Search PubMed⌕ Search

Biomedical subjects

S Neidle

Publications and source records attributed to S Neidle.

At least 145 records · Page 8Linked to original sources
PubMed1986

DNA sequence preferences for the anti-cancer drug mitoxanthrone and related anthraquinones revealed by DNase I footprinting.

The interaction has been studied of several anthraquinone-based intercalating drugs, including the anti-cancer agent mitoxantrone, with defined sites of DNA. A 160 base pair DNA sequence from tyrT was employed for footprinting with DNase I. The anthraquinones had aminoalkylamino substituents in various positions of the ring system. Inhibition of enzymatic cutting of the DNA was observed at various positions on the sequence, mostly around some of the pyrimidine-3',5'-purine sites. Enhancements to cutting were observed clustered around AT-rich regions. The compounds showed differences in detailed footprinting behaviour, which have been related to differences in their mode of interaction with DNA as found in earlier computer modelling studies.

Anthraquinones↗
PubMed1986

Structural aspects of drug-DNA complexes: molecular modelling of intercalative interactions.

The molecular aspects of drug-DNA interactions are presented, with special reference to anticancer drugs. The current status of, and results from, X-ray crystallographic studies on drug-oligonucleotide complexes are reviewed. The conformational features of these complexes are given in relation to the geometry of the drug binding site. Computerized molecular modelling for the rational analysis and design of DNA-binding drugs is discussed, taking the X-ray information as a starting point. Recent results from the author's laboratory on anthraquinones and anthracyclines are presented.

Animals↗
PubMed1985

Nucleic acid binding drugs. Part XIII. Molecular motion in a drug-nucleic acid model system: thermal motion analysis of a proflavine-dinucleoside crystal structure.

The high-resolution crystal structure of the intercalation complex between proflavine and cytidylyl-3',5'-guanosine (CpG) has been studied by thermalmotion analysis. This has provided information on the translational and librational motions of individual groups in the complex. Many of these motions are similar to, though of larger magnitude than in uncomplexed dinucleosides. Pronounced librational effects were observed along the base pairs and in the plane of the drug chromophore.

Acridines↗
PubMed1985

Comparative computer graphics and solution studies of the DNA interaction of substituted anthraquinones based on doxorubicin and mitoxantrone.

1-[[(Diethylamino)ethyl]amino]- and 1,4-, 1,5-, and 1,8-bis[[(diethylamino)ethyl]amino]anthraquinones are shown to intercalate into DNA. Computer graphics modelling of their intercalation into the self-complementary deoxydinucleoside d(CpG) showed differences in binding properties. While the 1-substituted compound can bind from either groove, the 1,8-disubstituted compound binds with both substituents in the major groove. In the low-energy state of the complex with the 1,5-disubstituted compound, this ligand "straddles" the site with a substituent in each groove--to do this, the compound must bind to a non-base-paired region, so inducing base pairing. The 1,4-compound binds from the major groove; "straddling" is also possible if full minimization of deoxydinucleoside geometry is performed. The differences in binding mode and interaction energies are reflected in the affinities of interaction (1,5- greater than 1,4- much greater than 1,8- greater than 1-); also the antiproliferative effects in vitro are in general agreement with this ranking.

Animals↗
PubMed1985

Structural studies on some tamoxifen derivatives.

The crystal structures of four derivatives of the antiestrogenic drug tamoxifen are described. These are of 2-hydroxy-, 3-hydroxy-, and 2-methyl-4-hydroxytamoxifen and of 1-(4-methoxyphenyl)-2-phenyl-1-[(tetrahydropyran-2-yloxy)phenyl]-1 -butanol, the synthetic precursor to 2-hydroxytamoxifen. All compounds have trans stereochemistry about the ethylene double bond, as in tamoxifen itself. The orientations of the hydroxy substituents have been found to differ by 180 degrees, depending on the nature of the compound. Empirical energy calculations have been used to show that the barrier to free rotation for the hydroxy-substituted phenyl rings is too high for interconversion to take place. These orientational differences are, it is suggested, related to the marked differences in estrogen receptor binding ability.

