Thermodynamic studies on the interactions of di-substituted anthraquinones with DNA.
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Anthraquinones↗
Biomedical subjects
S Neidle
Publications and source records attributed to S Neidle.
Molecular modelling of DNA-antitumour drug intercalation interactions: correlation of structural and energetic features with biological properties for a series of phenylquinoline-8-carboxamide compounds.
The crystal structure of the experimental antitumour compound N-(2-dimethylaminoethyl)-2-phenylquinoline-8-carboxamide has been determined. The geometry and conformation have been used as starting points for molecular modelling of the intercalative interactions with DNA shown by the parent compound and analogues with the phenyl ring located at alternative positions on the quinoline chromophore. A molecular mechanics force field program was used for energy minimization and calculation of intermolecular (enthalphic) binding energies. The parent quinoline-8-carboxamide and derivatives with a phenyl substituent at the 4- or 5-position were judged to be poor intercalators in both structural and energetic terms. By contrast, the 2-, 3-, and 6-phenyl derivatives all had high calculated binding energies with the phenyl groups involved in stacking with DNA base pairs. The order of energies calculated for this series of compounds has been found to correlate well with both the order of experimentally derived free energies and with the in vitro cytotoxic activity.
Antineoplastic Agents↗
Quinazoline antifolates inhibiting thymidylate synthase: computer modelling of the N10 substituent.
The synthesis and biological properties of N10-(2,2,2-trifluoroethyl)-5, 8-dideazafolic acid are described. It was fivefold less active as an inhibitor of L1210 thymidylate synthase (TS) than its N10-ethyl congener and sevenfold less active as an inhibitor of the growth of L1210 cells in culture. CNDO calculations were performed on the following N10 substituents in a model fragment of 5, 8-dideazafolic acid: propargyl, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, cyanomethyl and methyl. The resulting values of partial charge on the distal terminus of the substituent correlated with the TS inhibition induced by the substituent. In particular, the mildly net positive charge on the acetylenic hydrogen in the propargyl substituent (+0.064) was not matched by any other in the series. N10-propargyl-5, 8-dideazafolic acid continues as the best inhibitor in this series.
Animals↗
Structures of the anticancer compounds N-(2-hydroxyethyl)-2-(3-nitro-1,2,4-triazol-1-yl)-acetamide (RB-6110) and 5-(1-aziridinyl)-3-nitro-1-(3-oxo-1-butyl)-1,2,4- triazole (RB-6162).
RB-6110: C6H9N5O4, Mr = 215.17, monoclinic, C2/c, a = 20.595 (3), b = 4.713 (1), c = 19.914 (4) A, beta = 110.69 (1) degree, V = 1808.3 A3, Z = 8, Dx = 1.588 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.838 mm-1, F(000) = 675, T = 298 K, final R = 0.042 for 1219 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6162: C8H11N5O3, Mr = 225.21, monoclinic, P2(1)/c, a = 7.515 (1), b = 14.758 (2), c = 9.813 (1) A, beta = 108.49 (1) degree, V = 1032.1 A3, Z = 4, Dx = 1.450 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.927 mm-1, F(000) = 472, T = 298 K, final R = 0.042 for 1113 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6110 and RB-6162 are 3-nitro-1,2,4-triazoles with potential application as anticancer agents. The nitro groups are in the plane of the aromatic triazole ring with dihedral angles of 1.2 (4) and 4.6 (4) degrees, respectively. The arizidine substituent of RB-6162 is almost perpendicular [dihedral angle 80.1 (4) degrees] to the triazole plane. Molecular-orbital calculations on RB-6162 have confirmed that this geometry is energetically favoured. The energy barrier to rotation about the triazole-aziridine bond has been determined as 51.5 (5) kJ mol-1 by the dynamic NMR method.
Antineoplastic Agents↗
A molecular model for proflavine-DNA intercalation.
A molecular model has been derived for the intercalation of proflavine into the CpG site of the decamer duplex of d(GATACGATAC). The starting geometry of the intercalation site was taken from previous crystallographic studies on the d(CpG)-proflavine complex, and molecular mechanics used to obtain a stereochemically acceptable structure. This has widened grooves compared to standard A- or B- double helices, as well as distinct conformational, roll, twist and tilt features.
Acridines↗
The influence of the ethyl group on the conformational flexibility of aminoglutethimide.
