Iminosugars as Glycosidase Inhibitors, Nojirimycin and Beyond

American Journal of Pharmaceutical Education, Fall 1999 by Block, John H

ARNOLD E. STUTZ. Iminosugars as Glycosidase Inhibitors, Nojirimycin and Beyond. Weinheim Germany: Wiley-VCY 1999. xiv 397pp, 60figs., 13 tbls., $157.99

Iminosugars as Glycosidase Inhibitors, Nojirimycin and Beyond is an intriguing book. When I agreed to review it, I assumed that it would be a series of chapters typical of a multi-authored review text, I was pleasantly surprised. It is multi-authored, but there is a definite organization that results in a book suitable for both natural product and medicinal chemists.

First there is the focus on the chemistry of iminosugars, that are defined as N-heterocycles in which the hemiacetal or hemiketal oxygen has been replaced with a nitrogen. For example, hydroxy pyrrolidine is the imino analog of arabinose and ribose, The piperidine, nojiritnycin, is 5-amino-5-deoxy-D-glucopyranose. Its trivial name is derived from one of its biological sources. (The more common aminosugar happens when one of the hydroxy groups is replaced by an amine moiety.)

One of the chapters addresses the problems with consistent nomenclature. If the ring nitrogen is moved to what would be the anomeric position, the compound is called an isoimino sugar. The fused ring systems indolizidines, pyrrolizidines and nortropanes - sometimes are treated as iminosurgars. There is limited use of colored plates showing how the overlap between the natural sugar and its iminosugar analogue.

The second focus and the reason that the computer graphics are included in the text is the other part of the book's title . ....Gylcosidase Inhibitors." A significant portion of the book discusses the role of glycosidase and the reason that inhibitors could lead to useful drugs. Glycosidase is used by viruses (HIV CMV) to build their glycosylated envelope proteins. Human cancer cells use glycosidases to construct the surface oligosaccharides that are important in phenotyping. There is a hypothesis that some plants protect themselves against insects and nematodes by producing toxic iminosugars. Those insects which are not affected by these iminosugars have appropriate glycosidases. To date, the only human use of iminosugars is the alpha-glucosidase (maltase) inhibitor meglitol that is used in Type 2 Diabetes, Consistent with these examples, there are chapters on the structural characteristics of this enzyme and compounds known to be inhibitors.

The reader will find a well written chapter on plant sources. Most of the iminosugars were discovered in antibiotic screens or in plants that are toxic to livestock. Two chapters cover synthetic approaches. ln addition chapters on specific compounds will include their synthesis.

Faculty who teach graduate level medicinal chemistry courses will enjoy two chapters on the challenging problem of designing glycosidase inhibitors. Much of the focus has been on transition state inhibitors, Predicting which iminosugars will be good inhibitors has not been easy. For example, one cannot assume that the iminosugar analog of a natural sugar (eg., galactose) will inhibit galactosidase, Chapter nine has the intriguing title "Potent Glycoside Inhibitors: Transition State Mimics or Simply Fortuitous Binders?"

One of the most attractive features of this book is the 135 pages (33 percent of the total) of tables. Depending an the information available, each entry will contain nomenclature, spectral data, the glycosidases (with their EC number) that are inhibited including the Ki and IC50 values and the references that reported the information

Natural product and medicinal chemists should consider purchasing this book for their personal libraries, This book would be an appropriate text for a special topics or an advanced integrated natural products-medicinal chemistry course. It definitely belongs in university libraries.

John H. Block

Oregon State University