Ups and Downs in Drug Design

Dr. Victor E. Marquez After one year of postdoctoral studies at the National Cancer Institute (NCI)/National Institutes of Health (NIH), Dr. Marquez returned to Venezuela as Research Director of Cosmos Laboratories. In 1977, he rejoined the NCI as a Visiting Scientist, and from 1999 to 2009 he was Chief of the Laboratory of Medicinal Chemistry. In 2008, Dr. Marquez was named Maryland Chemist of the Year, and in 2010 he was inducted into the Medicinal Chemistry Hall of Fame. Dr. Marquez retired as Scientist Emeritus after 32 years of service.

In this book, Dr. Marquez goes to great lengths to explain the chemical rationales that he and his teams followed including the development and utilization of efficient synthetic schemes and the molecular mechanisms of action of the potential drug candidates that they pursued. The stories that Dr. Marquez relates illustrate the challenges they faced, the joys of the successes and the frustrations of the defeats in drug discovery. More importantly, they guide the reader through the thought processes and what was learned in each of these efforts even when the success was less than hoped for. This book is a wonderful lesson for those bright young minds who are considering careers in the biomedical sciences as well as those already on the pathway and indeed experienced practitioners too.- George A. Garcia, from the ForewordThe purpose of this book is to describe Dr. Marquez's journey/career in medicinal chemistry in a semi-autobiographical function. As it follows his own personal journey, the "chapters" seem random as they parallel his career path and the work/molecules he studied. It is a rather unique text as a career "summary" for Dr. Marquez.In my opinion as a pharmacy educator, the target audience of this book is primarily colleague medicinal chemists who can relate to the changes in the field over the past four decades. Graduate-level students in this field also may admire the pathway and trials and tribulations of a mentoring medicinal chemist. Based on his longstanding career, Dr. Marquez is a leader in this field and an educator.This is the first book of this style I have come across in my academic career. As the book is based on Dr. Marquez' personal journal, it is rather unique, but a second edition will not apply.- Patrick J. McDonnell, PharmD (Temple University School of Pharmacy)

• 1. STRUCTURE-ACTIVITY RELATIONSHIPS (SAR). 2. BRAIN ANTITUMOR AGENTS: THE STORY OF SPIROMUSTIN. 3. PRIVILEGED DRUG SCAFFOLDS: THE STORY OF LC-6 AND PYRIDINOLCARBAMATE. 4. CYTIDINE DEAMINASE: PART 1—THE CONCEPT OF TRANSITION-STATE INHIBITORS AND THE DISCOVERY OF ZEBULARINE. 5. CYTIDINE DEAMINASE: PART 2—LESSONS FROM NATURE’S TRANSITION STATE INHIBITORS. 6. TIAZOFURIN AND THE HISTORY OF THIAZOLE-4-CARBOXAMIDE ADENIDE DINUCLEOTIDE (TAD). 7. THE AIDS ERA: NUCLEOSIDE ANTIRETROVIRAL AGENTS. 8. THE AIDS ERA: SYNTHESES OF FLUORONUCLEOSIDES AND THE CLINICAL DEVELOPMENT OF LODENOSINE. 9. EXPLORATION OF NOVEL NUCLEOSIDE TEMPLATES IN SEARCH OF ACTIVE ANTI-HIV AND ANTIVIRAL DRUGS. 10. 3-DEAZANEPLANOCIN A AND CYCLOPENTENYLCYTOSINE. 11. EPIGENETICS AND CANCER: 5-AZA-CYTIDINE AND ZEBULARINE. 12. ZEBULARINE AS AN EPIGENETIC ANTICANCER AGENT. 13. 3-DEAZANEPLANOCIN A (DZNep) AS AN EPIGENETIC ANTICANCER AGENT. 14. BICYCLO[3.1.0]HEXANE NUCLEOSIDES: CHEMISTRY. 15. BICYCLO[3.1.0]HEXANE NUCLEOSIDES: BIOLOGY (PART 1). 16. BICYCLO[3.1.0]HEXANE NUCLEOSIDES: BIOLOGY (PART 2)—MORE ON KINASES/POLYMERASES AND DRUG DEVELOPMENT OF N-MCT. 17. BICYCLO[3.1.0]HEXANE NUCLEOSIDES: BIOLOGY (PART THREE)—INVESTIGATION OF MORE EXOTIC TARGETS. 18. BICYCLO[3.1.0]HEXANE NUCLEOSIDES: CHEMICAL VARIATIONS ON A COMMON THEME. 19. DIACYLGLYCEROL LACTONES AND PROTEIN KINASE C (PKC): A PHARMACOPHORE-GUIDED APPROACH. 20. DIACYLGLYCEROL LACTONES AND PROTEIN KINASE C (PKC): TRANSITION FROM A PHARMACOPHORE-GUIDED APPROACH TO A RECEPTOR-GUIDED APPROACH.