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Aminoglutethimide↗
Synthesis, molecular modeling, DNA binding, and antitumor properties of some substituted amidoanthraquinones.
A series of 1- and 1,4-substituted amidoanthraquinones have been prepared, with side chains possessing basic nitrogen atoms. Computer modeling and energy calculations have shown that all eight compounds can bind intercalatively to DNA and that there are significant differences in the additional nonbonded and electrostatic interactions possible at the DNA binding site. Solution DNA binding and closed-circular DNA unwinding studies confirmed intercalative interactions, and the predicted differences in strength of interactions between mono- and disubstituted compounds were found. All compounds were modestly cytotoxic to L1210 cells in culture. In vivo activity against L1210 and S180 tumors was not found for the monosubstituted compounds, whereas the four disubstituted ones had varying levels of measurable, though low, activity.
Animals↗
Experimental DNA-binding and computer modelling studies on an analogue of the anti-tumor drug amsacrine.
The DNA-binding properties of the anti-cancer drug amsacrine and a 9-aminoacridine analogue substituted at the 4 position with a 4-methanesulphonanilido-group, have been examined by means of unwinding, melting and equilibrium binding experiments. These find that the latter compound is at least as effective as a DNA-binder and intercalator as amsacrine itself. Molecular modelling and energetic calculations have confirmed this, and have produced plausible intercalation geometries. These show that there are subtle differences in the low-energy minor groove arrangements adopted by the substituents of the two drugs. Speculation is advanced that these differences may be relevant to the marked differences in cytotoxicity shown by the two compounds.
Amsacrine↗
Molecular modelling of the interactions of tetra-(4-N-methylpyridyl) porphin with TA and CG sites on DNA.
The molecular structure of the DNA-intercalating ligand tetra-(4-N-methylpyridyl) porphin has been determined by X-ray crystallography. The porphyrin has a precise centre of symmetry; the central core is planar, with the N-methylpyridyl groups inclined to it at angles of 66-72 degrees. Molecular modelling of this structure into TpA and CpG sites of intercalated DNA, has been performed, and approximate energetics calculated. It has been shown that only the CpG site can have full ligand intercalation, since the thymine methyl group sterically hinders such geometry at TpA sites. Modelling indicates the importance of electrostatic effects in the low-energy forms of intercalated and part-intercalated complexes at both sequences.
Base Composition↗
Conformational properties of 3'-azido-3'deoxy-thymidine (AZT), an inhibitor of HIV reverse transcriptase.
The low-energy conformations of 3'-azido-3'-deoxy-thymidine, (AZT), an inhibitor of retroviral reverse transcriptase, have been studied by molecular mechanics techniques. A force-field has been developed for the azido group by quantum-mechanical methods, and used in the analysis. The global low-energy structure of AZT has C3'-endo sugar pucker, an anti glycosidic angle, and a g+ C4'-C5' conformation. It is concluded that the AZT molecule has conformational properties that are very similar to those of standard deoxypyrimidines.
Antiviral Agents↗
The crystal structure of the DNA-binding drug berenil: molecular modelling studies of berenil-DNA complexes.
The crystal structure of the DNA minor-groove DNA-binding drug berenil has been determined. Molecular-modelling techniques have been used to establish plausible binding modes of the structure to A-T sequences. These have shown that specific hydrogen bonds are possible between the amidine groups of the drug molecule and 02 atoms of thymine, although global energy minimisations tended to emphasise electrostatic interactions with phosphate groups rather than these hydrogen bonds with bases.
Amidines↗
DNA structure and perturbation by drug binding.
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Base Sequence↗
DNA sequence preferences for an intercalating porphyrin compound revealed by footprinting.
The DNA sequence preferences of the compound meso-tetra-(4-N-methyl(pyridyl) porphyrin and its nickel complex have been investigated by means of footprinting experiments on several DNA fragments, using DNAase I and micrococcal nuclease as footprinting agents. A complex pattern of both AT and GC-protected sites was found. Ligand-induced long-range conformational changes were inferred in several instances to be related to the observed large-scale blockages of enzymatic cutting.
Base Sequence↗
Crystallographic and molecular mechanics calculations on the anti-tumor drugs N-[(2-dimethylamino)ethyl]-and N-[(2-dimethyl-amino)butyl]-9-aminoacridine-4-carboxamides and their dications: implications for models of DNA-binding.
