Oligomers of a new class of sugar amino acids (SAA) using a xylofuranoic acid has been shown to generate a robust 14-helix. The design involved the use of xylofuranose with a cis arrangement between the amine and carboxyl groups to promote the adoption of a 14-helix instead of a mixed 12/10-helix observed in a sugar oligomer using a ribofuranoic acid and beta-Ala. The observation of a stable right-handed 14-helix in a cis-SAA is unprecedented.
Conformationally constrained molecular frameworks of the 2,5-anhydro sugar diacid (9) and 2,5anhydro sugar diamines (10, 11) were used to construct architecturally beautiful novel C 2 symmetric peptidomimetics 1-8. Although none of these compounds showed any significant HIV-1 protease inhibitory activity, further refinements in design may lead to protease inhibitors based on these rigid carbohydrate-derived scaffolds. Among the several specific targets in the cell cycle of the human immunodeficiency virus (HIV), the virally encoded homodimeric HIV-1 protease, which is an aspartyl protease required for maturation of the infectious virion, has emerged as a promising target leading to the design and evaluation of a vast array of compounds with diverse structural motifs as possible inhibitors, some of which have already been approved for the treatment of AIDS. 1-6 We describe herein the development of a new class of compounds 1-8 as potential HIV-1 protease inhibitors that are based on carbohydrate-peptide hybrid structures. In this approach, identical peptide chains are anchored on both sides of a core carbohydrate motifa C 2 symmetric 2,5-anhydro sugar diacid or sugar diamine-leading to the formation of C 2 symmetric peptidomimetics. 7 Carbohydrate-based molecular designs are increasingly drawing chemists' attention. 8,9 Detailed studies on the development of new HIV-1 protease inhibitors based on acyclic carbohydrates have recently been reported. 10-12 It is also being increasingly felt that small molecule protease inhibitors need to have restricted degrees of freedom. The success of cyclic urea based inhibitors supports this feeling. 13,14 This has prompted us to look for cyclic carbohydrate based core foundations as conformationally rigid scaffolds to build a new class of molecular frameworks as potential protease inhibitors. Two different types of cyclic carbohydrate framework-sugar diacid and sugar diamine-are employed in our designs. These molecules are 2,5-anhydro-D-idaric acid (9), 1,6diamino-2,5-anhydro-1,6-dideoxy-D-iditol (10) and 1,6-diamino-2,5-anhydro-1,6-dideoxy-Correspondence to: T. K. Chakraborty.
The thermotropic liquid crystal (LC), 4,4‘-diheptylazoybenzene (HAB), exhibiting isotropic nematic and smectic phases, is investigated through 129Xe NMR and density studies. The temperature dependence of 129Xe chemical shifts and spin−lattice relaxation times (T 1) of the xenon gas dissolved in HAB have shown clear signatures of the phase transitions. We have applied an extended pairwise additive model to the smectic phase of HAB to account for the measured temperature dependence of chemical shifts. It is inferred that the LC−xenon molecular pair correlations have a significant effect on the shielding anisotropy in the nematic and smectic phases whereas they are negligible in the isotropic phase. The isotropic and anisotropic parts of the nuclear shielding and their dependences on liquid crystalline ordering (orientational and translational), density, and temperature are deduced for both the nematic and smectic phases. It is found that the shielding anisotropy is primarily due to orientational ordering of the LC molecules. In the smectic phase, xenon atoms preferentially occupy interlayer spacings rather than their interiors, leading to an increase in the isotropic part of the shielding. The activation energies (E a) associated with xenon dynamics in different phases are deduced from T 1 measurements. Despite the denser packing of molecules in the smectic phase, the E a in this phase is lower than that of the nematic phase. This finding is in agreement with the conclusions drawn from the analysis of the chemical shift data.
Enantiopure (3S,5S,6R,8S)- and (3S,5S,6S,8S)-6-hydroxypyrrolizidinone 3-N-(Boc)amino 8-methyl carboxylates (6R)- and (6S)-1 were synthesized in seven steps starting from (2S)-alpha-tert-butyl N-(PhF) aspartate beta-aldehyde (10). Carbene-catalyzed acyloin condensation of beta-aldehyde 10 followed by acetylation provided a separable mixture of diastereomeric (2S,5RS,7S)-diamino-4-oxo-5-acetoxysuberates (13). Reductive amination and lactam annulation of the respective alpha-acetoxy ketones 13 provided hydroxypyrrolizidinones (6R)- and (6S)-1 with retention of the C6-position stereochemistry. The X-ray crystallographic study of (6R)-1 indicated dihedral angles constrained within the heterocycle that were consistent with the ideal values for the i + 1 and i + 2 residues of a type II' beta-turn. Hydrogen-bonding studies on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamides (6R)- and (6S)-21 in DMSO-d6, demonstrated different NH chemical shift displacements and temperature coefficients for the amide and carbamate protons, indicative of solvent shielded and exposed hydrogens in a turn conformation. 6-Hydroxy pyrrolizidinone amino carboxylate 1 may thus find application as a constrained alaninylhydroxyproline dipeptide mimic. In addition, alkylation of the hydroxyl group provided orthogonally protected pyrrolizidinone amino dicarboxylate (6R)-25, demonstrating potential for expanding the diversity of these rigid dipeptide surrogates for the exploration of peptide conformation-activity relationships.
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