interactions of meso-tetra(4-N-methylpyridyl) porphine (TMPyP) and its Zn(II) and Ni(II) derivatives with DNA have been investigated by 31P NMR and viscometric titrations. TMPyP and its Ni derivative increase the viscosity of linear DNA, cause unwinding and reverse coiling of superhelical DNA, and induce a separate downfield peak in the 31P NMR spectrum of DNA. The Zn derivative slightly decreases the viscosity of linear DNA, does not unwind superhelical DNA, and does not give a downfield NMR peak. The main DNA 31P NMR signal is shifted slightly upfield on either the addition of TMPyP or the Ni compound. These results indicate that TMPyP and the Ni(II), but not the Zn(II), derivative bind to DNA by intercalation.

Animals↗
PubMed1983

Absorption and secretion of calcium and phosphorus in the alimentary tract of lambs infected with daily doses of Trichostrongylus colubriformis or Ostertagia circumcincta larvae.

The flows of endogenous and exogenous calcium and phosphorus in the digesta at the abomasum, ileum and in the faeces were measured in growing lambs infected daily with 3000 T. colubriformis larvae (TC), 5000 O. circumcincta larvae or no larvae. The lambs were given 0.70 or 1.0 kg per day of a pelleted diet and the flow rates were measured by reference to soluble and particulate radioactive markers. The fraction of Ca and P in digesta of endogenous origin was measured by the method of isotope dilution involving a single intravenous dose of 45Ca or 32P. Ostertagia circumcincta infection was without effect on the absorption and secretion of Ca and P in the digestive tract, other than producing a small but significant increase in the endogenous faecal Ca excretion. There was, however, a striking increase in the flow of digesta at the abomasum, the DM and Na content of which was consistent with an increased secretion from the mucus-type cells in the abomasal mucosa. The extra digesta was absorbed in the small intestine. Trichostrongylus colubriformis infections reduced the absorption of exogenous P by about 30 per cent and increased losses of endogenous P due to the action of worms on the mucosa of the small intestine. The net effect of this was to induce a P deficiency in TC lambs, leading to a reduced flow of salivary P and a reduction in the plasma concentrations of P. The effect of TC on Ca metabolism was limited to an increase in endogenous faecal excretion.

Animals↗
PubMed1982

Interactions of some novel amide-linked bis(acridines) with deoxyribonucleic acid.

A novel series of bis(acridines) has been synthesized in which the two potential intercalating chromophores are separated by symmetrical amide-linked chains varying in both length and conformational flexibility. By comparison to a monointercalating adduct, mono- vs. bis-intercalative behavior has been established for the bis(acridines). Spectrophotometric (visible, circular dichroism, and fluorescence) and viscometric (linear sonicated and closed circular superhelical DNA) experiments indicate that a highly rigid 8.8 A separated bis(acridine) monointercalates, whereas the longer and more flexible bis(acridines) are capable of bis-intercalation. In addition, spectrophotometric studies suggest a correlation between the tendency of intramolecular association and the ability to bis-intercalate. The results are in agreement with predictions based on the neighbor-exclusion principle and indicate that connecting chain rigidity is capable of playing a determining role in the mono- vs. bis-intercalation mechanism.

Acridines↗
PubMed1982

Viscometric analysis of the interaction of bisphenanthridinium compounds with closed circular supercoiled and linear DNA.

The interaction with closed circular supercoiled and linear DNA of bisphenanthridinium compounds substituted through both the meta and para positions of the 6-phenyl group, along with appropriate monomer intercalators as controls, has been investigated by viscometric titration. When CPK models for the phenanthridinium rings of the three bis-compounds are oriented in a parallel manner as a model for intercalation, their ring plane to ring plane distances are approximately 7 to 8 A (SR 2430), 11 A (SR 2193), and 15 A (SR 2166). In SR 2430 the two phenanthridines are linked through the para positions of the 6-phenyl group; this chain allows intercalation of the two rings at adjacent binding sites in DNA, but is not long enough to accommodate an excluded site. The viscometric titrations with both superhelical and linear DNA clearly indicate that SR 2430 gives results close to those of the monomer control compounds while SR 2193 and SR 2166 have approximately twice the unwinding angle and DNA length increase on binding to DNA as the monomer compounds. These phenanthridinium compounds, therefore, are capable of bisintercalation only if their linking groups are of sufficient length to allow an excluded binding site between base pairs. This conclusion is supported by DNA thermal denaturation experiments in the presence of these compounds.

