Adel Nefzi

Synthesis of Macrocyclic Compounds:

Considering the large number of biologically active cyclic peptides in nature and their potential as drugs in vivo, the synthesis of cyclic peptides and analogues remains an important goal for both academic and pharmaceutical laboratories. Numerous strategies to synthesize cyclic peptides have been reported, but a general, high-yielding route to small cyclic peptides has yet to be developed. We will continue with our work toward the development of innovative approaches for the generation of unique macrocyclic peptides. Examples of new strategies will include Hantzsch based macrocyclization approach for the synthesis of thaizole containing cyclopeptides.

Combinatorial Chemistry: Synthesis of small molecule compounds

The last decade has witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signaling pathways, as well as progress in miniaturization and robotics, enabling the development of high-throughput mechanism-based biological assays. One of the central objectives of organic and medicinal chemistry is the design, synthesis, and production of molecules having value as human therapeutic agents. Nitrogen heterocycles of different ring sizes, with different substitution patterns and embedded in various molecular frameworks constitute important structure classes in the search for bioactivity. We will continue with our work on the diversity-oriented synthesis of structurally unique fused and tethered biologically relevant heterocyclic libraries that will enrich and increase the diversity and uniqueness of the collection of compounds in the chemical space. Parallel solid phase synthesis and solution phase synthesis will be used to generate fused and/or tethered heterocyclic compounds. The compounds will be designed to follow known drug-likeness rules including “Lipinski’s Rule of Five”.  We will work closely with computational chemists to use cheminformatic tools to refine and enhance our selection of building blocks to ensure a better distribution of the synthesized compounds in chemical space.

Synthesis of glycopeptide libraries

Despite the recognized biological significance of cell-surface oligosaccharides as targets for bacterial, toxin, and viral attachment, and in mammalian cell-cell adhesion, approaches for the chemical assembly of sugar-containing libraries have not been extensively explored. Starting from resin-bound peptide and peptidomimetic libraries, and commercially available functional 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl compounds, we will perform the parallel synthesis of a variety of polyaminoglycoside libraries.

All small molecule, macrocyclic and glycopeptide libraries are natural product-like compounds that promise a high potential of generating biologically active molecules. All libraries will be screened in a series of assays representing a variety of fundamental biological functions. The diversity of the chemical structures of the final compounds, as well as the large number of compounds making up each class of structures greatly increases the ultimate probability of identifying compounds with desirable properties.

Our work will have a significant societal impact in by contributing to efforts to develop new chemistries for the synthesis of unique structurally complex compounds that can open up avenues for the development of novel therapeutics.

Education

• 1995:   Ph.D. Organic Chemistry, University of Lausanne, Switzerland.
• 1991:   Chemistry Diploma. University of Lausanne, Switzerland.

Positions

• 08/09-present: Director of the Department of Chemistry at Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL.
• 08/09-present: Affiliate Professor at Florida Atlantic University.
• 02/97-07/09: Head of the combinatorial chemistry department at Torrey Pines Institute for Molecular Studies, San Diego, CA.
• 01-2002/08-2008: Lecturer of Organic Chemistry, University of California San Diego.
• 10/95-01/97: Postdoctoral Fellow with Dr. Richard A. Houghten at Torrey Pines Institute for Molecular Studies.
• 1992-1995: PhD. Training with Prof. Manfred Mutter, University of Lausanne, Switzerland.
• 1994:  Diploma thesis with Prof. Pierre Vogel, University of Lausanne, Switzerland. “Contribution à la synthèse totale  de +/- Palitantin”

Professional Affiliations

• Member of American Chemical Society, 1995-Present.
• Member of American Peptide Society, 1995-Present.
• Member of American Association of Pharmaceutical Scientists, 2006-Present.
• Member of Fluorine Chemistry Society, 1995-Present.

