MEDICINAL CHEMISTRY OF NUCLEIC ACIDS MEDICINAL CHEMISTRY OF NUCLEIC ACIDS Edited by LI-HE ZHANG Peking University, Beijing, China ZHEN XI Nankai University, Tianjing, China JYOTI CHATTOPADHYAYA Uppsala University, Uppsala, Sweden A JOHN WILEY & SONS, INC., PUBLICATION Cover image credits: Shi, H., Moore, P.B The crystal structure of yeast phenylalanine tRNA at 1.93 A resolution: a classic structure revisited RNA, 6, pp 1091–1105, 2000 Pley, H.W., Flaherty, K.M., McKay, D.B Three-dimensional structure of a hammerhead ribozyme Nature, 372, pp 68–74, 1994 Juneau, K., Podell, E., Harrington, D.J., Cech, T.R Structural basis of the enhanced stability of a mutant ribozyme domain and a detailed view of RNA—solvent interactions Structure, 9, pp 221–231, 2001 Vicens, Q., Westhof, E Crystal Structure of a Complex between the Aminoglycoside Tobramycin and an Oligonucleotide Containing the Ribosomal Decoding A Site Chem Biol., 9, pp 747– 755, 2002 Copyright © 2011 John Wiley & Sons, Inc All rights 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print may not be available in electronic formats For more information about Wiley products, visit our web site at www.wiley.com Library of Congress Cataloging-in-Publication Data: Medicinal chemistry of nucleic acids / edited by Li He Zhang, Zhen Xi, Jyoti Chattopadhyaya p ; cm Includes index ISBN 978-0-470-59668-5 (cloth) Pharmaceutical chemistry Nucleic acids–Therapeutic use I Zhang, Li He II Xi, Zhen III Chattopadhyaya, Jyoti [DNLM: Nucleic Acids–pharmacology Nucleic Acids–therapeutic use QV 185] RS400.M438 2011 615 19—dc22 2011008300 Printed in the United States of America oBook ISBN: 978-1-118-09280-4 ePDF ISBN: 978-1-118-09283-5 ePub ISBN: 978-1-118-09281-1 10 CONTENTS FOREWORD vii CONTRIBUTORS xi INTRODUCTION xv RECENT ADVANCES IN CARBOCYCLIC NUCLEOSIDES: SYNTHESIS AND BIOLOGICAL ACTIVITY Jianing Wang, Ravindra K Rawal, and Chung K Chu STRUCTURES AND FUNCTIONS OF NUCLEIC ACIDS MODIFIED WITH S, Se, AND Te AND COMPLEXED WITH SMALL MOLECULES 101 Wen Zhang, Jia Sheng, and Zhen Huang UNRAVELING OF THE NAD CYCLIZING AND CALCIUM SIGNALING FUNCTIONS OF HUMAN CD38 142 Hon Cheung Lee DNA AND RNA BINDING SMALL MOLECULES 164 Shibo Li and Zhen Xi v vi CONTENTS G-QUADRUPLEX DNA AND ITS LIGANDS IN ANTICANCER THERAPY 206 Zhi-Shu Huang, Jia-Heng Tan, Tian-Miao Ou, Ding Li, and Lian-Quan Gu MOLECULAR MODELING IN NUCLEIC ACID-TARGETED DRUG DESIGN 258 Lidan Sun, Hongwei Jin, Liangren Zhang, and Lihe Zhang STRUCTURE OF 10–23 DNAzyme IN COMPLEX WITH THE TARGET RNA IN SILICO—A PROGRESS REPORT ON THE MECHANISM OF RNA CLEAVAGE BY DNA ENZYME 272 Oleksandr Plashkevych and Jyoti Chattopadhyaya LABELING OLIGONUCLEOTIDES TOWARD THE BIOMEDICAL PROBE 292 Il Joon Lee and Byeang Hyean Kim LOCKED NUCLEIC ACID OLIGONUCLEOTIDES TOWARD CLINICAL APPLICATIONS 335 Rakesh N Veedu and Jesper Wengel 10 THE PHARMACOKINETICS RESEARCH OF NUCLEIC ACID DRUGS 349 Shengqi Wang, Dandan Lu, Qingqing Wang, Haifeng Song, Chan Gao, Caihong Liu, and Ying Wang 11 INDUCIBLE RNAi AND DRUG TARGET VALIDATION 390 Wei Xiong, Jing Zhao, Yufan Zhang, Jinxi Wang, Yong-Xiang Zheng, Qiu-Chen He, Li-He Zhang, and De-Min Zhou 12 siRNA: THE SPECIFICITY AND OFF-TARGET EFFECTS 405 Quan Du, Huang Huang, and Zicai Liang INDEX 423 FOREWORD Nucleic acids have now been of interest to the research communities of chemists and biochemists for a number of decades Although the synthesis of DNA, and even RNA, is now considered “routine,” the current level of sophistication was achieved only after meeting the challenges associated with the preparation of the nucleoside building blocks of DNA and RNA The synthesis of DNA and RNA oligonucleotides is actually quite complex, requiring the identification and use of suitable protecting groups for the nucleobases and sugar moieties of RNA and DNA, not to mention efficient methods for creating phosphate ester linkages between individual nucleosides Because nucleic acids are polyanions, the newly synthesized DNAs and RNAs also required novel methods for purification, which took cognizance of their ready solubility only in aqueous and other polar solvents Another major challenge has been the analysis of the primary, secondary, and tertiary structures of DNA and RNA, as well as their interactions with macromolecular and low-molecular-weight ligands The discovery and development of biophysical and biochemical techniques has enabled this challenge to be met with increasing facility and sophistication The chemical and biochemical communities have worked together productively for many years to drive new discoveries involving nucleic acids These discoveries have created new opportunities for both communities The finding that nucleic acids participated in the decoding of genetic information as well as its storage provided numerous opportunities for chemical intervention in the mechanisms of RNA synthesis and splicing, in addition to that of protein synthesis The resulting probe molecules and their analogues, such as puromycin, actinomycin D, and chloramphenicol, in turn facilitated the mechanistic analyses of biochemical function The remarkable discovery that certain RNA molecules are vii viii FOREWORD responsible for their own biosynthetic processing, reflecting the existence of an early world driven by RNAs as the primary catalysts, has enabled the identification of RNAs and DNAs capable of effecting highly selective transformations not represented in nature The techniques used to identify novel processes in recognition and catalysis employ iterative cycles of molecular interactions/selections and amplifications and have involved increasingly sophisticated and complex biological systems The recent findings that gene expression can be regulated by gene transpositions, G-quadruplex structures associated with specific genes, RNA interference, and riboswitches have further enriched our understanding of