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Victor E. Marquez, Ph.D.

Victor E. Marquez, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Chemical Biology Laboratory

RESEARCH SUMMARY

Dr. Marquez's main research interests centered on nucleoside chemistry and synthetic organic chemistry as tools for the rational design of antitumor and antiviral agents. One of the principal goals of his research was understanding the geometry of bioequivalent pharmacophores-present in diacylglycerol (DAG) and in the more potent phorbol esters that appeared 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.  His laboratory also described the first synthesis of a conformationally locked bicyclo[3.1.0]hexane nucleoside.

Areas of Expertise

1) nucleoside chemistry 2) synthetic organic chemistry

Publications

Selected Key Publications

Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS

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 ]

Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP

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 ]

A new synthesis of sultams from amino alcohols

Lad N, Sharma R, Marquez VE, Mascarenhas M.
Tetrahedron Letters. 54: 6307-6309, 2013. [ Journal Article ]

Diacylglycerol Lactones Targeting the Structural Features That Distinguish the Atypical C1 Domains of Protein Kinase C ? and ? from Typical C1 Domains

Pu Y, Kang JH, Sigano DM, Peach ML, Lewin NE, Marquez VE, Blumberg PM.
J. Med. Chem.. 57: 3835-44, 2014. [ Journal Article ]

Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16

Ueda K, Yoshimi A, Kagoya Y, Nishikawa S, Marquez VE, Nakagawa M, Kurokawa M.
Cancer Sci.. 105: 512-9, 2014. [ Journal Article ]

Covers

Cover of The Journal of Organic Chemistry, Jan. 20, 2012

Synthesis of Conformationally North-Locked Pyrimidine Nucleosides Built on an Oxabicyclo[3.1.0]hexane Scaffold

Published Date

Beginning with a known 3-oxabicyclo[3.1.0]-hexane scaffold, the relocation of the fused cyclopropane ring bond and the shifting of the oxygen atom to an alternative location engendered a new 2-oxabicyclo[3.1.0]hexane template that mimics more closely the tetrahydrofuran ring of conventional nucleosides. The synthesis of this new class of locked nucleosides involved a novel approach that required the isocyanate with a hydroxyl-protected scaffold as a pivotal intermediate that was obtained in 11 steps from a known dihydrofuran precursor.

Citation

See: Synthesis of Conformationally North-Locked Pyrimidine Nucleosides Built on an Oxabicyclo[3.1.0]hexane Scaffold by Olaf R. Ludek and Victor E. Marquez in the Journal of Organic Chemistry201277(1), 815-824.

Cover of ChemBioChem, May 2, 2011

Effect of North Bicyclo[3.1.0]hexane 2'-Deoxypseudosugars on RNA Interference: A Novel Class of siRNA Modification

Published Date

The inside cover picture shows how siRNAs modified with North bicyclo[3.1.0]hexane 2'-deoxy-pseudosugars are able to activate the RNA interference machinery. The paper confirms that the North conformation is critical for RNAi activity. 

Citation

For further details, see Effect of North Bicyclo[3.1.0]hexane 2'-Deoxypseudosugars on RNA Interference: A Novel Class of siRNA Modification by Montserrat Terrazas, Sandra M. Ocampo, José Carlos Perales, Victor E. Marquez and Ramon Eritja in ChemBioChem 201112 (7), 1056 – 1065.

Cover of ChemBioChem, September 24, 2010

Membrane-Surface Anchoring of Charged Diacylglycerol-Lactones Correlates with Biological Activities

Published Date

The inside cover picture shows the molecular structure of a DAG lactone derivative on top of the inner leaflet of a DMPC bilayer. The confocal microscopy image illustrates DAG-lactone-stimulated membrane localization of PKCδ-ECFP in living cells, while the space-filling model shows the surface of the C1B domain of PKCδ, the target of the lactone. 

Citation

For more information, see: Membrane-Surface Anchoring of Charged Diacylglycerol-Lactones Correlates with Biological Activities by Or Raifman, Sofiya Kolusheva, Said El Kazzouli, Dina M. Sigano, Noemi Kedei, Nancy E. Lewin, Ruben Lopez-Nicolas, Ana Ortiz-Espin, Juan C. Gomez-Fernandez, Peter M. Blumberg, Victor E. Marquez, Senena Corbalan-Garcia and Raz Jelinek in ChemBioChem 201011 (14), 2003-2009

Cover of ChemMedChem, August 2009

North- and South-Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti-HIV Activity

Published Date

The picture shows the locked north (blue) and south (red) bicyclo[3.1.0]hexane nucleosides in the normal pseudorotational cycle, and the corresponding shift to a smaller cycle (nmax=7°) caused by the insertion of a double bond. The former nucleosides are inactive, while the flattening of the embedded cyclopentene ring provides active compounds against HOS cells infected with HIV.

Citation

See: North- and South-Bicyclo[3.1.0]Hexene Nucleosides: The Effect of Ring Planarity on Anti-HIV Activity by Pamela L. Russ, Maria J. Gonzalez-Moa, B. Christie Vu, Dina M. Sigano, James A. Kelley, Christopher C. Lai, Jeffrey R. Deschamps, Stephen H. Hughes and Victor E. Marquez in ChemMedChem 20094 (8), 1354 - 1363.

Cover of Journal of Medicinal Chemistry, October 7, 2004

A 4'-C-Ethynyl-2',3'-Dideoxynucleoside Analogue Highlights the Role of the 3'-OH in Anti-HIV Active 4'-C-Ethynyl-2'-deoxy Nucleosides

Published Date

Interaction of the β-L-enantiomer of a 4'-C-ethynyl-2',3'-dideoxynucleoside analogue (ent-14-TP) at the active site of HIV reverse transcriptase.

Citation

See: A 4'-C-Ethynyl-2',3'-Dideoxynucleoside Analogue Highlights the Role of the 3'-OH in Anti-HIV Active 4'-C-Ethynyl-2'-deoxy Nucleosides by Maqbool A. Siddiqui, Stephen H. Hughes, Paul L. Boyer, Hiroaki Mitsuya, Que N. Van, Clifford George, Stefan G. Sarafinanos, and Victor E. Marquez in the Journal of Medicinal Chemistry 200447, 5041-5048.

Cover of Nucleic Acids Research, July 23, 2004

Caught in the act: visualization of an intermediate in the DNA base-flipping pathway induced by HhaI methyltransferase

Published Date

HHAI methyltransferase (blue ribbon) bound to oligonucleotide (strands with bonds colored yellow and green) containing a pseudorotationally constrained sugar analogue at the target position (orange bonds with cyan atoms). The south-constrained pseudosugar is rotated about its flanking phosphodiester bonds, 90° from its initial position in B-form DNA, but short of a completely flipped position with 180° rotation. Thus, it is trapped in the middle of the flipping pathway via the major groove side. This structure provides clues to DNA-protein interactions in a potential transition state.

Citation

See: Caught in the act: visualization of an intermediate in the DNA base-flipping pathway induced by HhaI methyltransferase by John R. Horton, Gary Ratner, Nilesh K. Banavali, Niu Huang, Yongseok Choi, Martin A. Maier, Victor E. Marquez, Alexander D. MacKerell Jr and Xiaodong Cheng in Nucleic Acids Res. 200432 (13), 3877–3886.