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.

The presence of antiviral compounds in the Guttiferae family as medicinal plants and the long traditional use of species of the genus Hypericum for the treatment of many viral infections have developed a strong interest. Among the natural products of plant origin, the ones from Hypericum genus were cited as promising anti-HIV agents. This chapter will report an updated review of carbocyclic nucleoside analogues as anti-HIV agents from iridoids. Moreover, the partial synthesis of antiviral agents from iridoid glucosides to carbocyclic nucleosides as new anti-HIV agents is reviewed.

Metallosupramolecular helicates with trigonal‐antiprismatic geometry thread through and fit perfectly into the central hydrophobic cavity of a three‐way DNA junction. Six hydrophobic rings of the drug stack on six DNA bases, with three more sandwiched in the minor grooves. This work reveals and enables a new approach to targeting DNA and specifically DNA junctions. For more details, see the Communication by M. Coll, M. J. Hannon, and co‐workers on page 1227 ff.

The correct spelling of the surname of the first author of this Communication is Oleksy, as shown in the author list here.

Metallosupramolekulare Helicate mit trigonal‐antiprismatischer Form füllen den zentralen hydrophoben Hohlraum eines Drei‐Wege‐DNA‐Knotenpunkts perfekt aus. Sechs hydrophobe Ringe des Wirkstoffs stapeln sich mit sechs DNA‐Basen und drei weitere sind sandwichartig in die kleinen Furchen eingelagert. Die Zuschrift von M. Coll, M. J. Hannon et al. auf S. 1249 ff. zeigt neue Möglichkeiten für Wechselwirkungen mit DNA und vor allem mit DNA‐Knotenpunkten.

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. Prodigiosin-DNA intercalation was analyzed using a competition dialysis assay with different DNA base sequences. Topoisomerase I and II inhibition was studied in vitro by a cleavage assay, and in cultured cells, by analysis of its ability to form covalent complexes. Furthermore, we analyzed DNA damage by pulse-field gel electrophoresis and by immunocytochemistry. Apoptosis inducing factor (AIF)/phospho-H2AX (p-H2AX) double labeling by confocal microscopy was performed to determine the possible implication of AIF in the prodigiosin-DNA damage. Finally, we studied the ability of this drug to induce copper-mediated DNA damage at different pH by a DNA cleavage assay. Our results demonstrate prodigiosin-DNA interaction in vitro and in cultured cells. It involves prodigiosin-DNA intercalation, with some preference for the alternating base pairs but with no discrimination between AT or CG sequences, dual abolition of topoisomerase I and II activity and, as consequence, DNA cleavage. Prodigiosin-DNA damage is independent of AIF. Furthermore, we found that copper-mediated cleavage activity is associated with pH (occurring at pH 6.8 rather than pH 7.4) and with the Cu(2+) ion concentration. These results indicate DNA a therapeutic target for prodigiosin and could explain the apoptosis mechanism of action induced by this antineoplastic drug.

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. The 1.5 A resolution structure of ellipticine complexed to a 6 bp oligonucleotide unveils its mode of binding and enables a detailed analysis of the distorting effects of the drug on the DNA.

The crystal and molecular structure of the antimalarial compound 5,7-methoxy-8-(3-methyl-1-buten-3-ol)-coumarin, C16H18O5, Mr = 290.3 Da, has been determined from X-ray diffraction data. The material crystallizes in the monoclinic space group P21/c with 4 molecules per unit cell of dimensions a = 8.9044(9), b = 17.623(1), c = 10.175(1) Å, β = 113.97(1)°, crystal density Dc = 1.322 g/cm3. The structure was determined using direct methods and refined by full-matrix least squares to a conventional R index of 0.066 for 2416 measured reflections and 206 parameters.The coumarin ring system is almost planar with the methoxy C atoms rotated slightly out of the coumarin mean plane. Apart from the terminal CH3 groups C(12) and C(13), which are 1.184(3) Å above and −1.315(3) Å below the plane, the 3-methyl-1-buten-3-ol substituent is planar (rms deviation 0.009 Å) making an angle of 6.31(7)° with the phenyl ring. One intermolecular hydrogen bond is present in the crystal structure between O(5)–HO(5) and the symmetry related O(2′) oxygen, generated by the symmetry operation (x, 1/2 – y, −1/2 + z).