nucleic acid function Perhaps equally importantly, they provide new opportunities for intervention leading to further mechanistic understanding and therapeutic gain The structural integrity of DNA is essential to enable its role as the repository of genetic information Agents that alter DNA structure are mutagenic and potentially carcinogenic Accordingly, organisms have evolved elaborate systems to recognize and repair DNA damage Because these systems protect cancerous as well as normal cells, using DNA as a target for therapeutic intervention does not intrinsically provide a source of tumor cell selectivity Efforts in antitumor therapy have led to numerous clinically used agents that function at the level of nucleic acids, but the poor therapeutic indices for such agents have often limited their utility Ongoing efforts to better understand the mechanisms that control gene expression have progressed impressively in recent years, providing targets (e.g., telomeric assemblies, micro RNAs, and G-quadruplex structures associated with individual genes) that seem likely to lead to more selective therapy of cancer and other diseases New chemistries used for the elaboration of therapeutic oligonucleotides, as well as new strategies for their more effective delivery, have significantly enhanced the therapeutic potential of these agents; successes in advanced clinical trials make it seem likely that agents of this type will appear with some frequency as newly marketed drugs The discovery of multiple natural mechanisms for the regulation of gene expression with oligonucleotides will undoubtedly extend the therapeutic reach of such drugs This book provides an excellent overview of a number of current research activities relevant to the medicinal chemistry of nucleic acids This includes Chapters and 4, which deal with carbocyclic nucleosides and small molecules that bind to DNA or RNA These areas have attracted significant attention over a period of years due to the novel chemistry involved and the biochemical/biological activities associated with many of these compounds Studies of this type have led to numerous important clinically used agents, whose mechanisms involve disruption of nucleic acid synthesis and function, especially in viruses and cancers Additional drugs of this type will undoubtedly be found Strongly enabling future studies in this area are modeling studies that permit the nature of small molecule–nucleic acid interaction to be better understood at the levels of affinity and selectivity, and thereby enhance our capacity for the design of improved agents These are ably summarized in Chapter Structural studies of nucleic acids play a critical role in monitoring interactions of nucleic acids with both large and small substrates and in providing FOREWORD ix high-resolution information pertinent to such binding events Such studies are represented in Chapter 8, dealing with the labeling of oligonucleotides with suitable reporter groups, and in Chapter from Professor Zhen Huang’s laboratory, which summarizes strategies for the preparation and x-ray crystallographic characterization of nucleic acid analogues containing S, Se, and Te More recently addressed opportunities in medicinal chemistry include a focus on nucleoside-containing cofactors, such as cyclic ADP-ribose, a substrate for the multifunctional enzyme CD38 (Chapter 3), which is involved in intracellular calcium signaling The critical functions of G-quadruplex structures makes them a logical focus for medicinal chemistry studies, and their structural variety promises potentially enhanced selectivity of action, as evidenced by the data summarized in Chapter Increasing sophistication in the preparation and characterization of nucleic acids has brought research on oligonucleotides firmly within the realm of medicinal chemistry Tools required for success in this area at a therapeutic level include optimization of the chemistries employed to facilitate the delivery and stability of oligonucleotide probes of interest Chapter 10, dealing with the pharmacokinetic issues involved, provides a summary of current studies in this area Better chemistries are required to realize improved potency and selectivity of oligonucleotide targeting, and Chapter by Veedu and Wengel describes locked nucleic acid oligonucleotides, which achieve important increases in potency through conformational constraint of the nucleoside building blocks The efficiency of nucleic acid targeting could be improved dramatically if the therapeutic agents functioned catalytically; Chapter from the Chattopadhyaya laboratory provides an insightful account of a DNAzyme, which cleaves an RNA target Finally, Chapters 11 and 12 deal with different aspects of RNA interference (RNAi) In addition to its importance in genomic studies, and as a tool for drug target validation, the study of the mechanism RNAi can provide mechanistic information of potential utility in improving the delivery and efficacy of therapeutic oligonucleotides The range of topics in this volume accurately reflects the vigor of current investigations over a range of topics in the area of nucleic acids and underscores the expanding opportunities for medicinal chemistry in this central discipline Sidney M Hecht Arizona State University .. .MEDICINAL CHEMISTRY OF NUCLEIC ACIDS MEDICINAL CHEMISTRY OF NUCLEIC ACIDS Edited by LI-HE ZHANG Peking University, Beijing, China ZHEN XI Nankai University, Tianjing, China JYOTI CHATTOPADHYAYA... Beijing 100191, China Qingqing Wang, Beijing Institute of Radiation Medicine, Taiping Road 27, Haidian District, Beijing 100850, People’s Republic of China Shengqi Wang, Beijing Institute of Radiation... range of topics in this volume accurately reflects the vigor of current investigations over a range of topics in the area of nucleic acids and underscores the expanding opportunities for medicinal