The molecular structures of the N-(2-dimethylamino)ethyl and N-(2-dimethylamino)butyl derivatives of 9-aminoacridine-4-carboxamide, of current interest as potential anti-cancer agents have been determined by X-ray Crystallography. Both are in the free base form and have an intramolecular-hydrogen bond between N10 of the acridine and the nitrogen atom of the carboxamide substituent. Molecular mechanics calculations have been used to explore the conformational flexibility of this substituent with respect to the chromophore in order to determine the low-energy conformers of both free base and protonated forms. These have revealed flexibility in the system with relatively low energy cost, especially in the physiological condition when the N10 atom is protonated and suggest that a previously published model for the interaction of these compounds with DNA, is energetically feasible. Implications for interactions with DNA have also been examined by computer modelling.
Aminoacridines↗
The influence of intercalator structure on DNA binding strength: the importance of side chain orientation.
A naphthothiophene intercalator with a cationic side chain linked to the ring through an ester group (1E) has been shown to bind to DNA almost an order of magnitude more strongly than a similar compound with the side chain linked to the ring through an amide group (1A) (W.D. Wilson, et al., Biophys. Chem. 24, 101-109 (1986]. X-ray crystallographic analysis of these two compounds indicates that both the ester and amide groups are essentially planar but that the amide is twisted approximately 30 degrees out of the aromatic plane of the naphthothiophene while the ester and ring system are co-planar. Proton NMR studies of the DNA complexes of these two compounds indicate that the naphthothiophene ring is intercalated in both 1A and 1E but that the protons of the ring system near the side chain interact with DNA base pairs at the binding site significantly better in 1E than in 1A. The protons next to the ester group on the side chain of 1E are also shifted upfield significantly more on addition of DNA than those of 1A. The large planar area of 1E, thus, allows greater stacking, complex geometry optimization, and dipolar interactions of the ester group with DNA base pairs at the binding site to account for the larger binding constant of this compound relative to 1A.
Base Composition↗
Podophyllotoxin analogues: synthesis and computer modelling investigation of structure-activity relationships.
The conformations of four 2-substituted-4-deoxy-analogues of podophyllotoxin have been studied using data obtained from X-ray structure determinations and molecular modelling studies. In these, root mean square differences between these structures and those of the cytotoxic agents 6'-bromopodophyllotoxin and colchicine were determined. Attempts have been made to correlate structure with the available biological activity data.
Antineoplastic Agents↗
Origins of stereospecificity in DNA damage by anti-benzo[a]pyrene diol-epoxides. A molecular modelling study.
A general computational procedure for the modelling of intercalated DNA-ligand complexes has been developed, and is used here to model intercalated complexes of the (+)-anti and (-)-anti enantiomers of benzo[a]pyrene diol-epoxide (BPDE) with cytosine-3',5'-guanosine double-stranded DNA sequences (dCpG). Results are presented indicating differences between the behaviours of the two enantiomers which have implications for the understanding of the stereospecificity of DNA strand breakage by benzo[a]pyrene diol-epoxides.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Nucleic acid binding drugs--XIV. The crystal structure of 1-methyl amsacrine hydrochloride; relationships to DNA-binding ability and anti-tumour activity.
The crystal structure of the 1-methyl derivative of the anticancer drug amsacrine [4'-(acridin-9-ylamino)-3'-methoxy-methanesulphonanilide+ ++] as its hydrochloride salt has been determined. The compound crystallizes in the monoclinic space group P21/n with cell dimensions a = 15.302(3), b = 8.035(2), c = 18.258(4) A and beta = 102.68(2) degrees, and has been refined to a final R of 0.055. The acridine chromophore is significantly non-planar, with a butterfly conformation about the C(9)-N(11) bond. The bonding geometry about the C(9) atom has been significantly altered compared to non-distorted amsacrine structures, as a result of this non-planarity. Energy calculations have been used to examine the flexibility of the molecule with respect to rotations about the C(9)-N(11) and N(11)-C(12) bonds, and with respect to intercalation into a dinucleoside duplex model for DNA. The latter calculations have been compared with solution DNA-binding and in vitro activity data for 1-methyl-amsacrine hydrochloride. The molecular modelling studies find that the energy of interaction between 1-methyl-amsacrine and a DNA intercalation fragment is significantly higher than for amsacrine itself, in accord with the biological data.
Amsacrine↗