Victor E. Marquez, Ph.D.
Victor E. Marquez, Ph.D.
Scientist Emeritus

Center for Cancer Research
National Cancer Institute

Building 376
Frederick, MD 21702-1201
301-846-5954

Dr. Marquez received his Ph.D. in Medicinal Chemistry from the University of Michigan in 1970. After 1 year of postdoctoral training at the NCI, he worked in private industry for 5 years in Venezuela. He rejoined the NCI in 1977 as a Visiting Scientist, was awarded tenure as a Principle Investigator in 1987 after becoming a naturalized citizen, and then promoted to Lab Chief in 2001. His main research interests are nucleoside chemistry and synthetic organic chemistry as tools for the rational design of antitumor and antiviral agents. Dr. Marquez has authored or coauthored almost 400 publications and has received 29 U.S. patents. Dr. Marquez retired as Lab Chief on September 30, 2009 and is now Scientist Emeritus.

Areas of Expertise
nucleoside chemistry

Rational Design of Antitumor and Antiviral Agents Ultrapotent Ligands for PKC and Other Phorbol Ester Receptors

One of the principal goals of this research is the understanding of the geometry of bioequivalent pharmacophores-present in diacylglycerol (DAG) and in the more potent phorbol esters-that appear to be responsible for binding to the regulatory C1 domains of protein kinase C (PKC) and other target proteins. These domains, which act as a molecular hydrophobic switch, represent regulatory modules in several families of proteins involved in signal transduction, including the PKC, chimaerin, and RasGRP families. Many of the features that characterize the interaction between ligands and PKC can be understood at the level of the isolated C1 domain. A receptor-guided approach, which utilizes as its basis the x-ray structure of the C1b domain of PKC-delta in complex with phorbol-13-O-acetate, helped us identify the 'recognition domain' for DAG, which consisted of a similar network of hydrogen bonds as those utilized by phorbol. The application of this model to DAGs and to the more potent DAG-lactones that were designed later suggested that both classes of compounds can bind to the C1 domain in two distinct orientations, so-called sn-1 and sn-2 orientations. Since in each of these orientations the hydrophobic groups or 'affinity domains' of the ligand are directed into rather different directions, the interactions of these groups with a cluster of conserved hydrophobic amino acids located on the top half of the C1 domain were incorporated into the model. The optimization of binding to this hydrophobic cluster has already produced ligands that display low nanomolar binding affinities for PKC and related C1 domain-containing protein targets. The first subnanomolar binding ligand for beta-2 chimaerin, which surpasses even the phorbol esters in binding potency, was developed. Furthermore, some of these novel ligands have shown potent antitumor activities in the NCI 60-cell line in vitro screen. A combination of small library approaches and molecular dynamics simulations has contributed to our understanding of the nature of these important hydrophobic interactions.

Conformationally Locked Nucleosides

Nucleosides and nucleotides are inherently flexible molecules. Hence, one of the main obstacles in interpreting structure-activity correlations has been this high level of flexibility. In 1993, our laboratory described the first synthesis of a conformationally locked bicyclo[3.1.0]hexane nucleoside. Although other types of locked nucleosides have been devised by others, only the bicyclo[3.1.0]hexane pseudosugar can successfully mimic both antipodal North and South conformations typical of conventional nucleosides. Significant differences in the biological activity of locked nucleoside antipodes, which depend on the precise interaction of these rigid molecules with specific target enzymes, have been clearly demonstrated. The principal theme in this area is and has been the study of 'shape' in the recognition of individual nucleosides and nucleotides by specific enzymes (e.g., adenosine deaminase, reverse transcriptase, HSV-1 thymidine kinase, etc.). Recently, this concept has been extended to the study of DNA segments incorporating locked nucleotide units. It is well known that the binding of proteins to DNA elicits a unique conformational response of the double helix, which is tied to the function of the associated protein. Studies with cytosine (C5)-methyltransferase, an important enzyme in the control of gene expression, revealed important differences between target abasic sites locked in both antipodal conformations. Furthermore, the incorporation of conformationally locked nucleotides into DNA is a powerful tool to reinforce or disrupt typical B- or A-DNA forms associated with South and North conformations, respectively.

