NUCLEIC-ACID BINDING-DRUGS .7. MOLECULAR-MECHANICS STUDIES ON THE CONFORMATIONAL PROPERTIES OF THE ANTI-CANCER DRUG DAUNOMYCIN - SOME OBSERVATIONS ON THE USE OF DIFFERING POTENTIAL-ENERGY FUNCTIONS

The conformation of the anti-cancer drug daunomycin has been investigated in detail by potential-energy calculations. The flexibility around the ether linkage, connecting the anthracycline chromophore and the amino sugar group, has been evaluated using several types of potential-energy function. The results largely support the hypothesis that the crystallographically observed conformation is the most stable one, although considerable detailed variation with respect to potential function was found

NUCLEIC-ACID BINDING DRUGS .2. PROFLAVINE FREE BASE

C13HIIN3.H20 , orthorhombic, Cmc21, a= 14.493 (8), b= 14.675 (8), c= 5.772 (5) A, Din= 1.29 (1), De= 1.298 g cm -3 for Z=4. Equi-inclination Weissenberg intensities, scanned with an automatic densitometer. The structure, solved by direct methods, was refined to R 0.0928 and Rw 0.0910 for 418 reflexions. The ring system is slightly non-planar, and the crystal structure is characterized by a lack of interplanar stacking

NUCLEIC-ACID BINDING-DRUGS .6. THE STRUCTURE OF 3,9-DIAMINO-7-ETHOXYACRIDINE (RIVANOL) AS THE LACTATE MONOHYDRATE SALT

C15H16N3 O+ • C3H50~-. H20, M r = 361.4, triclinic, Pi, with a = 7.912 (2), b = 10.016 (1), c = 12.246 (3)/k, = 107.75 (1),/~ = 103.08 (2), y = 94.47 (2) °, U = 888.9 ,/k 3, Z = 2, D m = 1.35 (2), D c = 1.350 Mg m -3, F(000) = 380, 2(Cu Ka) = 1.5418/~, /t = 0.836 mm -~. 3542 reflections were measured, of which 2149 had significant intensity. The structure refined to an R of 0.063 after having been solved by reciprocal-space search methods. The molecular geometry reflects the 3,9-diamino substitution of the planar acridine ring, in terms of bond distances. The crystal structure is extensively hydrogen-bonded with interactions involving anions, acridine substituents and water molecules

9-CHLOROACRIDINE

C~3HsNC1, orthorhombic, P212~2 ~, a = 6.850 (3), b = 11.662 (5), c = 12.705 (5) A, O m = 1.40 (1), D c = 1.393 g cm -3 for Z = 4. Equi-inclination Weissenberg intensities, scanned with an automatic densitometer. The structure, solved by direct methods, refined to R 0.0577 and R w 0.0649 for 1653 reflexions. The crystal structure is characterized by partial stacking of the chromophores, these are slightly non-planar

Mapping the sequences of potential guanine quadruplex motifs.

The knowledge that potential guanine quadruplex sequences (PQs) are non-randomly distributed in relation to genomic features is now well established. However, this is for a general potential quadruplex motif which is characterized by short runs of guanine separated by loop regions, regardless of the nature of the loop sequence. There have been no studies to date which map the distribution of PQs in terms of primary sequence or which categorize PQs. To this end, we have generated clusters of PQ sequence groups of various sizes and various degrees of similarity for the non-template strand of introns in the human genome. We started with 86 697 sequences, and successively merged them into groups based on sequence similarity, carrying out 66 clustering cycles before convergence. We have demonstrated here that by using complete linkage hierarchical agglomerative clustering such PQ sequence categorization can be achieved. Our results give an insight into sequence diversity and categories of PQ sequences which occur in human intronic regions. We also highlight a number of clusters for which interesting relationships among their members were immediately evident and other clusters whose members seem unrelated, illustrating, we believe, a distinct role for different sequence types

Quadruplex Nucleic Acids as Novel Therapeutic Targets

Quadruplex-forming sequences are widely prevalent in human and other genomes, including bacterial ones. These sequences are over-represented in eukaryotic telomeres, promoters and 5' untranslated regions. They can form quadruplex structures, which may be transient in many situations in normal cells since they can be effectively resolved by helicase action. Mutated helicases in cancer cells are unable to unwind quadruplexes, which are impediments to transcription, translation or replication, depending on their location within a particular gene. Small molecules that can stabilise quadruplex structures augment these effects and produce cell and proliferation growth inhibition. This article surveys the chemical biology of quadruplexes and critically examines the major classes of quadruplex-binding small molecules that have been developed to date, and the various approaches to discovering selective agents. The challenges of requiring (and achieving) small-molecule targeted selectivity for a particular quadruplex are discussed in relation to the potential of these small molecules as potentially clinically-useful therapeutic agents

CRYSTAL AND MOLECULAR-STRUCTURE OF 8,2'-CYCLOADENOSINE TRIHYDRATE

8,2'-Cycloadenosine, C IoHi~NsO4.3H20, is a modified arabinosyladenosine nucleoside which has been cyclized at the C(8) and 0(2') atoms. THe trihydrate crystallizes in the orthorhombic space group P2~2~2~, with a = 8.680 (2), b = 5.991 (2), c = 27.203 (4) A, Z = 4. The structure was refined to R = 0.0672 for 1411 unique reflections, photographically recorded. The arabinofuranose ring has a flattened C(4')-endo-C(3')- exo pucker. The conformation about C(4')-C(5') is gauche-gauche, and that about the sugar-base bond is high anti. The crystal structure involves extensive base-base hydrogen bonding, N(1), N(6) and N(7) all being participants

Predictive modelling of topology and loop variations in dimeric DNA quadruplex structures.

We have used a combination of simulated annealing (SA), molecular dynamics (MD) and locally enhanced sampling (LES) methods in order to predict the favourable topologies and loop conformations of dimeric DNA quadruplexes with T2 or T3 loops. This follows on from our previous MD simulation studies on the influence of loop lengths on the topology of intramolecular quadruplex structures [P. Hazel et al. (2004) J. Am. Chem. Soc., 126, 16 405-16 415], which provided results consistent with biophysical data. The recent crystal structures of d(G4T3G4)2 and d(G4BrUT2G4) (P. Hazel et al. (2006) J. Am. Chem. Soc., in press) and the NMR-determined topology of d(TG4T2G4T)2 [A.T. Phan et al. (2004) J. Mol. Biol., 338, 93-102] have been used in the present study for comparison with simulation results. These together with MM-PBSA free-energy calculations indicate that lateral T3 loops are favoured over diagonal loops, in accordance with the experimental structures; however, distinct loop conformations have been predicted to be favoured compared to those found experimentally. Several lateral and diagonal loop conformations have been found to be similar in energy. The simulations suggest an explanation for the distinct patterns of observed dimer topology for sequences with T3 and T2 loops, which depend on the loop lengths, rather than only on G-quartet stability

STRUCTURE OF BENZ[A]ANTHRACENE-7,12-DIONE

C18H1002, monoclinic, C2/c, a = 10.918 (1), b = 11.369(1), c = 19.850(1)A, /~= 97.224(7) ° , U = 2444.4 A 3, Z = 8, D,n = 1.41 (2), D c = 1.403 Mg m -3, F(000) = 1072, 2(CuKa) = 1.5418/~, ~t = 0.742 mm -1. 2253 reflections were measured, of which 1039 had significant intensities. Refinement converged to a final R of 0.045. The molecule is approximately planar. Ring C is significantly non-delocalized. Bonds C(3)-C(4) and C(5)-C(6) are short, and indicate pronounced olefinic character for these bonds