Polypyrrolinone Project - Smith/Hirschmann Collaboration (1987-2011)

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In collaboration with Professor Ralph Hirschmann we have developed the nitrogen-displaced and carbonyl-displaced pyrrolinone scaffolds were designed to mimic both the hydrogen-bonding pattern and side-chain orientation of the b-sheet/b-strand conformation of peptides.The success of this design led to the development of potent pyrrolinone-based inhibitors of several proteolytic enzymes including HIV-1 protease, Renin, and matrix metalloproteases. More recently, we have extended the utility of the pyrrolinone scaffold by demonstrating that simple structural modifications lead to turned conformations mimicking the peptidal b-turn. Current pyrrolinone research is focused on improving the potency of our HIV-1 protease inhibitors and further development of the pyrrolinones as peptidomimetic scaffolds capable of adopting b-strand, b-turn, and helical conformations.

Referenced Publications: 
J. L. Wood, D. R. Jones, R. Hirschmann and A. B. Smith, III. A Versatile, Efficient Synthesis of (–) (2S, 3R, 4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane, The Abbott Pseudodipeptidyl Insert. Tetrahedron Lett. 1990, 31, 6329-6330.
A. B. Smith, III, T. P. Keenan, R. C. Holcomb, P. A. Sprengeler, M. C. Guzman, J. L. Wood, P. J. Carroll, and R. Hirschmann. Design, Synthesis, and Crystal Structure of a Pyrrolinone-Based Peptidomimetic Possessing the Conformation of a β-Strand: Po
A. B. Smith, III, R. C. Holcomb, M. C. Guzman, T. P. Keenan, P. A. Sprengeler, and R. Hirschmann. An Effective Synthesis of Scalemic 3,5,5-Trisubstituted Pyrrolin-4-ones. Tetrahedron Lett. 1993, 34, 63-66.
A. B. Smith, III, R. Hirschmann, A. Pasternak, R. Akaishi, M. C. Guzman, D. R. Jones, T. P. Keenan, P. A. Sprengeler, P. L. Darke, E. A. Emini, M. K. Holloway, and W. A. Schleif. Design and Synthesis of Peptidomimetic Inhibitors of HIV-1 Protease an
A. B. Smith, III, M. C. Guzman, P. A. Sprengeler, T. P. Keenan, R. C. Holcomb, J. L. Wood, P. J. Carroll, and R. Hirschmann. De Novo Design, Synthesis, and X-ray Crystal Structures of Pyrrolinone-Based β-Strand Peptidomimetics. J. Am. Chem. Soc. 19
Smith, Amos B., III; Pasternak, Alexander; Yokoyama, Akihisa; Hirschmann, Ralph. Enantioretentive alkylation of oxazolidinone aluminum enolates with epoxides: preparation of uncoded homoserine analogs. Tetrahedron Letters (1994), 35(48), 8977-80.
Hirschmann, R.; Smith, A. B.; Sprengeler, P. A. Some interactions of macromolecules with low molecular weight ligands. Recent advances in peptidomimetic research. New Perspectives in Drug Design, [based on the Proceedings of the International Round Table
Smith, III, Amos B.; Akaishi, Ryouichi; Jones, David R.; Keenan, Terence P.; Guzman, Mark C.; Holcomb, Ryan C.; Sprengeler, Paul A.; Wood, John L.; Hirschmann, Ralph; Holloway, M. Katharine. Design and synthesis of nonpeptide peptidomimetic inhibitors of
Hirschmann, Ralph; Hynes, John, Jr.; Spoors, P. Grant; Smith, Amos B., III. Chemoselective monoalkylation of 5-(trifluoroacetamido)- and 5-acetamido-1-pentanol derivatives via N,O-bisdeprotonation. Quantitation of evolved H2 as a probe of anion formation.