Scientific Focus Areas:
Chemical Biology
Selected Publications
  1. Pu Y, Kang JH, Sigano DM, Peach ML, Lewin NE, Marquez VE, Blumberg PM.
    J. Med. Chem.. 57: 3835-44, 2014. [ Journal Article ]
  2. Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez VE, Nakagawa M, Kurokawa M.
    Cancer Sci.. 105: 512-9, 2014. [ Journal Article ]
  3. Ciarapica R, Carcarino E, Adesso L, De Salvo M, Bracaglia G, Leoncini PP, Dall Agnese A, Verginelli F, Milano GM, Boldrini R, Inserra A, Stifani S, Screpanti I, Marquez VE, Valente S, Mai A, Puri PL, Locatelli F, Palacios D, Rota R.
    BMC Cancer. 14: 139, 2014. [ Journal Article ]
  4. Garcia LC, Donadío LG, Mann E, Kolusheva S, Kedei N, Lewin NE, Hill CS, Kelsey JS, Yang J, Esch TE, Santos M, Peach ML, Kelley JA, Blumberg PM, Jelinek R, Marquez VE, Comin MJ.
    Bioorg. Med. Chem.. 22: 3123-40, 2014. [ Journal Article ]
  5. A new synthesis of sultams from amino alcohols.
    Lad N, Sharma R, Marquez VE, Mascarenhas M.
    Tetrahedron Letters. 54: 6307-6309, 2013. [ Journal Article ]

Dr. Marquez received his Ph.D. in Medicinal Chemistry from the University of Michigan in 1970. After 1 year of postdoctoral training at the NCI, he worked in private industry for 5 years in Venezuela. He rejoined the NCI in 1977 as a Visiting Scientist, was awarded tenure as a Principle Investigator in 1987 after becoming a naturalized citizen, and then promoted to Lab Chief in 2001. His main research interests are nucleoside chemistry and synthetic organic chemistry as tools for the rational design of antitumor and antiviral agents. Dr. Marquez has authored or coauthored almost 400 publications and has received 29 U.S. patents. Dr. Marquez retired as Lab Chief on September 30, 2009 and is now Scientist Emeritus.

Summary

Dr. Marquez received his Ph.D. in Medicinal Chemistry from the University of Michigan in 1970. After 1 year of postdoctoral training at the NCI, he worked in private industry for 5 years in Venezuela. He rejoined the NCI in 1977 as a Visiting Scientist, was awarded tenure as a Principle Investigator in 1987 after becoming a naturalized citizen, and then promoted to Lab Chief in 2001. His main research interests are nucleoside chemistry and synthetic organic chemistry as tools for the rational design of antitumor and antiviral agents. Dr. Marquez has authored or coauthored almost 400 publications and has received 29 U.S. patents. Dr. Marquez retired as Lab Chief on September 30, 2009 and is now Scientist Emeritus.

Areas of Expertise
nucleoside chemistry

Research

Rational Design of Antitumor and Antiviral Agents Ultrapotent Ligands for PKC and Other Phorbol Ester Receptors

One of the principal goals of this research is the understanding of the geometry of bioequivalent pharmacophores-present in diacylglycerol (DAG) and in the more potent phorbol esters-that appear to be responsible for binding to the regulatory C1 domains of protein kinase C (PKC) and other target proteins. These domains, which act as a molecular hydrophobic switch, represent regulatory modules in several families of proteins involved in signal transduction, including the PKC, chimaerin, and RasGRP families. Many of the features that characterize the interaction between ligands and PKC can be understood at the level of the isolated C1 domain. A receptor-guided approach, which utilizes as its basis the x-ray structure of the C1b domain of PKC-delta in complex with phorbol-13-O-acetate, helped us identify the 'recognition domain' for DAG, which consisted of a similar network of hydrogen bonds as those utilized by phorbol. The application of this model to DAGs and to the more potent DAG-lactones that were designed later suggested that both classes of compounds can bind to the C1 domain in two distinct orientations, so-called sn-1 and sn-2 orientations. Since in each of these orientations the hydrophobic groups or 'affinity domains' of the ligand are directed into rather different directions, the interactions of these groups with a cluster of conserved hydrophobic amino acids located on the top half of the C1 domain were incorporated into the model. The optimization of binding to this hydrophobic cluster has already produced ligands that display low nanomolar binding affinities for PKC and related C1 domain-containing protein targets. The first subnanomolar binding ligand for beta-2 chimaerin, which surpasses even the phorbol esters in binding potency, was developed. Furthermore, some of these novel ligands have shown potent antitumor activities in the NCI 60-cell line in vitro screen. A combination of small library approaches and molecular dynamics simulations has contributed to our understanding of the nature of these important hydrophobic interactions.