Crystallography↗
PubMed1985

Variability in the geometry of RNA double helices generated from dinucleoside building-blocks.

A graphical method is presented for the generation of helical parameters from single-crystal structures of RNA nucleic acid fragments that are minimally dinucleosides. The method is compared with other published procedures, for a number of text examples. The RNA double helices generated from three different salts of the dinucleoside monophosphate GpC are examined in relation to the variations in helix morphology that are produced. It is shown that small differences between these GpC salts can be amplified to very distinct helix characteristics.

Dinucleoside Phosphates↗
PubMed1984

Studies on the conformation and dynamics of the C8-substituted guanine adduct of the carcinogen acetylaminofluorene; model for a possible Z-DNA modified structure.

The structure of an adduct between guanine and the carcinogen acetylaminofluorene has been examined in the solid state by X-ray crystallography, and in solution by NMR techniques. The observed conformations have been compared with predictions from energy calculations and their relevance to models of adducts with DNA has been examined.

2-Acetylaminofluorene↗
PubMed1984

Synthesis and biophysical studies of short oligodeoxynucleotides with novel modifications: a possible approach to the problem of mixed base oligodeoxynucleotide synthesis.

The syntheses of 1,2-dideoxy-D-ribofuranose and 1,2-dideoxy-1-phenyl-beta-D-ribofuranose are described. Oligodeoxynucleotides containing these analogues have been synthesised and hybridized to their complementary strands. Hypochromicity studies have shown that these duplices are less stable than either the totally complementary duplex or those containing A.C and G.T mismatches.

Deoxyribose↗
PubMed1984

Molecular models for the interaction of the anti-tumour drug nogalamycin with DNA.

Computer graphics and non-bonded energy calculations have been used to model the intercalative binding of the anti-tumour antibiotic nogalamycin, to double-stranded DNA. The drug is predicted to bind preferentially to A-T rich sites. Specific hydrogen bonds to the exocyclic amino group of adenine bases on the 3' side of an intercalative site have been found by the modelling procedure.

DNA↗
PubMed1984

Structural and sequence-dependent aspects of drug intercalation into nucleic acids.

Information gained from X-ray crystallographic studies on drug-nucleic acid complexes is described, with emphasis on the intercalation process. Relevant data from NMR experiments are examined in order to highlight similarities and differences between solution and solid-state structures. Theoretical analyses of intercalation complexes are also discussed and evaluated, with respect to the structural methods, with special reference being made to nucleic acid conformation and positions of drug molecules in the binding sites.

Base Sequence↗
PubMed1983

Experimental and computer graphics simulation analyses of the DNA interaction of 1,8-bis-(2-diethylaminoethylamino)-anthracene-9,10-dione, a compound modelled on doxorubicin.

The crystal structure of the anthraquinone derivative 1,8-bis-(2-diethylaminoethylamino)-anthracene-9,10-dione has been established. This compound was prepared as a potential DNA-intercalating agent based on the proven intercalators doxorubicin and mitoxantrone. Its DNA-binding properties have been examined experimentally by spectroscopic, thermal denaturation and ccc-DNA unwinding techniques: the results are consistent with an intercalative mode of binding to DNA. Computer graphics stimulation of the intercalative docking of this compound into the self-complementary dimer of d(CpG) has provided a minimum energy geometrical arrangement for the bound drug in the intercalation site comparable to that for proflavine when intercalated into the same d(CpG) model system. Entry of the compound into the site can only occur via the major groove.

Animals↗
PubMed1983

The antitumor complex ethylenediamine platinum (II) malonate: x-ray structure analysis, and studies of its stability in solution.

The anti-tumour compound ethylenediamine platinum (II) malonate has been examined by x-ray crystallography. The molecular structure has a square-planar arrangement around the platinum atom, with the malonate group in a boat conformation and cis to the ethylenediamine group. Solution studies have shown that the malonate ion may be readily displaced from the complex, especially by chloride ion, and at low pH. The implications of this finding for in vivo drug administration are discussed.

Antineoplastic Agents↗