Intercalative DNA binding of the marine anticancer drug variolin B.

Variolin B is a rare marine alkaloid that showed promising anti-cancer activity soon after its isolation. It acts as a cyclin-dependent kinase inhibitor, although the precise mechanism through which it exerts the cytotoxic effects is still unknown. The crystal structure of a variolin B bound to a DNA forming a pseudo-Holliday junction shows that this compound can also contribute, through intercalative binding, to either the formation or stabilization of multi-stranded DNA forms.

Micro-molding with ultrasonic vibration energy: new method to disperse nanoclays in polymer matrices.

Ultrasound technology was proved as an efficient processing technique to obtain micro-molded specimens of polylactide (PLA) and polybutylene succinate (PBS), which were selected as examples of biodegradable polyesters widely employed in commodity and specialty applications. Operational parameters such as amplitude, molding force and processing time were successfully optimized to prepare samples with a decrease in the number average molecular weight lower than 6%. Ultrasonic waves also seemed an ideal energy source to provide effective disaggregation of clay silicate layers, and therefore exfoliated nanocomposites.

Pharmacological chaperones for enzyme enhancement therapy in genetic diseases.

Pharmacological chaperone therapy (PCT) is a rather new approach consisting in targeting incorrectly folded proteins by small molecules, thus, facilitating the correct folding of the protein and inducing a recovery of its functionality. Many diseases result from mutations on specific genes; this patent review focuses on those pathologies where PCT has a potential application for enzymatic enhancement. Rare diseases are the main area where PCT has been applied and the most advanced compounds are aiming to cure lysosomal storage disorders such as Fabry, Pompe or Gaucher.

Solid-phase synthesis of oligomers carrying several chromophore units linked by phosphodiester backbones.

A method for the preparation of oligomers by linking chromophore units is described. Specifically, the synthesis of chromophore units having a protected-hydroxyl group and a phosphoramidite function is described, along with a method to link several units using solid-phase phosphite-triester protocols.

Design, synthesis and antiproliferative properties of oligomers with chromophore units linked by amide backbones.

The preparation of oligomers made up of several chromophore units as compounds with potential fluorescent and antiproliferative properties is described. Specifically, chromophore units with protected-amino groups and one carboxylic group are described, together with methods to assemble these units using peptide chemistry. Some of these compounds have antiproliferative activity.

The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs.

Ellipticine is a natural plant product that has been found to be a powerful anticancer drug. Although still unclear, its mechanism of action is considered to be mainly based on DNA intercalation and/or the inhibition of topoisomerase II. Many experimental data suggest an intercalation based on stacking interactions along the major base-pair axis, but alternative binding modes have been proposed, in particular for ellipticine derivatives.

DNA interaction and dual topoisomerase I and II inhibition properties of the anti-tumor drug prodigiosin.

Prodigiosin is a red pigment produced by Serratia marcescens with apoptotic activity. We examined the mechanism of action of this tripyrrole alkaloid, focusing on its interaction with DNA and its ability to inhibit both topoisomerase I and topoisomerase II. We also evaluated the DNA damage induced in cancer cell lines.

Intercalation of an acridine-peptide drug in an AA/TT base step in the crystal structure of [d(CGCGAATTCGCG)](2) with six duplexes and seven Mg(2+) ions in the asymmetric unit.

We present the crystal structure of an acridine drug derivatized at carbon 9, [N(alpha)-(9-acridinoyl)-tetraarginine], intercalated within the dodecamer [d(CGCGAATTCGCG)](2). The presence of a lateral chain at the central carbon 9 atom differentiates this compound from most acridine drugs hitherto studied, which are usually derivatized at carbon 4. The DNA:drug interaction we observe differs from that observed in previous studies, which primarily involves shorter, mainly hexameric sequences, in two important regards: the acridine intercalates within an AA/TT base step, rather than within a CG/CG base step; and the binding site is located at the center of the sequence, rather than at one end of the duplex.

The inherent properties of DNA four-way junctions: comparing the crystal structures of holliday junctions.

Holliday junctions are four-stranded DNA complexes that are formed during recombination and related DNA repair events. Much work has focused on the overall structure and properties of four-way junctions in solution, but we are just now beginning to understand these complexes at the atomic level. The crystal structures of two all-DNA Holliday junctions have been determined recently from the sequences d(CCGGGACCGG) and d(CCGGTACCGG).

Crystallization and preliminary X-ray analysis of the antimalarial and cytotoxic alkaloid cryptolepine complexed with the DNA fragment d(CCTAGG)2.

Crystals of the indoloquinoline alkaloid cryptolepine complexed with the DNA fragment d(CCTAGG)(2) have been grown by the hanging-drop technique at 293 K using ammonium sulfate as the precipitating agent. Over a period of three weeks, yellow tapering bullet-shaped crystals grew to maximum dimensions of 0.2 x 0.

Crystallization and preliminary X-ray analysis of the DNA decamers d(CCGGATCCGG) and d(CCGGCGCCGG).

The DNA decamers d(CCGGATCCGG) and d(CCGGCGCCGG) have been crystallized for X-ray analysis in order to investigate the effects of changing the two central base pairs of the DNA fragment d(CCGGGACCGG). Previous studies have already demonstrated that the structure of the former DNA fragment contains a DNA Holliday junction. Crystals were obtained at 293 K by the hanging-drop vapour-diffusion technique using the Nucleic Acid Mini Screen.