Smith, Amos B,. III; Hirschmann, Ralph; Pasternak, Alexander; Guzman, Mark C.; Yokoyama, Akihisa; Sprengeler, Paul A.; Darke, Paul L.; Emini, Emilio A.; Schleif, William A. Pyrrolinone-Based HIV Protease Inhibitors. Design, Synthesis, and Antiviral Activi
Smith, Amos B., III; Knight, Steven D.; Sprengeler, Paul A.; Hirschmann, Ralph. The design and synthesis of 2,5-linked pyrrolinones. A potential non-peptide peptidomimetic scaffold. Bioorganic & Medicinal Chemistry (1996), 4(7), 1021-1034.
Smith, Amos B., III; Benowitz, Andrew B.; Favor, David A.; Sprengeler, Paul A.; Hirschmann, Ralph. A second-generation synthesis of scalemic 3,5,5-trisubstituted pyrrolin-4-ones: incorporation of functionalized amino acid side-chains. Tetrahedron Letters
Smith, Amos B., III; Hirschmann, Ralph; Pasternak, Alexander; Yao, Wenquing; Sprengeler, Paul A.; Holloway, M. Katharine; Kuo, Lawrence C.; Chen, Zhongguo; Darke, Paul L.; Schleif, William A. An Orally Bioavailable Pyrrolinone Inhibitor of HIV-1 Protease:
Sudoh, Masao; Pauletti, Giovanni M.; Yao, Wenqing; Moser, William; Yokoyama, Akihisa; Pasternak, Alexander; Sprengeler, Paul A.; Smith, Amos B., III; Hirschmann, Ralph; Borchardt, Ronald T. Transport characteristics of peptidomimetics. Effect of the pyrro
Smith, Amos B. ,III; Benowitz, Andrew B.; Guzman, Mark C.; Sprengeler, Paul A.; Hirschmann, Ralph; Schweiger, Edwin J.; Bolin, David R.; Nagy, Zoltan; Campbell, Robert M.; Cox, Donald C.; Olson, Gary L. Design, synthesis, and evaluation of a pyrrolinone-p
Smith, Amos B., III; Sasho, Setsuya; Barwis, Bari A.; Sprengeler, Paul; Barbosa, Joseph; Hirschmann, Ralph; Cooperman, Barry S. Design and synthesis of a tetrahydropyran-based inhibitor of mammalian ribonucleotide reductase. Bioorganic & Medicinal Chemist
Smith, Amos B., III; Favor, David A.; Sprengeler, Paul A.; Guzman, Mark C.; Carroll, Patrick J.; Furst, George T.; Hirschmann, Ralph. Molecular modeling, synthesis, and structures of N-methylated 3,5-linked pyrrolin-4-ones toward the creation of a privile
E. D. Soli, A. S. Manoso, M. C. Patterson, P. Deshong, D. A. Favor, R. Hirschmann and A. B. Smith, III. Azide and Cyanide Displacements via Hypervalent Silicate Intermediates. J. Org. Chem. 1999, 64, 3171-3177.
S. Liehr, J. Barbosa, A. B. Smith, III, and B. S. Cooperman, Synthesis and Biological Activity of Cyclic Peptide Inhibitors of Ribonucleotide Reductase. Org. Lett. 1999, 1, 1201-1204.
Smith, Amos B., III; Benowitz, Andrew B.; Sprengeler, Paul A.; Barbosa, Joseph; Guzman, Mark C.; Hirschmann, Ralph; Schweiger, Edwin J.; Bolin, David R.; Nagy, Zoltan; Campbell, Robert M.; Cox, Donald C.; Olson, Gary L. Design and Synthesis of a Competent
A. B. Smith, III, H. Liu, and R. Hirschmann. A Second-Generation Synthesis of Polypyrrolinone Nonpeptdomimetics: Prelude to the Synthesis of Polypyrrolinones on Solid Support. Org. Lett. 2000, 2, 2037-2040.
A. B. Smith, Ill, H. Liu, H. Okumura, D. A. Favor, and R. Hirschmann. Synthesis of Polypyrrolinones on Solid Support. Org. Lett. 2000, 2, 2041-2044.
