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

Beyond the double helix: DNA structural diversity and the PDB

The determination of the double helical structure of DNA in 1953 remains the landmark event in the development of modern biological and biomedical science. This structure has also been the starting point for the determination of some 2000 DNA crystal structures in the subsequent 68 years. Their structural diversity has extended to the demonstration of sequence-dependent local structure in duplex DNA, to DNA bending in short and long sequences and in the DNA wound round the nucleosome, and to left-handed duplex DNAs. Beyond the double helix itself, in circumstances where DNA sequences are or can be induced to unwind from being duplex, a wide variety of topologies and forms can exist. Quadruplex structures, based on four-stranded cores of stacked G-quartets, are prevalent though not randomly distributed in the human and other genomes and can play roles in transcription, translation, and replication. Yet more complex folds can result in DNAs with extended tertiary structures and enzymatic/catalytic activity. The Protein Data Bank is the depository of all these structures, and the resource where structures can be critically examined and validated, as well as compared one with another to facilitate analysis of conformational and base morphology features. This review will briefly survey the major structural classes of DNAs and illustrate their significance, together with some examples of how the use of the Protein Data Bank by for example, data mining, has illuminated DNA structural concepts

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

CRYSTAL-STRUCTURE OF 5-BENZOYLOXYOCTAETHYLPORPHYRIN

5-Benzoyloxyoctaethylporphyrin, C43HsoN402, monoclinic, .P2~/c, a = 15.105 (1), b = 20-729 (2), c-=- 12-721 (1) A, fl = 112.05 (2) °, D m = I. 18, D c = 1.177 gcm -3 for Z = 4. The structure was solved by direct methods, and refined to R = 0.0474, R w = 0.0510 for 4076 reflections measured on an automatic diffractometer. The central porphyrin system is distinctly non-planar, and adopts a shallow saucer shape. A 'halfhydrogen' atom has been located attached to each central nitrogen atom; however, it is not clear whether these are truly representative of N-H tautomerism, or are crystallographic artifacts

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

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

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

Loop flexibility in human telomeric quadruplex small-molecule complexes

Quadruplex nucleic acids can be formed at the ends of eukaryotic chromosomes. Their formation and stabilisation by appropriate small molecules can be used as a means of inhibiting the telomere maintenance functions of telomerase in human cancer cells. The crystal structures have been determined for a number of complexes between these small molecules and human telomeric DNA and RNA quadruplexes. The detailed structural characteristics of these complexes have been surveyed here and the variations in conformation for the TTA and UUA loops have been explored. Loop conformations have been classified in terms of a number of discrete types and their distribution among the crystal structures. Sugar conformation and backbone angles have also been examined and trends highlighted. One particular loop class has been found to be most prevalent. Implications for in particular, rational drug design, are discussed