The Organic Chemistry of Drug Design and Drug Action

Book Preface

Ten years have rolled by since the publication of the second edition, and the field of medicinal chemistry has undergone a number of changes. To aid in trying to capture the essence of new directions in medicinal chemistry, I decided to add a coauthor for this book. Mark W. Holladay was my second graduate student (well, that year I took four graduate students into my group, so he’s actually from my second class of graduate students), and I knew from when he came to talk to me, he was going to be a great addition to the group (and to help me get tenure!). In my naivete as a new assistant professor, I assigned Mark a thesis project to devise a synthesis of the newly-discovered antitumor natural product, acivicin, which was believed to inhibit enzymes catalyzing amido transfer reactions from L-glutamine that are important for tumor cell growth. That would be a sensible thesis project, but I told him that the second part of his thesis would be to study its mechanism of action, as Mark had indicated a desire to do both organic synthesis and enzymology. Of course, this would be a 10-year doctoral project if he really had to do that, but what did I know then? Mark did a remarkable job, independently working out the total synthesis of the natural product (my proposed synthetic route at the beginning failed after the second step) and its C-5 epimer, and he was awarded his Ph.D. for the syntheses. He moved on to do a postdoc with Dan Rich, the extraordinary peptide chemist now retired from the University of Wisconsin, and joined Abbott Laboratories as a senior scientist. After 15 years at Abbott, and having been elected to the Volwiler Society, an elite honor society at Abbott Labs for their most valuable scientists, he decided to move to a smaller pharmaceutical environment, first at SIDDCO, then Discovery Partners International, and now at Ambit Biosciences. Because of his career-long association with the pharmaceutical industry (and my knowledge that he was an excellent writer), I invited him to coauthor the third edition to give an industrial pharmaceutical perspective. It has been a rewarding and effective collaboration. Although both of us worked equally on all of the chapters, I got the final say, so any inconsistencies or errors are the result of my oversight.

Richard B. Silverman