University of Vermont

College of Arts and Sciences

Department of Chemistry

UVM Chemistry Research: Jose Madalengoitia

José S. Madalengoitia

José S. Madalengoitia, Ph.D., Associate Professor of Chemistry

  • Ph.D., University of Virginia, Charlottesville, VA 1993
  • postdoctoral fellowship, University of California at Irvine, 1993-95
  • Assistant Professor of Chemistry, University of Vermont, 1995
  • Associate Professor of Chemistry, University of Vermont, 2001
  • Curriculum vitae
Area of expertise

organic chemistry, bioorganic chemistry, peptide mimetics

Contact Information

Email: Jose.Madalengoitia@uvm.edu

Phone: (802) 656-8247

Office: Cook Rm A232

Research

Research in our group spans the sub disciplines of synthesis and bioorganic chemistry and capitalizes in the synergy between the two areas. Our projects span a range of projects from the synthesis of peptide mimics, to proteomic approaches to the identification of protein-protein interactions, to development of methodology for the synthesis of combinatorial libraries to development of new synthetic methods. The synergy between bioorganic chemistry and synthesis is a strength of our program. For example, our peptidomimetic approaches are well grounded in organic chemistry principles such as conformational analysis and synthesis while often peptidomimetic targets necessitate the need for new synthetic methods and incidental chemistry inspires new synthetic methods.

Design and Synthesis and Evaluation of Poly-L-Proline Type II Peptide Mimics:

The Poly-L-Proline Type II (PPII) secondary structure has emerged as a key secondary structure motif in mediating protein-protein interactions. For example, SH3 domains, some SH2 domains, EVH1 domains, WW domains and MHC-II proteins all recognize and bind PPII helices in other proteins. PPII helices in globular proteins incorporate amino acids in addition to proline and it is often these non-prolyl amino acids that are important for recognition and binding of the PPII helix by the specific domain. Thus our approach to the construction of PPII helices must not only mimic the desired peptide backbone conformation, but it must also incorporate non-prolyl side chain functionalities. To accommodate these requirements, approach to mimics of the PPII secondary structure involve first the synthesis of what we call proline templated amino acids (PTAAs) which when coupled sequentially adopt the PPII secondary structure and incorporate the desired non-prolyl-side chain functionality.

Fig 1a Fig 1b

Protein Kinases: We are currently applying the PTAA methodology to a couple of problems. Protein kinases are enzymes that phosphorylate proteins and enzymes, most commonly as a regulatory mechanism of protein or enzyme function. There are over 600 different protein kinases in the human kinome. Protein kinases achieve selectivity in the proteins they phosphorylate in part through the recognition of specific sequences of amino acids. Based on the X-ray crystal structures of protein kinases bound with peptide substrates or pseudo-substrates, we propose the hypothesis that at least a subset of protein kinases binds their recognition sequences in the PPII conformation. We are currently testing this hypothesis through the synthesis of PPII mimics as substrates or inhibitors for specific protein kinases. The successful development of protein kinase inhibitors based on the PPII scaffold would result in highly specific probes with which to study cell signaling through protein kinases.

SH3 Domains: We are additionally interested in developing peptidomimetic ligands that are able to disrupt interactions between PPII binding domains and their endogenous PPII helix ligands. The long-range goals of this project would be to develop PPII ligands for specific PPII binding domains and use these to study cell signaling through these domains.

Fig 2

We are currently interested in developing PPII mimic ligands for a number of SH3 domains. Inspiration for our design comes from X-ray and NMR solution structures of SH3 domains in complex with proline-rich peptides like the structure above of the PI3K SH3 domain (blue) in complex with a proline rich peptide (red) (Cell, 1994, 76, 933). Investigations in our laboratories have resulted in the design on the novel SH3 binder shown below. Work is ongoing to develop more potent and selective SH3 ligands.

