Molecular modeling, synthesis, and structures of N-methylated 3,5-linked pyrrolin-4-ones toward the creation of a privileged nonpeptide scaffold.
The molecular modeling, synthesis, and elucidations of the solid state and solution structures of N-methylated 3,5-linked bispyrrolin-4-ones are described. Prior investigations established that the 3,5-linked pyrrolin-4-one based scaffold can be incorporated into mimics of beta-sheet/beta-strands and into potent, orally bioavailable inhibitors of the HIV-1 protease. To extend the utility of this scaffold beyond that of the initially designed mimics of beta-sheet/beta-strands, we have now explored the structure of N-methylated pyrrolinones. Molecular modeling indicated that N-methylated bispyrrolinones could adopt three low-energy backbone conformations (ca. 165 degrees, 289 degrees, and 320 degrees). Upon their successful synthesis, structural elucidation both in the solid state and in solution revealed the existence of two of the three predicted backbone conformers (ca. 165 degrees and 289 degrees). Two structures were particularly noteworthy and completely unexpected. Mono-N-methyl bispyrrolinone (+)-1 self assembled in the solid state to form a novel helix, while the acetylene-linked dimer of (+)-1, designed to potentiate the observed helical array, instead associated via an intermolecular hydrogen bond in parallel columns. These serendipitous observations led us to speculate that the pyrrolinone moiety may in fact represent a privileged nonpeptide scaffold, able to mimic not only the extended beta-sheet/beta-strand conformation as initially targeted, but also diverse conformations including those analogous to beta-turns and helices. These seemingly unlimited conformations greatly expand the scope of this scaffold for the development of low-molecular weight ligands for biologically important macromolecules.
Smith
A B
AB
Department of Chemistry, University of Pennsylvania, Philadelphia 19104, USA.
Favor
D A
DA
Sprengeler
P A
PA
Guzman
M C
MC
Carroll
P J
PJ
Furst
G T
GT
Hirschmann
R
R
D018360:Crystallography, X-Ray; D017320:HIV Protease Inhibitors / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D011758:Pyrroles / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry*; D013053:Spectrophotometry
C119056:4-(4-tert-butyl-2,3-dihydro-1-methyl-3-oxopyrrol-2-yl)-2-isopropyl-2-(3-methyl-2-buten-1-yl)-3(2H)-pyrrolinone; D017320:HIV Protease Inhibitors; D011758:Pyrroles; D011760:Pyrrolidinones