Selected Publications (10 of 87)

1. Nefzi, A.; Arutyunyan, S.; Fenwick, J. E. Two-Step Hantzsch Based Macrocyclization Approach for the Synthesis of Thiazole-Containing Cyclopeptides. J. Org. Chem. 2010, 75, 7939–7941
2. Liu, A., Nefzi. A. Solid-Phase Synthesis of N-Substituted Pyrrolidinone Tethered N-substituted Piperidines via Ugi Reaction. J. Com. Chem. 2010, 12 , 566–570.
3. Nefzi, A., Appel, J., Arutyunyan, S., Houghten, R.A.   Parallel synthesis of chiral pentaamines and pyrrolidine containing bis-heterocyclic libraries. Multiple scaffolds with multiple building blocks: A double diversity for the identification of new antitubercular compounds. Bioorganic & Medicinal Chemistry Letters 2009, 19,  5169-5175.
4. Nefzi, A., Ostresh, J. M., Appel, J. R., Bidlack, J., Dooley, C. T., Houghten, R. A. Identification of potent and highly selective chiral tri-amine and tetra-amine µ opioid receptors ligands. An example of lead optimization using mixture based libraries. Bioorg. Med. Chem. Lett. 2006, 16, 4331-4338.
5. Nefzi, A., Hoesl, C. E., Pinilla, C., Kauffman, G. B., Maggiora, G. M.,  Pasquale, E., Houghten, R. A. Synthesis of platinum(II) chiral tetraamine coordination complexes. J. Comb. Chem. 2006, 8:780-783
6. Hensler, M. E., Bernstein, G., Nizet, V., Nefzi, A. Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug resistant gram‑positive pathogens identified from a mixture-based combinatorial library. Bioorg. Med. Chem. Lett. 2006, 16:5073-5079.
7. Nefzi, A., Santos, R. T. A versatile access to new macrocyclic oligohetercycles (MOH). Bioorg. Med .Chem. Lett. 2006, 16:3358-3361.
8. Nefzi, A., Santos, R. T. Efficient Approaches Toward the Solid-Phase Synthesis of New Heterocyclic Azoniaspiro Ring Systems: Synthesis of Tri- and Tetra-Substituted-10-oxo-3,9-diaza-6-azoniaspiro[5.5]undecanes. J. Org. Chem, 2005, 70:9622-9625.
9. Nefzi, A., Ostresh, J. M., Houghten, R. A. Combinatorial Chemistry: Libraries from Libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. J. Org. Chem. 2004, 69:3603-3609.
10. Nefzi, A., Ostresh, J. M., and Houghten, R. A. The Current Status of Heterocyclic Combinatorial Libraries. Chemical Reviews 1997, 97, 449-472.

Patents

• Combinatorial libraries of cyclic urea and cyclic thiourea derivatives and compounds therein. U.S. Patent No. 5,786,448. Issued  July 28, 1998.  Inventors: Adel Nefzi, John.M. Ostresh, and R.A. Houghten.
• Diketoazacyclic compounds, diazacyclic compounds, and combinatorial libraries thereof. U.S. Patent No. 6,441,172. Issued August 27, 2002. Adel Nefzi, John. M. Ostresh, J.M., and Richard A. Houghten.
• Diketoazacyclic compounds, diazacyclic compounds, and combinatorial libraries thereof. U.S. Patent No. 6,809,202. Issued October 26, 2004. Adel Nefzi, John. M. Ostresh, J.M., and Richard A. Houghten.
• Methods and compositions using peptidyl and nonpeptidyl compounds for derepression of IAP-inhibited caspase, therapeutic use, and methods for identification of agents.  Reed, John C.; Houghten, Richard A.; Nefzi, Adel; Ostresh, John M.; Pinilla, Clemencia; Welsh, Kate.  PCT Int. Appl.  (2003), 182 pp.  CODEN: PIXXD2 WO  2003045974  A2  20030605  CAN 139:30774  AN 2003:434582.
• Peptidyl and nonpeptidyl compounds for derepression of IAP-inhibited caspase and therapeutic and drug screening uses. Reed, John C.; Houghten, Richard A.; Nefzi, Adel; Ostresh, John M.; Pinilla, Clemencia; Welsh, KateU.S. Pat. Appl. Publ.  (2005),     182 pp., Cont.-in-part of U.S. Ser. No. 302,811.  CODEN: USXXCO  US 2005119176  A1  20050602  CAN 143:19969  AN 2005:474920.
• Melanin-concentrating hormone receptor antagonists and methods of use. Civelli, Olivier; Nagasaki, Hiroshi; Houghten, Richard A.; Dooley, Colette; Nefzi, Adel. PCT Int. Appl.  (2005), 69 pp.  CODEN: PIXXD2  WO  2005094817  A1  20051013  CAN 143:360142  AN 2005:1103573.