A5068605061- HIV/AIDS drug development and treatment
- Protein Kinase Regulation and GTPase Signaling
- Biochemical and Molecular Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Carbohydrate Chemistry and Synthesis
- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- Synthetic Organic Chemistry Methods
- Polydiacetylene-based materials and applications
- Receptor Mechanisms and Signaling
- Ubiquitin and proteasome pathways
- Asymmetric Synthesis and Catalysis
- TGF-β signaling in diseases
- Lipid Membrane Structure and Behavior
- HIV Research and Treatment
- Chemical Reaction Mechanisms
- Oxidative Organic Chemistry Reactions
- Cytomegalovirus and herpesvirus research
- Sphingolipid Metabolism and Signaling
- Herpesvirus Infections and Treatments
- Melanoma and MAPK Pathways
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Chemical Synthesis and Reactions
National Institute of Industrial Technology
2013-2024
Consejo Nacional de Investigaciones Científicas y Técnicas
2013-2021
National University of General San Martín
2020
University of Siena
2013
National Institutes of Health
2006-2009
Center for Cancer Research
2003-2009
National Cancer Institute
2005-2009
Frederick National Laboratory for Cancer Research
2005-2009
Ben-Gurion University of the Negev
2005-2007
Fundación Ciencias Exactas y Naturales
1999-2006
Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation Rac1, member family small GTPases, is associated with tumorigenesis, cancer progression, invasion metastasis. Particularly, Rac1 overexpressed hyperactivated highly aggressive breast cancer. Thus, appears to be promising relevant target for development novel anticancer drugs. We identified inhibitor ZINC69391...
Abstract: Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly failure of existing therapies. Deregulation small GTPases signaling, in particular Rac1 activity, plays a key role invasive phenotype gliomas. Here we report effect ZINC69391, specific inhibitor developed our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able interfere with interaction Dock180, relevant activator...
The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as conformational mimic the anti-HIV agent stavudine (1, D4T) is described. unsaturated methanocarbocyclic pseudosugar N-MCD4T (2) was constructed from an iodo-substituted precursor by DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded desired target after deprotection. Both D4T are in North (N) hemisphere pseudorotational cycle but 70 degrees away perfect N (P = 0 )...
The herpes virus thymidine kinase (HSV-tk) is a critical enzyme for the activation of anti-HSV nucleosides. However, successful therapeutic outcome depends not only on activity this but also ability compound(s) to interact effectively with cellular kinases and target viral or DNA polymerases. Herein, we describe synthesis study two nucleoside analogues built conformationally locked bicyclo[3.1.0]hexane template designed investigate conformational preferences HSV-tk 2'-deoxyribose ring....
A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross metathesis step designed to functionalize appropriate terminal olefin bicyclo[3.1.0]hexane precursor and carbene-mediated intramolecular cyclopropanation reaction on corresponding diazo intermediate. This combined methodology allowed diastereoselective introduction chemically diverse substituents at tip cyclopropane group, except in cases where consisted...
The Rho GTPase Rac1 is involved in the control of cytoskeleton reorganization and other fundamental cellular functions. Aberrant activity its regulators common human cancer. In particular, deregulated expression/activity Rac GEFs, responsible for activation, has been associated to a metastatic phenotype drug resistance. Thus, development novel Rac1-GEF interaction inhibitors promising strategy finding new preclinical candidates. Here, we studied structure-activity relationships within family...
The replacement of the furanose ring by a cyclopentane in nucleosides generates group analogues known generically as carbocyclic nucleosides. These compounds have increased chemical and enzymatic stability due to absence true glycosyl bond that characterizes conventional additional fusion cyclopropane produces bicyclo[3.1.0]hexane system depending on its location relative nucleobase is able lock embedded into conformations mimic typical north south templates already provided important clues...
Synthetic diacylglycerol lactones (DAG lactones) are effective modulators of critical cellular signaling pathways downstream the lipophilic second messenger that activate a host protein kinase C (PKC) isozymes as well other non‐kinase proteins share with PKC similar C1 membrane‐targeting domains. A fundamental determinant biological activity these amphiphilic molecules is nature their interactions membranes. This study characterizes membrane and bilayer anchoring series DAG in which...
Abstract The synthesis of prototype models purine and pyrimidine carbanucleosides built on a 6‐thiabicyclo[3.1.0]hexane system as pseudosugar moiety has been investigated. These proved to be very stable compounds, in contrast the parent epoxy analogs, which experienced epoxide ring‐opening due intramolecular enol base attack. In addition, thiirane fused five‐membered ring is not trivial synthetic task, validation optimization existing methods for episulfide preparation were required access...
Using the reaction between phenylacetaldehyde and nitrostyrene catalyzed by pyrrolidine as a simple model, we have studied diastereochemical outcome of organocatalytic Michael reactions benzylic aldehydes nitrostyrenes. We found that anti adduct was obtained in high yield diastereoselection demonstrated X-ray structure product. In situ NMR studies showed different pathway when compared to aliphatic syn major isomer.
Abstract The stereoselective syntheses of the (+)‐ D and (−)‐ L enantiomers iso ‐methanocarbathymidine ( ‐MCT) was achieved through two independent linear approaches that converged on antipodal enantiomers, common to a key precursor used in synthesis racemic ‐MCT. In study reported herein we identified 3 [ ‐(+)‐ ‐MCT] as active enantiomer exclusively recognized by herpes simplex virus 1 thymidine kinase (HSV1‐tk), predicted molecular modeling. For this purpose, human osteosarcoma (HOS) cell...
DAG-lactones represent useful templates for the design of potent and selective C1 domain ligands PKC isozymes. The ester moiety at sn-1 position, a common feature in this template, is relevant interactions, but it represents labile group susceptible to endogenous esterases. An interesting challenge involves replacing these while still maintaining biological activity. Here, we present synthesis functional characterization novel diacylglycerol-lactones containing heterocyclic ring substituents...
Diacylglycerol lactones built with a rigid 4-[(methylphenyl)ethynyl]phenyl rod that is separated from the exocyclic acylcarbonyl of DAG-lactone core by spacer unit variable length were synthesized and studied. Binding affinities for panel classical novel PKC isozymes in two different phospholipid environments, one corresponding to plasma membrane cells, determined. The kinetics site translocation α δ upon treatment compounds also studied as well early response ERK phosphorylation late...