Fig 3

PPII Mimic Combinatorial Libraries: Because a number of our targets have an affinity for PPII helices that incorporate arginine residues, we are interested in developing methodology for the facile synthesis of arginine-containing PPII mimic combinatorial libraries. Through and iterative synthesis approach, using only six PTAAs and 20 N-Pmc thioureas, a significantly complex library can be generated that incorporates arginine PTAAs at three positions of a peptide.

Fig 4

The 1,3-diaza-Claisen Rearrangement, New methodology for the Synthesis of Guanidine-Containing Natural Products:

We are currently evaluating the scope and limitations of a novel reaction developed in our laboratory, the zwitterionic 1,3-diaza-Claisen rearrangement. In this transformation an N-sulfonyl-N'-alkyl thiourea is converted in situ to an N-sulfonyl-N'-alkyl carbodiimides that in turn react with a tertiary allylic amine forming a zwitterionic intermediate. The zwitterionic intermediate is then poised to undergo a 1,3-diaza-Claisen rearrangement affording an allylic guanidine.

Fig 5

The successful development of this rearrangement would allow facile access to a number of guanidine natural products through this novel reaction. In particular, the Batzelladine alkaloids and Isoptilocaulin are of interest.

Fig 6

Selected Publications

R. M. Aranha, A. M. Bowser, J. S. Madalengoitia, “Facile 1,3-diaza-Claisen Rearrangements of Tertiary Allylic Amines Bearing an Electron Deficient Alkene” Org. Lett. 2009, 11, 575-578.

S. Flemer, A. Wurthmann, A. Mamai, J. S. Madalengoitia, “Strategies for the Solid-Phase Diversification of Poly-L-Proline Type II Peptide Mimic Scaffolds and Peptide Scaffolds Through Guanidinylation” J. Org. Chem. 2008, 73, 7953.

N. Huang, T. Jiang, T. Wang, M. Soukri, R. Ganorkar, B. Deker, J.-M. Leger, J. Madalengoitia, M. E. Kuehne, “The Acyclic Dieneamine Indoloacrylate Addition Route to Catharanthine” Tetrahedron 2008, 64, 9850.

S. Flemer, J. S. Madalengoitia, “Synthetic Routes into N-Pmc-N', N"-Disubstituted Guanidine Systems via Guanylation of Amines with N-Pmc-N'-alkyl Substituted Thioureas: Scope and Limitations of the Reaction” Synthesis 2007, 13, 81.

R. Ganorkar, A. Natarajan, A. Mamai, J. S. Madalengoitia "Synthesis of Conformationally Constrained Lysine Analogs" J. Org Chem. 2006, 71, 5004.

R. Zhang, A. Natarajan, S. Flemer, A. Mamai, C. Nickl, W. Dostmann, and J. S. Madalengoitia "Poly-L-Proline Type II Peptide Mimics as Probes of the Active Site Occupancy Requirements of cGMP Dependent Protein Kinase" J. Peptide Res. 2005, 66, 151-9.

A. M. Bowser and J. S. Madalengoitia "Synthesis of Highly Substituted Ureas and Thioureas Through 1,3-Diaza-Claisen Rearrangements" Tetrahedron Lett. 2005, 46, 2869.

A. M. Bowser and J. S. Madalengoitia "A 1,3-Diaza-Claisen Rearrangement that Affords Guanidines" Org. Lett. 2004, 6, 3409.

Mamai, A.; Madalengoitia, J. S. "Solid-Phase Guanidinylation as a Diversification Strategy of Poly-L-Proline Type II Peptide Mimic Scaffolds," Org. Lett. 2001, 3, 561.

Madalengoitia, J. S. "A Novel Peptide Fold: A Repeating βII'-Turn Secondary Structure" J. Am. Chem. Soc. 2000, 122, 4986.

Zhang, R.; Brownewell, F. E.; Madalengoitia, J. S. "Pseudo A(1,3) Strain as a Key Conformational Control Element in the Design of Poly-L-Proline Type II Peptide Mimics" J. Am. Chem. Soc. 1998, 120, 3894.

Last modified April 21 2011 08:21 AM

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