Conformationally Locked Nucleosides

Nucleosides and nucleotides are inherently flexible molecules. Hence, one of the main obstacles in interpreting structure-activity correlations has been this high level of flexibility. In 1993, our laboratory described the first synthesis of a conformationally locked bicyclo[3.1.0]hexane nucleoside. Although other types of locked nucleosides have been devised by others, only the bicyclo[3.1.0]hexane pseudosugar can successfully mimic both antipodal North and South conformations typical of conventional nucleosides. Significant differences in the biological activity of locked nucleoside antipodes, which depend on the precise interaction of these rigid molecules with specific target enzymes, have been clearly demonstrated. The principal theme in this area is and has been the study of 'shape' in the recognition of individual nucleosides and nucleotides by specific enzymes (e.g., adenosine deaminase, reverse transcriptase, HSV-1 thymidine kinase, etc.). Recently, this concept has been extended to the study of DNA segments incorporating locked nucleotide units. It is well known that the binding of proteins to DNA elicits a unique conformational response of the double helix, which is tied to the function of the associated protein. Studies with cytosine (C5)-methyltransferase, an important enzyme in the control of gene expression, revealed important differences between target abasic sites locked in both antipodal conformations. Furthermore, the incorporation of conformationally locked nucleotides into DNA is a powerful tool to reinforce or disrupt typical B- or A-DNA forms associated with South and North conformations, respectively.

Scientific Focus Areas:
Chemical Biology

Publications

Selected Publications
  1. Pu Y, Kang JH, Sigano DM, Peach ML, Lewin NE, Marquez VE, Blumberg PM.
    J. Med. Chem.. 57: 3835-44, 2014. [ Journal Article ]
  2. Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez VE, Nakagawa M, Kurokawa M.
    Cancer Sci.. 105: 512-9, 2014. [ Journal Article ]
  3. Ciarapica R, Carcarino E, Adesso L, De Salvo M, Bracaglia G, Leoncini PP, Dall Agnese A, Verginelli F, Milano GM, Boldrini R, Inserra A, Stifani S, Screpanti I, Marquez VE, Valente S, Mai A, Puri PL, Locatelli F, Palacios D, Rota R.
    BMC Cancer. 14: 139, 2014. [ Journal Article ]
  4. Garcia LC, Donadío LG, Mann E, Kolusheva S, Kedei N, Lewin NE, Hill CS, Kelsey JS, Yang J, Esch TE, Santos M, Peach ML, Kelley JA, Blumberg PM, Jelinek R, Marquez VE, Comin MJ.
    Bioorg. Med. Chem.. 22: 3123-40, 2014. [ Journal Article ]
  5. A new synthesis of sultams from amino alcohols.
    Lad N, Sharma R, Marquez VE, Mascarenhas M.
    Tetrahedron Letters. 54: 6307-6309, 2013. [ Journal Article ]

Biography

Dr. Marquez received his Ph.D. in Medicinal Chemistry from the University of Michigan in 1970. After 1 year of postdoctoral training at the NCI, he worked in private industry for 5 years in Venezuela. He rejoined the NCI in 1977 as a Visiting Scientist, was awarded tenure as a Principle Investigator in 1987 after becoming a naturalized citizen, and then promoted to Lab Chief in 2001. His main research interests are nucleoside chemistry and synthetic organic chemistry as tools for the rational design of antitumor and antiviral agents. Dr. Marquez has authored or coauthored almost 400 publications and has received 29 U.S. patents. Dr. Marquez retired as Lab Chief on September 30, 2009 and is now Scientist Emeritus.