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). A detailed comparison of the two structures helps to distinguish distortions of the DNA conformation that are inherent to the cross-overs of the junctions in this crystal system from those that are consequences of the mismatched dG.dA base-pair in the d(CCGGGACCGG) structure. This analysis shows that the junction itself perturbs the sequence-dependent conformational features of the B-DNA duplexes and the associated patterns of hydration in the major and minor grooves only minimally. This supports the idea that a DNA four-way junction can be assembled at relatively low energetic cost. Both structures show a concerted rotation of the adjacent duplex arms relative to B-DNA, and this is discussed in terms of the conserved interactions between the duplexes at the junctions and further down the helical arms. The interactions distant from the strand cross-overs of the junction appear to be significant in defining its macroscopic properties, including the angle relating the stacked duplexes across the junction.

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. In addition, we observe a novel crystal packing arrangement, with six dodecamer duplexes and seven hydrated magnesium ions in the asymmetric unit of a large (66.5 x 68.4 x 77.4 A(3)) unit cell in space group P2(1)2(1)2(1). The duplexes are organized in layers parallel to the ab plane, with consecutive layers crossing each other at right angles.

The crystal and molecular structure of the antimalarial compound artesunate has been determined by direct methods. Crystals are orthorhombic, P212121, a = 9.8371(12), b = 10.517(2), c = 18.7594(5) Å, Z = 4, Dc = 1.316 mg/mL. The molecule is comprised of a fused ring system containing a six-membered ring C which includes an oxygen bridge and a peroxy bridge. The 9-atom oxygen–carbon chain from O(5)—C(12)... to ... O(2)—C(6) displays a striking sequence of short, long, short, long ... bonds while these distances are all within the ranges of a normal single bond or partial double bond. It is proposed that this pattern is caused by the delocalization of the lone pair electrons on the oxygen atoms. The ring C has a distorted boat conformation and the C—O—O—C torsion angle is 46.3(2)°. Rings A and D have ideal chair conformations. Ring junctions A/B and A/D are cis junctions, B/D and C/D are trans. Packing of the molecules is stabilized by one strong hydrogen bond involving the hydroxyl group on the ester linkage and the oxygen atom of the lactone ring.

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. Over a period of two weeks, hexagonal plates appeared. For the DNA fragment d(CCGGATCCGG), the crystals belong to space group P3(1), with unit-cell parameters a = b = 33.54, c = 46.39 A, alpha = beta = 90, gamma = 120 degrees, and diffract to 2.2 A. In the case of the DNA fragment d(CCGGCGCCGG) the crystals belong to the space group C2, with unit-cell parameters a = 65.35, b = 24.07, c = 37.34 A, beta = 109.97 degrees, and diffract to 2.0 A.

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 0.1 x 0.1 mm. The crystals belong to space group P6(4), with unit-cell parameters a = b = 29.960, c = 39.64 A, alpha = beta = 90, gamma = 120 degrees, and diffract to 1.4 A.

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. Its crystal structure has been determined and refined using data up to 1. 75 A resolution. The molecule displays the alpha+beta folding topology typical for members of the ribonuclease A superfamily. The catalytic active site residues are conserved with respect to other ribonucleases of the superfamily but some differences appear at substrate recognition subsites, which may account, in part, for the low catalytic activity. Most strikingly, 19 surface-located arginine residues confer a strong basic character to the protein. The high concentration of positive charges and the particular orientation of the side-chains of these residues may also be related to the low activity of ECP as a ribonuclease and provides an explanation for its unique cytotoxic role through cell membrane disruption.