) The principal aims for the 04-07 years of AI-42010 are: (A) To enhance the potency of our 3,5-linked (nitrogen displaced) pyrrolinone FIIV-1 protease inhibitors via (1) optimization of the Asp29 (N-H)/inhibitor (carbamate C=O) hydrogen-bond and (2) improvement of the binding interaction at the S2 binding pocket; (B) To design and synthesize a second-generation HIV-1 protease inhibitor based on the 2,5-linked (carbonyl displaced) pyrrolinone scaffold which incorporates a carbamate moiety at P2; (C) To improve the potency of our MMP inhibitors by increasing the size and length of the P1' side-chains; and (D) To design and synthesize a series of 3,5-linked pyrrolinone inhibitors for the enzyme glutathione S-transferase. The availability of our newly developed solid-support pyrrolinone chemistry will significantly augment these efforts (vide infra). To support the demand for varied 3,5-linked pyrrolinones, we will also (E) extend our 3-step iterative solid-support synthetic method to a more efficient 2-step protocol employing unsaturated a-aminolactones. This synthetic venture will require (F) the development an effective synthesis of the requisite unsaturated a-aminolactone building blocks possessing both coded or non-coded amino acid side chains. We will then (G) elaborate focused libraries aimed at the discovery of improved MMP enzyme inhibitors. In the 2,5-linked polypyrrolinone area, we will develop (H) a convergent synthetic protocol. To define the solution conformational features of the (nitrogen displaced) polypyrrolinone scaffold, we will (I) perform both aggregation and spectroscopic studies on a series of 3,5-linked polypyrrolinones. Finally, we will (J) complete the synthesis of a 3,5-linked tetrapyrrolinone beta-turn mimetic, (K) test its biological activity at the somatostatin receptor, and (L) incorporate a 3,5-linked trispyrrolinone onto a dodecapeptide sequence to explore the use of the nitrogen displaced pyrrolinone motif to mimic helical structures in peptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042010-05
Application #
6510753
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Litterst, Charles L
Project Start
1997-07-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$259,740
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Smith 3rd, Amos B; Wang, Wenyong; Charnley, Adam K et al. (2010) Design, synthesis, and structural analysis of D,L-mixed polypyrrolinones. 1. From nonpeptide peptidomimetics to nanotubes. Org Lett 12:2990-3
Smith 3rd, Amos B; Xiong, Hui; Charnley, Adam K et al. (2010) Design, synthesis, and structural analysis of D,L-mixed polypyrrolinones. 2. Macrocyclic hexapyrrolinones. Org Lett 12:2994-7
Smith 3rd, Amos B; Charnley, Adam K; Harada, Hironori et al. (2006) Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2' side chains. Bioorg Med Chem Lett 16:859-63
Smith 3rd, Amos B; Charnley, Adam K; Mesaros, Eugen F et al. (2005) Design, synthesis, and binding affinities of pyrrolinone-based somatostatin mimetics. Org Lett 7:399-402
Smith 3rd, Amos B; Cantin, Louis-David; Pasternak, Alexander et al. (2003) Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors. J Med Chem 46:1831-44
Smith 3rd, A B; Nittoli, T; Sprengeler, P A et al. (2000) Design, synthesis, and evaluation of a pyrrolinone-based matrix metalloprotease inhibitor. Org Lett 2:3809-12