http://www.mdpi.com/journal/molecules/special_issues/nucleic-acid/ Submission All papers should be submitted to molecules@mdpi.org with copy to the guest editor. To be published continuously until the deadline and papers will be listed together at the special websites. Submitted papers should not have been previously published nor be currently under consideration for publication elsewhere. All papers are refereed through a peer review process. A guide for authors, sample copies and other relevant information for submitting papers are available on the Instructions for Authors page. Molecules is an international peer-reviewed monthly journal published by Molecular Diversity Preservation International. Please visit the Instructions for Authors page before submitting a paper. Open Access publication fees are 800 CHF per paper. English correction fees (250 CHF) will be added in certain cases (1050 CHF per paper for those papers that require extensive additional formatting and/or English corrections.). http://www.mdpi.com/1420-3049/14/5/1725/ In the present overview, we describe the bases of intercalation of small molecules (cationic and polar neutral compounds) in DNA. We briefly describe the importance of DNA structure and principles of intercalation. Selected syntheses, possibilities and applications are shown to exemplify the importance, drawbacks and challenges in this pertinent, new, and exciting research area. Additionally, some clinical applications (molecular processes, cancer therapy and others) and trends are described. http://www.mdpi.com/1420-3049/14/5/1725/ Thu, 07 May 2009 00:00:00 CEST Molecules 2009-05-07 14 5 Review 1725 1746 1420-3049 Recent Developments in the Chemistry of Deoxyribonucleic Acid (DNA) Intercalators: Principles, Design, Synthesis, Applications and Trends 2009-05-07 doi: 10.3390/molecules14051725 Brenno A. D. Neto Alexandre A. M. Lapis http://www.mdpi.com/1420-3049/14/4/1353/ Oligonucleotide aptamers are highly structured DNA or RNA molecules, or modified versions thereof, that can bind to targets with specific affinities comparable to antibodies. They are identified through an in vitro selection process termed SELEX (Systematic Evolution of Ligands by EXponential enrichment) to recognize a wide variety of targets, from small molecules to proteins, and from cultured cells to whole organisms. Aptamers possess a number of desirable properties, such as ease of synthesis, stability, robustness, and lack of immunogenicity. Standard SELEX libraries require two primers, one on each side of a central random domain, to amplify the target-bound sequences via PCR or RT-PCR. However, these primer sequences cause non-specific binding by their nature, and have been reported to lead to large numbers of false-positive binding sequences, or to interfere with binding of sequences within the random regions. This review is focused on methods which have been developed to eliminate fixed primer interference during the SELEX process. http://www.mdpi.com/1420-3049/14/4/1353/ Fri, 27 Mar 2009 00:00:00 CET Molecules 2009-03-27 14 4 Review 1353 1369 1420-3049 The Shorter the Better: Reducing Fixed Primer Regions of Oligonucleotide Libraries for Aptamer Selection 2009-03-27 doi: 10.3390/molecules14041353 Weihua Pan Gary A. Clawson http://www.mdpi.com/1420-3049/14/3/1304/ Antisense molecules do not readily cross cell membranes. This has limited the use of antisense to systems where techniques have been worked out to introduce the molecules into cells, such as embryos and cell cultures. Uncharged antisense bearing a group of guanidinium moieties on either a linear peptide or dendrimer scaffold can enter cells by endocytosis and subsequently escape from endosomes into the cytosol/nuclear compartment of cells. These technologies allow systemic administration of antisense, making gene knockdowns and splice modification feasible in