Downloaded by 91.204.15.155 on June 23, 2016 | http://pubs.acs.org Publication Date: December 7, 1994 | doi: 10.1021/bk-1994-0580.pr001
Preface I H E THERAPEUTIC UTHJTY OF OLIGONUCLEOTIDES has gained increasing credibility and attention in the past decade because of in vitro and in vivo efficacy. The number of scientists committed to oligonucleotide drug discovery and development has increased from a handful to perhaps as many as several thousand. The pace of discoveries has been so rapid and global that it has become difficult for scientists intimately involved with antisense technology to remain abreast of recent advances. It is an even bigger challenge to disseminate this information to newcomers in the field of antisense technology. To our surprise, there is very little crossover of information between scientists who apply this technology to design drugs for therapeutics and those who specialize in carbohydrate chemistry. We believe that these scientists will be quite interested in the similarities between the two disciplines. This thought motivated the organization of the symposium on which this volume is based. This book presents the latest research results on carbohydrate chemistry required to create new oligonucleotides for antisense applications. Much of the synthetic chemistry effort directed toward development of improved antisense agents has focused on modifying the carbohydrate portion of oligonucleotides to achieve stability toward nuclease degeneration and to enhance the binding affinity to a target strand of RNA. Several chapters describe phosphate modification to include sulfur (i.e., phosphorothioates) or a carboranyl moiety, as well as the complete replacement of the phosphate linkage by ethers, sulfides, amides, and amines to provide a nonionic backbone for oligonucleotides. The utility of uniquely branched or 2',5'-linked oligonucleotides for antisense research has been included. Some drastic sugar ring alterations, such as 4'-thio sugars and hexopyranosyl- and bicyclo-DNA analogues, have been prepared, and their applications are discussed Contributions on basemodified thiopurine analogues and the influence of sugar modifications on the conformational properties of oligonucleotides are presented. The need for pure synthetic RNA in antisense research is crucial, and this topic is also discussed. Contributors to this volume are chemists and biologists working in university and industrial settings in many countries toward a common goal. Their research efforts should be valuable to those who conduct interdisciplinary research and to those who wish to enter this field without any prior background. Taken together, these chapters provide an
vii Sanghvi and Cook; Carbohydrate Modifications in Antisense Research ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
appropriate historical background and summary of several recent developments in the concepts and synthetic strategies of antisense applications using carbohydrate chemistry. The overview chapter provides a more complete picture of the current status and future prospects of this emerging technology.
Downloaded by 91.204.15.155 on June 23, 2016 | http://pubs.acs.org Publication Date: December 7, 1994 | doi: 10.1021/bk-1994-0580.pr001
Acknowledgments
We acknowledge the contributing authors for the time and effort expended in preparing this volume. The credit for an up-to-date account of rapidly moving technology goes to all of the authors. We thank the many expert reviewers who insisted on inclusion of the latest results and provided their comments in a timely manner. We gratefully acknowledge the Division of Carbohydrate Chemistry for its support in organizing the symposium and publication of this volume. We appreciate the financial support provided by Isis Pharmaceuticals, Ciba-Geigy, Gilead Sciences, and Millipore, which allowed us to organize a successful symposium. YOGESH S. SANGHVI
P. DAN COOK Isis Pharmaceuticals 2292 Faraday Avenue Carlsbad, CA 92008 July 19, 1994
viii Sanghvi and Cook; Carbohydrate Modifications in Antisense Research ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