K. H. Lee, G. L. Olson, D. R. Bolin, A. B. Benowitz, P. A. Sprengeler, A. B. Smith, III, R. F. Hirschmann, and D. C. Wiley. The Crystal Structure of a Pyrrolinone-Peptide Hybrid Ligand Bound to the Human Class II MHC Protein HLA-DR1. J. Am. Chem. So
Smith, Amos B., III; Wang, Wenyong; Sprengeler, Paul A.; Hirschmann, Ralph. Design, Synthesis, and Solution Structure of a Pyrrolinone-Based b-Turn Peptidomimetic. Journal of the American Chemical Society (2000), 122(44), 11037-11038.
A. B. Smith, III, T. Nittoli, P. A. Sprengeler, J. J.-W. Duan, R.-Q. Liu, and R. F. Hirschmann. Design, Synthesis, and Evaluation of a Pyrrolinone-Based Matrix Metalloprotease Inhibitor. Org. Lett, 2000, 2, 3809-3812.
A. B. Smith, III, L. Ducry, R. M. Corbett and R. Hirschmann. Intramolecular Hydrogen-Bond Participation in Phosphonylammonium Salt Formation. Org. Lett. 2000, 2, 3887-3890.
A. B. Smith, III, Y. S. Cho, L. E. Zawacki, R. Hirschmann, and G. R. Pettit. First Generation Design, Synthesis, and Evaluation of Azepine-Based Cryptophycin Analogs. Org. Lett. 2001, 3, 4063-4066.
A. B. Smith, III, L.-D. Cantin, A. Pasternak, L. Guise-Zawacki, W. Yao, A. Charnleyl J. Barbosa, P. A. Sprengeler, R. Hirschmann, S. Munshi, D. B. Olsen, W. A. Schleif and L. C. Kuo. Design, Synthesis and Biological Evaluation of Monopyrrolinone-Bas
R. Hirschmann and A. B. Smith, III. Search for Biologically Active Peptidomimetics of β-Turns and β-Strands. Designed Scaffolds and Serendipitous Observations. Peptide Revolution: Genomics, Proteomics & Therapeutics. eds. M. Chorev and T. K. Sawye
A. B. Smith, III, A. K. Charnley, E. F. Mesaros, O. Kikuchi, W. Wang, A. Benowitz, and R. Hirschmann. Design, Synthesis, and Biological Evaluation of Novel Pyrrolinone-Based Somatostatin Mimetics. Org. Lett. 2005, 7, 399-402.
A. B. Smith, III, A. K. Charnley, H. Harada, J. J. Beiger, L.-D. Cantin, C. S. Kenesky, R. Hirschmann, S. Munshi, D. B. Olsen, M. W. Stahlhut, W. A. Schleif, and L. C. Kuo. Design, Synthesis and Biological Evaluation of Monopyrrolinone-Based HIV-1 P
A. B. Smith, III. “Ralph F. Hirschmann, May 6, 1922-June 20, 2009.” Organic Reactions 2009, IX-XI.
A. B. Smith, III, W. Wang, A. K. Charnley, P. J. Carroll, C. S. Kenesky and R. Hirschmann. Design, Synthesis and Structural Analysis of D,L-Mized Polypyrrolinones 1: From Nonpeptide Peptidomimetics to Nanotubes. Org. Lett. 2010, 12, 2990-2993. PMC2
A. B. Smith, III, H. Xiong, A. K. Charnley, M. Brenner, E. F. Mesaros, C. S. Kenesky, L. di Costanzo, D. Christianson and R. Hirschmann. Design, Synthesis and Structural Analysis of D, L-Mixed Polypyrrolinones 2: Macrocyclic Hexapyrrolinones. Org.
A. B. Smith, III, A. K. Charnley and R. Hirschmann. Pyrrolinone-Based Peptidomimetics. “Let the Enzyme or Receptor be the Judge”. Acc. Chem. Res. 2011, 44, 180-193. PMC3078624.