adult animals; this review presents examples of such animal studies. Techniques developed with PPMOs, which are an arginine-rich cell-penetrating peptide linked to a Morpholino oligo, can also be performed using commercially available Vivo-Morpholinos, which are eight guanidinium groups on a dendrimeric scaffold linked to a Morpholino oligo. Antisense-based techniques such as blocking translation, modifying pre-mRNA splicing, inhibiting miRNA maturation and inhibiting viral replication can be conveniently applied in adult animals by injecting PPMOs or Vivo-Morpholinos. http://www.mdpi.com/1420-3049/14/3/1304/ Wed, 25 Mar 2009 00:00:00 CET Molecules 2009-03-25 14 3 Review 1304 1323 1420-3049 Gene Knockdowns in Adult Animals: PPMOs and Vivo-Morpholinos 2009-03-25 doi: 10.3390/molecules14031304 Jon D. Moulton Shan Jiang http://www.mdpi.com/1420-3049/14/3/1279/ Several strains of Thermus thermophilus were tested in order to detect purine nucleoside synthase activity using pyrimidine nucleosides as the sugar-donor and adenine or hypoxanthine as bases. High productivity values (t =1 hr) were obtained while completely avoiding adenosine-deaminase degradation of the products. N-2-deoxy-ribosyltransferase activity is described for the first time in hyperthermophilic bacteria. http://www.mdpi.com/1420-3049/14/3/1279/ Tue, 24 Mar 2009 00:00:00 CET Molecules 2009-03-24 14 3 Article 1279 1287 1420-3049 Thermus thermophilus Strains Active in Purine Nucleoside Synthesis 2009-03-24 doi: 10.3390/molecules14031279 Marcos Almendros José-Vicente Sinisterra Gago José Berenguer Carlos http://www.mdpi.com/1420-3049/14/3/1183/ For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials. http://www.mdpi.com/1420-3049/14/3/1183/ Mon, 23 Mar 2009 00:00:00 CET Molecules 2009-03-23 14 3 Review 1183 1226 1420-3049 Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases 2009-03-23 doi: 10.3390/molecules14031183 Tadeusz Robak Anna Korycka Ewa Lech-Maranda Pawel Robak http://www.mdpi.com/1420-3049/14/1/122/ Neem oil is obtained from the seeds of the tree Azadirachta indica. Its chemical composition is very complex, being rich in terpenoids and limonoids, as well as volatile sulphur modified compounds. This work focused on the evaluation of a component of the whole Neem oil obtained by methanolic extraction and defined as MEX. Cytotoxicity was assessed on two different cell populations: a stabilized murine fibroblast line (3T6) and a tumor cell line (HeLa). The data presented here suggest a differential sensitivity of these two populations, the tumor line exhibiting a significantly higher sensitivity to MEX. The data strongly suggest that its toxic target is the cell membrane. In addition the results presented here imply that MEX may contain one or more agents that could find a potential use in anti-proliferative therapy. http://www.mdpi.com/1420-3049/14/1/122/ Wed, 31 Dec 2008 00:00:00 CET Molecules 2008-12-31 14 1 Article 122 132 1420-3049 Differential Cytotoxicity of MEX: a Component of Neem Oil Whose Action Is Exerted at the Cell Membrane Level 2008-12-31 doi: 10.3390/molecules14010122 Francesca Ricci Valerio Berardi Gianfranco Risuleo http://www.mdpi.com/1420-3049/14/1/102/ We previously isolated a novel natural product, designated kohamaic acid A (KA-A, compound 1), as an inhibitor of the first cleavage of fertilized sea urchin eggs, and found that this compound could selectively inhibit the activities of mammalian DNA polymerases (pols). In this paper, we investigated the structure and bioactivity of KA-A and its chemically synthesized 11 derivatives (i.e., compounds 2–12), including KA-A - fatty acid conjugates. The pol inhibitory activity of compound 11 [(1S*,4aS*,8aS*)-17-(1,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-naphthalen-1-yl)heptadecanoic acid] was the strongest among the synthesized compounds, and the range of IC50 values for