Chemical Phenomena↗
PubMed1982

Interaction of actinomycin D, ethidium, quinacrine, daunorubicin, and tetralysine with DNA: 31P NMR chemical shift and relaxation investigation.

The binding of actinomycin D, ethidium, quinacrine, daunorubicin, and tetralysine to DNA has been investigated using 31P NMR. Titration of DNA with actinomycin yields a new downfield peak or overlapping peaks as would be expected from the slow dissociation kinetics of this compound. The other intercalators shift the DNA 31P signal downfield as a single exchange averaged peak. Tetralysine causes a slight upfield shift. The chemical shift titration curves for the intercalators are sigmoid curves suggesting that cooperative processes or competing effects on the chemical shift are being observed. The magnitude of the chemical shift change at saturation of DNA with the compounds is found to vary significantly and to be linearly related to the DNA base pair unwinding angle for the compounds. Analysis of 31P spin lattice relaxation times (T1) and linewidths as a function of temperature (below Tm) and titration with the above compounds indicates that T1 does not change significantly while linewidth increases with decreasing temperature and increasing bound intercalator. One interpretation of these results is that in both cases the overall motion of DNA becomes slower while the internal motion is not greatly affected.

Animals↗
PubMed1980

The effect of ionic strength on DNA-ligand unwinding angles for acridine and quinoline derivatives.

We have quantitatively examined the unwinding angles for the complexes of a related series of acridine and quinoline derivatives with DNA. Ethidium bromide was used as a control for determining superhelix densities at different ionic strengths. Relative to ethidium, 9-aminoacridine and quinacrine had an essentially constant unwinding angle of approximately 17 degrees at all ionic strengths tested. The apparent unwinding angle for chloroquine and 9-amino-1,2,3,4-tetrahydroacridine was found to be ionic strength dependent, increasing with increasing ionic strength. This suggests that competitive nonintercalative binding at low ionic strengths causes an apparent lowering of the quinoline unwinding angle. This can also explain why 4-aminoquinaldine, examined at low ionic strength, gives a quite low apparent unwinding angle. Quinacrine along with chloroquinine and 9-aminoacridine approaches a limiting value for their unwinding angle of approximately 17 degrees. 4-aminoquinaldine and 9-amino-1,2,3,4-tetrahydroacridine could not be examined at an ionic strength above 0.03 because of their very low equilibrium binding constants.

Aminacrine↗
PubMed1979

Comparative viscometric analysis of the interaction of chloroquine and quinacrine with superhelical and sonicated DNA.

Unwinding angles for the structurally related antimalarial drugs chloroquine and quinacrine have been determined with superhelical Col E1 plasmid DNA by applying the quantitative method developed by Vinograd and co-workers (Revet, B.M., Schmir, M. and Vinograd, J. (1971) Nat. New Biol. 229, 10). The value for chloroquine, 8.6 degrees, calculated assuming an unwinding angle of 26 degrees for ethidium bromide, is significantly lower than the value for quinacrine, 22.5 degrees, calculated in the same manner. Viscometric titrations with sonicated calf thymus DNA were quantitated using available binding constants for the two drugs and indicated that chloroquine also causes significantly smaller DNA length increases on intercalation relative to quinacrine. The conclusion from these experiments is that chloroquine does not bind to DNA by the classical intercalation mechanism typical of quinacrine and ethidium.

Bacteriocin Plasmids↗
PubMed1979

Dimerization of coralyne and its propyl analogue and their association with DNA.

Dimerization of coralyne, Ia, and its propyl analogue Ic has been analyzed at neutral pH as a function of ionic strength. Even at low ionic strength (I = 0.02) dimerization constants (molar units) for both compounds are 10(5) or greater, which is considerably larger than values obtained for similar intercalating molecules. Coralyne seems to undergo association to higher aggregates somewhat easier than Ic, which could be due to the fact that the propyl group on Ic provides some steric hinderance in forming higher aggregates. Both compounds readily associate with DNA. At high ratios of ligand to DNA, the spectra for Ia or Ic are similar to that of a highly aggregated complex. At low ratios of ligand to DNA, the spectra for both compounds approach a limit, which is relatively independent of ionic strength and concentration, and can be identified with the intercalated species. The slight differences between Ia and Ic in dimerization or in association with DNA do not seem capable of explaining the significant differences in antileukemic activity of these compounds.

Antineoplastic Agents↗