Victor E. Marquez, Ph.D.

 

Dr. Victor E. Marquez was born in Caracas, Venezuela. He obtained a B.S. degree in Pharmacy in 1966 from Universidad Central de Venezuela and Master and Ph.D. degrees in Medicinal Chemistry from the University of Michigan in 1988 and 1970, respectively, under the tutelage of Professor Joseph H. Burckhalter. His career at the National Cancer Institute (NCI) started in 1971 when he joined as Visiting Fellow in the Medicinal Chemistry Section of the Developmental Therapeutics Program. During his NIH fellowship (1971-1972), while working under the supervision of Dr. John S. Driscoll, Dr. Marquez developed a novel hydantoin template for the delivery of nitrogen mustards specifically to the CNS. This research led to the design of the active brain antitumor agent, spiromustine. Phase I evaluation of spiromustine commenced in 1987, but neurotoxicity presented as alterations in cortical integrative functions led to its eventual withdrawal from further clinical use. Dr. Marquez then returned to Venezuela for a five-year period (1972-1976) where he worked as Director of Research in Laboratorios Cosmos, S.A. in Caracas. There, he developed a new class of orally active anaphylactic inhibitor, which was patented under U.S. pat. No. 4,167,577 in 1979. In 1977, Dr. Marquez rejoined the NCI as a Visiting Scientist and was awarded tenure as a Principal Investigator in 1987 after becoming a naturalized citizen. In 1988 he became Deputy Laboratory Chief and in 2000 he was promoted to Laboratory Chief. Dr. Marquez retired as Lab Chief on September 1, 2009 and is now Scientist Emeritus at the NCI. During his career at the NCI his discoveries have helped translate elements of basic research into solutions for specific medical problems as exemplified by cyclopentenyl cytosine (CPE-C) and 9-(2’,3’-dideoxy-2’-fluoro-beta-D-threo-pentofuranosyl)adenine, the latter also known as lodenosine. These drugs entered clinical trials in the late 1990’s and early 2000 as antitumor and anti-HIV drugs, respectively. They were later suspended from further clinical use due to unexpected toxicity. Currently, North-methanocarba thymidine, a potent antiherpes drug is schedule to enter phase I clinical trials. In addition, zebularine, a DNA methylase inhibitor, and 3-deazaneplanocin A, a histone methylase inhibitor, are important candidates under study for the epigenetic treatment of cancer. Other important discoveries that have resulted from his work in the area of nucleosides and nucleotides have been based on mechanistic approaches to inhibit key enzymatic reactions. Some of the most important highlights in this area are: (1) Design and synthesis of the most potent transition-state analogue inhibitors of cytidine deaminase based on a novel 5-hydroxy-perhydro-1,3-diazepin-2-one nucleoside system; (2) synthesis of thiazole-4-carboxamide adenine dinucleotide (TAD) and the corresponding metabolically stable phosphonate analogue (beta-methylene TAD), two of the most potent inhibitors of inosine monophosphate dehydrogenase; (3) synthesis and discovery of 3-deazaneplanocin A, the most potent inhibitor known against S-adenosylhomocysteine hydrolase; (4) synthesis and discovery of cyclopentenyl cytosine (CPE-C), the most potent inhibitor known to date against cytidine triphosphate synthase; (5) design and synthesis of the first, acid-stable dideoxypurine inhibitor of HIV reverse transcriptase; (6) design and synthesis of conformationally locked carbocyclic nucleosides as important biological probes; (7) design and synthesis of zebularine, an orally active DNA methylase inhibitor; and (8) design and synthesis of oligodeoxynucleotides containing conformationally restricted abasic sites as potent inhibitors of cytosine DNA methyltransferase. Concomitant to the work performed above, theoretical studies with conformationally locked nucleosides and oligonucleotides containing locked units have helped understand the role of sugar conformation in determining the affinity of nucleosides and nucleotides for kinases and polymerases. These studies have also set the basis for the design of delayed polymerase chain terminators effective against the scission repair mechanisms of resistant HIV reverse transcriptase. In a second line of research, Dr. Marquez developed a series of diacylglycerol mimetics, dubbed DAG-lactones that bind to the regulatory domain of protein kinase C (PKC) at nanomolar concentrations. Some DAG-lactones display isozyme selectivity for specific members of the PKC family and have shown potent antitumor activity in the NCI 60 cell line screen as well as exceptional apoptosis inducing properties. Dr. Marquez has received many awards and distinctions during his career, including the U.S. Department of Commerce Inventor’s award (1979); Medical Research Council Visiting Professorship at the Universities of Saskatchewan and Manitoba, Canada (1984-85); NIH Merit Award (1992); Vice-chair and Chair of Gordon Research Conference on Purines, Pyrimidines and Related Compounds (1993 and 1995); National Cancer Institute, Division of Basic Sciences Intramural Research Award (1997); Pharmazie-Wissenschaftpreiss 2001 (Pharmazeutische Chemie) sponsored by Phoenix Pharmahandel AG & Co (2001); Senior Biological Research Scientist appointment (2002); Member of the Medicinal Chemistry Division Long Range Planning Committee (2003-2005); Belleau Memorial Lecturer, McGill Chemical Society, McGill University (2003); Intramural AIDS Targeted Antiviral Program (IATAP) award (2005 and 2006); Leopoldo García-Colín-Scherer Medal, Mexico City, Mexico (2007); Symposium Honoring Victor Marquez for His Contributions to Conformational Analysis, Nucleosides, Nucleotides and Oligonucleotides, Division of Carbohydrate Chemistry, American Chemical Society, 236th National Meeting, Philadelphia, PA (2008); Elected Vice-President of the International Society for Nucleosides, Nucleotides and Nucleic Acids (2008); Maryland Chemist of the Year (2008); and Raymond U. Lemieux Lecture On Biotechnology, University of Alberta (2009). To date, the entire portfolio of his research is contained in more than 340 publications (71 in the Journal of Medicinal Chemistry with over 2476 citations), 11 book chapters, and 30 patents. Dr. Marquez has received over 120 invitations as a speaker to various symposia, universities and pharmaceutical companies.