mammalian pols was 3.22 to 8.76 µM; therefore, the length of the fatty acid side chain group of KA-A is important for pol inhibition. KA-A derivatives could prevent human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of mammalian pols. Since pol β is the smallest molecule, we used it to analyze the biochemical relationship with KA-A derivatives. From computer modeling analysis (i.e., docking simulation analysis), these compounds bound selectively to four amino acid residues (Leu11, Lys35, His51 and Thr79) of the N-terminal 8-kDa domain of pol β, and the binding energy between compound 11 and pol β was largest in the synthesized compounds. The relationship between the three-dimensional molecular structures of KA-A-related compounds and these inhibitory activities is discussed. http://www.mdpi.com/1420-3049/14/1/102/ Mon, 29 Dec 2008 00:00:00 CET Molecules 2008-12-29 14 1 Article 102 121 1420-3049 The Inhibitory Action of Kohamaic Acid A Derivatives on Mammalian DNA Polymerase β 2008-12-29 doi: 10.3390/molecules14010102 Yoshiyuki Mizushina Daisuke Manita Toshifumi Takeuchi Fumio Sugawara Yuko Kumamoto-Yonezawa Yuki Matsui Masaharu Takemura Mitsuru Sasaki Hiromi Yoshida Hirosato Takikawa http://www.mdpi.com/1420-3049/14/1/10/ This study found that in Tris-HCl buffer, the resonance light scattering (RLS) intensity of the Eu3+-nicotinic acid system can be greatly enhanced by nucleic acids and the enhanced intensity is proportional to the concentration of nucleic acid in the range of 7×10-8-1×10-5 g∙mL-1 for fsDNA, and its detection limit is 2×10-8 g∙mL-1. Based on this, a new method for the determination of nucleic acids is proposed. Synthetic and actual samples are determined satisfactorily. The interaction mechanism is also studied. It is thought that nucleic acid can bind with the Eu3+-nicotinic acid complex through electrostatic attraction and thus form a large Eu3+-nicotinic acid-nucleic acid complex. http://www.mdpi.com/1420-3049/14/1/10/ Tue, 23 Dec 2008 00:00:00 CET Molecules 2008-12-23 14 1 Article 10 18 1420-3049 A New Method for the Determination of Nucleic Acid Using an Eu3+– nicotinic Acid Complex as a Resonance Light Scattering Probe 2008-12-23 doi: 10.3390/molecules14010010 Meng Guo Lin-Tong Wang Xia Wu Wei Xu Jing-He Yang http://www.mdpi.com/1420-3049/13/12/3117/ Spectroscopic, viscometric, and molecular docking analysis of binding of cationic bis-porphyrins linked with p- or m-xylylenediamine (H2pXy and H2mXy) and their zinc(II) complexes (ZnpXy and ZnmXy) to duplex DNA are described. H2pXy and H2mXy bound to calf thymus DNA (CTDNA) stronger than unichromophoric H2TMPyP, and showed exciton-type induced circular dichroism spectra of their Soret bands. The H2TMPyP-like units of the metal-free bis-porphyrins did not intercalate into CTDNA, and thus the binding mode is outside binding with intramolecular stacking. ZnpXy showed favorable binding to A·T over G·C region, and should lie in the major groove of A·T region. http://www.mdpi.com/1420-3049/13/12/3117/ Mon, 15 Dec 2008 00:00:00 CET Molecules 2008-12-15 13 12 Article 3117 3128 1420-3049 Binding of Cationic Bis-porphyrins Linked with p- or m-Xylylenediamine and Their Zinc(II) Complexes to Duplex DNA 2008-12-15 doi: 10.3390/molecules13123117 Yoshinobu Ishikawa Naoki Yamakawa Tadayuki Uno http://www.mdpi.com/1420-3049/13/12/3092/ Enantioselective syntheses from dimethyl tartrate of 1,3,5-triazine homo-N-nucleoside analogs, containing a 1,4-dioxane moiety replacing the sugar unit in natural nucleosides, were accomplished. The triazine heterocycle in the nucleoside analogs was further substituted with combinations of NH2, OH and Cl in the 2,4-triazine positions. http://www.mdpi.com/1420-3049/13/12/3092/ Wed, 10 Dec 2008 00:00:00 CET Molecules 2008-12-10 13 12 Article 3092 3106 1420-3049 Synthesis of Novel Homo-N-Nucleoside Analogs Composed of a Homo-1,4-Dioxane Sugar