The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites.

Cryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)(2) in a base-stacking intercalation mode.

Three-dimensional crystal structure of human eosinophil cationic protein (RNase 3) at 1.75 A resolution.

Eosinophil cationic protein (ECP; RNase 3) is a human ribonuclease found only in eosinophil leukocytes that belongs to the RNase A superfamily. This enzyme is bactericidal, helminthotoxic and cytotoxic to mammalian cells and tissues. The protein has been cloned, heterologously overexpressed, purified and crystallized.

Crystal structure of a DNA Holliday junction.

DNA recombination is a universal biological event responsible both for the generation of genetic diversity and for the maintenance of genome integrity. A four-way DNA junction, also termed Holliday junction, is the key intermediate in nearly all recombination processes. This junction is the substrate of recombination enzymes that promote branch migration or catalyze its resolution.

DNA minor groove recognition of a non-self-complementary AT-rich sequence by a tris-benzimidazole ligand.

The crystal structure of the non-self-complementary dodecamer DNA duplex formed by d(CG[5BrC]ATAT-TTGCG) and d(CGCAAATATGCG) has been solved to 2.3 A resolution, together with that of its complex with the tris-benzimidazole minor groove binding ligand TRIBIZ. The inclusion of a bromine atom on one strand in each structure enabled the possibility of disorder to be discounted.

Three-dimensional crystal structure of the A-tract DNA dodecamer d(CGCAAATTTGCG) complexed with the minor-groove-binding drug Hoechst 33258.

The molecular structure of the DNA A-tract dodecamer d(CGCAAATTTGCG) complexed with the drug Hoechst 33258 has been determined by X-ray diffraction analysis. The Hoechst molecule binds in the DNA minor groove covering the sequence AATTT of the central A-tract, with the piperazine group close to one of the GC regions. The drug molecule makes two three-centered hydrogen bonds from the nitrogen atoms of the benzimidazole rings to the N3 and O2 atoms of the DNA bases.

Molecular structure of the A-tract DNA dodecamer d(CGCAAATTTGCG) complexed with the minor groove binding drug netropsin.

The molecular structure of the complex between the minor groove binding drug netropsin and the dodecamer d(CGCAAATTTGCG) has been solved and refined by X-ray diffraction analysis to an R-factor of 19.8% and 2.2-A resolution.

Crystal structure of a helical oligopeptide model of polyglycine II and of other polyamides: acetyl-(glycyl-beta-alanyl)2-NH propyl.

We synthesized and solved the crystalline structure of the oligopeptide acetyl-(glycyl-beta-alanyl)2-NH propyl. The crystal is formed by layers of helical molecules with the same chirality; however, right-handed layers alternate with left-handed ones. Inside every layer, the packing of helices is pseudohexagonal with hydrogen bonds between neighbor molecules.

Molecular structure of a complete turn of A-DNA.

We have determined the crystal structure of the dodecamer d(CCCCCGCGGGGG), showing for the first time a complete turn of A-DNA. It has average structural parameters similar to those determined in fibres. Nevertheless it shows a considerable local variation in structure which is in part associated with the presence of a bound spermine molecule.

Molecular structure of nicked DNA: a substrate for DNA repair enzymes.

The molecular structure of a nicked dodecamer DNA double helix, made of a ternary system containing d(CGCGAAAACGCG) + d(CGCGTT) + d(TTCGCG) oligonucleotides, has been determined by x-ray diffraction analysis at 3 A resolution. The molecule adopts a B-DNA conformation, not unlike those found in intact dodecamer DNA molecules crystallized in a somewhat different crystal lattice, despite a gap due to the absence of a phosphate group in the molecule. The helix has a distinct narrow minor groove near the center of the molecule at the AAAA region.

Satellite DNAs contain sequences that induced curvature.

The repeating units of mouse, rat, and alpha-monkey satellites have been cloned. All three show properties that are characteristic of curved DNA: (i) their migration in polyacrylamide gels is slower than predicted from their sequences, and (ii) they appear as curved molecules when visualized by electron microscopy. All three satellite repeats contain runs of d(A.

Binding of a Hoechst dye to d(CGCGATATCGCG) and its influence on the conformation of the DNA fragment.

Hoechst dye 33258 is a planar drug molecule that binds to the minor groove of DNA, especially where there are a number of A.T base pairs. We have solved the structure of the Hoechst dye bound to the DNA dodecamer d(CGCGATATCGCG) at 2.

The propeller DNA conformation of poly(dA).poly(dT).

Physical properties of the DNA duplex, poly(dA).poly(dT) differ considerably from the alternating copolymer poly(dAT). A number of molecular models have been used to describe these structures obtained from fiber X-ray diffraction data.

Effects of 5-fluorouracil/guanine wobble base pairs in Z-DNA: molecular and crystal structure of d(CGCGFG).

The chemotherapeutic agent 5-fluorouracil is a DNA base analogue which is known to incorporate into DNA in vivo. We have solved the structure of the oligonucleotide d(CGCGFG), where F is 5-fluorouracil (5FU). The DNA hexamer crystallizes in the Z-DNA conformation at two pH values with the 5FU forming a wobble base pair with guanine in both crystal forms.