The book covers up-to-date information on nucleosides and antiviral chemotherapy contributed by the world experts in the field of nucleoside. This book is the result of a meeting honoring Dr. Jack J. Fox, who was one of the pioneers in nucleoside chemistry and chemotherapy. This book consists of 15 excellent chapters in the area, which include topics from recent synthetic methodologies, nucleoside kinase implicated in chemotherapy and drug design, excellent reviews on antiviral agents, nucleoside metabolism/mode of action in parasites, new compounds under clinical and pre-clinical trials, IMPDH inhibitors to review on nucleoside prodrugs.

• Up-to-date review on the chemistry and biology of nucleosides • Modern synthetic methodology • Comprehensive coverage of antiviral nucleosidesThis book summarizes the recent advances in nucleosides chemistry and chemotherapy over the past 10-15 years. It covers recently discovered nucleoside antiviral agents, their therapeutic aspects and biochemistry, and also extensive reviews on their chiral synthesis.

Due to the worldwide epidemic of acquired immunodeficiency syndrome (AIDS), the past ten years have witnessed a flurry of activity in the chemotherapy of viral diseases. Unprecedented scientific efforts have been made by scientists and clinicians to combat infections of human immunodeficiency virus (HIY), the causative agent. Looking back over the past ten years, we have made remarkable progress toward the treatment of the viral disease: isolation of HIV only two years after the identification of the disease, plus major strides in the areas of the molecular biology and virology of the retrovirus, etc. More remarkably, the discovery of the chemotherapeutic agent AZT (Retrovir) was made within two years after the isolation and identification of the virus, followed by unprecedented drug development efforts to culminate in the FDA approval of AZT in twenty-three months, which was a record-breaking time for approval of any drug for a major disease. The last six to seven years have particularly been an exciting and productive period for nucleoside chemists. Since the activity of AZI' was established in 1985, nucleoside chemists have had golden opportunities to discover additional anti-HIV nucleosipes, which are hoped to be less toxic and more effective than AZT, and the opportunity continues. As we all are aware, AZT possesses extremely potent anti-HIY activity, and no other nucleoside or non nucleoside has surpassed the potency of AZT in vitro.

This publication contains the Review Lectures given at a joint NATO Advanced Study Institute and a FEB S Advanced Study Course, held at Sogesta (Nr. Urbino), Italy from the 7th - 18th May 1979. The Course entitled "Nucleoside Analogues : Chemistry, Biology and Medical Applications" was held for several reasons. In the past few years, many useful and potentially-useful nucleoside analogues have either reached the stage of clinical use or are undergoing clinical trials. Many more compounds have been synthesised by the organic chemist and little more has been done with them other than possibly a few perfunctory biological tests. This is often due to either a lack of interest or an inadequate knowledge of the testing proced ures available or a lack of communication between the chemist, biochemist, pharmacologist and the clinician such that few compounds receive the testing and evaluation which they deserve. The aim of this meeting was to gather together many of the experts in the different scientific disciplines which are involved in the design, synthesis, testing and clinical use of nucleoside analogues, primarily as anti-viral and anti-cancer agents, and to discuss in depth the fundamental principles of each discipline so that participants could understand each other's problems and be more aware of the information required and that which can be obtained.

Interest in chemical entities capable of blocking or modifying cell metabolism ultimately goes back to the discovery of the structure of DNA in the 1950s. Understanding of the biochemical processes involved in cell metabolism rapidly led to the idea that compounds could be designed which might interfere with these processes, and thus could be used in the treatment of the diseases caused by viral infection. Since then, several classes of drugs have been discovered which depend for their effect on modification of the proper functioning of nucleic acids and, with the introduction of acyclovir for the treatment of Herpes infections, nucleoside analogues have become the cornerstone of antiviral chemotherapy. The success of the early nucleoside agents, the toxicity and metabolic instability of many nucleoside analogues, and the effects of viral pathogens on public health are driving the design, synthesis and evaluation of new nucleoside analogues, with much attention turning to nucleosides containing `non natural' sugar analogues. This book focuses on the development of these agents, and draws together all the available material in an easily consulted form, which at the same time guides the reader into the research literature on the subject. Written primarily for the medicinal chemist, coverage includes both synthetic strategies and outline guidance on the main trends in biological activity. Particular attention is drawn to the comparison of synthetic routes to compounds with their natural analogues. Finally, the important antiviral activities of the compounds are treated, including anti-retrovirus, anti-hepadnavirus and anti-herpes virus properties. Written mainly for medicinal chemists in the pharmaceutical industry and synthetic organic chemists in academe, this book will also be attractive to researchers in institutions focusing on cellular metabolism. Advanced students of organic chemistry will find the clear discussion of the synthetic strategies adopted in the development of these compounds a useful introduction to this exciting and challenging area.

Successful cancer chemotherapy relies heavily on the application of various deoxynucleoside analogs. Since the very beginning of modern cancer chemotherapy, a number of antimetabolites have been introduced into the clinic and subsequently applied widely for the treatment of many malignancies, both solid tumors and hematological disorders. In the latter diseases, cytarabine has been the mainstay of treatment of acute myeloid leukemia. Although many novel compounds were synthesized in the 1980s and 1990s, no real improvement was made. However, novel technology is now capable of elucidating the molecular basis of several inborn errors as well as some specific malignancies. This has enabled the synthesis of several deoxynucleoside analogs that could be applied for specific malignancies, such as pentostatin and subsequently chlorodeoxyadenosine (cladribine) for the treatment of hairy cell leukemia. Already in the early stage of deoxynucleoside analog development, it was recognized that several of these compounds were very effective in the treatment of various viral infections, such as for the treatment of herpes infections. This formed the basis initially for the design of azidothymidine and subsequently many other analogs, which are currently successfully used for the treatment of HIV infections. As a spin-off of these research lines, some compounds not eligible for development as antiviral agents appeared to be very potent anticancer agents. The classical example is gemcitabine, now one of the most widely applied deoxynucleoside analogs, used for the (combination) treatment of non-small cell lung cancer, pancreatic cancer, bladder cancer, and ovarian cancer.

Compiles current tested and proven approaches to synthesize novel nucleoside analogues Featuring contributions from leading synthetic chemists from around the world, this book brings together and describes tested and proven approaches for the chemical synthesis of common families of nucleoside analogues. Readers will learn to create new nucleoside analogues with desired therapeutic properties by using a variety of methods to chemically modify natural nucleosides, including: Changes to the heterocyclic base Modification of substituents at the sugar ring Replacement of the furanose ring by a different carbo- or heterocyclic ring Introduction of conformational restrictions Synthesis of enantiomers Preparation of hydrolitically stable C-nucleosides Chemical Synthesis of Nucleoside Analogues covers all the major classes of nucleosides, including pronucleotides, C-nucleosides, carbanucleosides, and PNA monomers which have shown great promise as starting points for the synthesis of nucleoside analogues. The book also includes experimental procedures for key reactions related to the synthesis of nucleoside analogues, providing a valuable tool for the preparation of a number of different compounds. Throughout the book, chemical schemes and figures help readers better understand the chemical structures of nucleoside analogues and the methods used to synthesize them. Extensive references serve as a gateway to the growing body of original research studies and reviews in the field. Synthetically modified nucleosides have proven their value as therapeutic drugs, in particular as antiviral and antitumor agents. However, many of these nucleoside analogues have undesirable side effects. With Chemical Synthesis of Nucleoside Analogues as their guide, researchers have a new tool for synthesizing a new generation of nucleoside analogues that can be used as therapeutic drugs with fewer unwanted side effects.