Analog and Substituted 1,3,5-Triazine Base Equivalents 2008-12-10 doi: 10.3390/molecules13123092 Qiang Yu Dirk Schwidom Alexander Exner Per Carlsen http://www.mdpi.com/1420-3049/13/12/2962/ A dioxane homo-sugar analog, (2S,5S)-and (2R,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-iodomethyl-1,4-dioxane was prepared from (2R,3R)-dimethyl tartrate, and further elaborated into the corresponding homo-N-nucleoside analogs by its reactions with uracil and adenine, respectively. http://www.mdpi.com/1420-3049/13/12/2962/ Wed, 03 Dec 2008 00:00:00 CET Molecules 2008-12-03 13 12 Article 2962 2974 1420-3049 Enantioselective Synthesis of Homo-N-Nucleosides Containing a 1,4-Dioxane Sugar Analog 2008-12-03 doi: 10.3390/molecules13122962 Qiang Yu Per Carlsen http://www.mdpi.com/1420-3049/13/12/2948/ Dehydroaltenusin is a selective inhibitor of mammalian DNA polymerase α (pol α) from a fungus (Alternaria tennuis). We have designed, synthesized, and characterized a derivative of dehydroaltenusin conjugated with a C12-alkyl side chain (dehydroaltenusin-C12 [C12]). C12 was the strongest pol α inhibitor in vitro. We introduced C12 into NIH3T3 cells with the help of a hypotonic shift, that is, a transient exposure of cultured cells in hypotonic buffer with small molecules which can not penetrate cells. The cells that took in C12 by hypotonic shift showed cell growth inhibition. At a low concentration (5 μM), DNA replication was inhibited and several large replication protein A (RPA) foci, which is different from dUTP foci. Furthermore, when C12 was incubated with aphidicolin, RPA foci were not observed in cells. Finally, these findings suggest that C12 inhibited DNA replication through pol α inhibition, and generated single-stranded DNA, resulted in uncoupling of the leading strand and lagging strand synthesis. These findings suggest that C12 could be more interesting as a molecule probe or anticancer agent than aphidicolin. C12 might provide novel markers for the development of antiproliferative drugs. http://www.mdpi.com/1420-3049/13/12/2948/ Mon, 01 Dec 2008 00:00:00 CET Molecules 2008-12-01 13 12 Article 2948 2961 1420-3049 Effect of Dehydroaltenusin-C12 Derivative, a Selective DNA Polymerase α Inhibitor, on DNA Replication in Cultured Cells 2008-12-01 doi: 10.3390/molecules13122948 Isoko Kuriyama Takeshi Mizuno Keishi Fukudome Kouji Kuramochi Kazunori Tsubaki Takeo Usui Naoko Imamoto Kengo Sakaguchi Fumio Sugawara Hiromi Yoshida Yoshiyuki Mizushina http://www.mdpi.com/1420-3049/13/10/2659/ The Pdx-1 transcription factor plays crucial functions both during pancreas development and in the adult β cells. Previous studies have indicated that ectopic Pdx-1 expression in liver or intestinal primary and immortalized cells is sufficient to promote activation of insulin gene expression. This work is focused on the molecular and physiological consequences of Pdx-1 overexpression in liver cells. We present evidence that Pdx-1 affects the level of expression of one of the four mammalian hexokinase isozymes. These are glucose phosphorylating enzymes involved in essential cellular functions such as glucose sensing, metabolic energy production and apoptosis. Specifically, our data show that over-expression of Pdx-1 in cultured hepatocytes is able to repress the expression of hexokinase 2 (Hxk 2) and the phenomenon is mediated via binding of Pdx-1 to a specific sequence on the Hxk 2 gene promoter. As a consequence, liver cells over-expressing Pdx-1 present interesting alterations concerning glucose metabolism. http://www.mdpi.com/1420-3049/13/10/2659/ Tue, 28 Oct 2008 00:00:00 CET Molecules 2008-10-28 13 10 Article 2659 2673 1420-3049 Overexpression of the Pdx-1 Homeodomain Transcription Factor Impairs Glucose Metabolism in Cultured Rat Hepatocytes 2008-10-28 doi: 10.3390/molecules13102659 Rudolf Tito Pillich Gianfranco Scarsella Gianfranco Risuleo