Synthesis and evaluation of novel 8,6-fused bicyclic peptidomimetic compounds as interleukin-1beta converting enzyme inhibitors.
ABSTRACT Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with numerous compounds exhibiting caspase-1 IC(50)s less than 10nM.
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ABSTRACT: This compendium focuses on functionalised sugar amino acids (SAAs) and their 3- to 6-membered nitrogen heterocyclic and carbocyclic analogues. The main benefit of using SAAs and their related nitrogen and carbon congeners in the production of peptidomimetics and glycomimetics is that their properties can be readily altered via modification of their ring size, chemical manipulation of their numerous functional groups and fine-tuning of the stereochemical arrangement of their ring substituents. These building blocks provide access to hydrophilic and hydrophobic peptide isosteres whose physical properties allow entry to a region of chemotherapeutic space which is still under-explored by medicinal chemists. These building blocks are also important in providing amino acids whose inherent conformational bias leads to predisposition to secondary structure upon oligomerisation in relatively short sequences. These foldamers, particularly those containing ω-amino acids, provide an additional opportunity to expand access to the control of structures by artificial peptides. The synthesis and biological evaluation of these building blocks in glycomimetics and peptidomimetics systems keep expanding the reach of the glycosciences to the medical sciences, provide a greater outlook onto the wide range of cellular functions of saccharides and their derivatives involved and greater insight into the nature of oligosaccharide and protein folding.Amino Acids 08/2013; · 3.65 Impact Factor
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ABSTRACT: Substituted 1,2,3,4-tetrahydroquinoxaline, benzo-annulated unsymmetrical chiral -N(3) peraza, and -N(4) peraza-macrocycles have been synthesized employing an inter- and intramolecular Mitsunobu reaction from an amino acid derived common synthetic intermediate 3. The metal complexation study of these macrocycles has been investigated by UV-visible spectroscopic technique with binding constant (K(b)) value 1.84 × 10(3) dm(3) mol(-1) using the Benesi-Hildebrand equation and a Gibbs free energy (ΔG) -19.4 kJ mol(-1) at 35 °C for 14d with Co(2+). The binding properties of the metal were dependent on the structure of polyaza-macrocycles that were confirmed by the DFT optimized structure of two macrocycles. A detailed investigaton of UV-visible spectra of macrocycles and their complete interpretation with the help of TD-DFT along with the frontier molecular orbital calculations are presented.Organic & Biomolecular Chemistry 02/2012; 10(8):1553-64. · 3.49 Impact Factor
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ABSTRACT: As a result of their easy availability in enantiomerically enriched form and their possession of synthetically transformable diverse functional groups, amino acids have been extensively used by synthetic organic and medicinal chemists as a chiral pool for access to heterocycles (monocycles, bicycles or polycycles, either bridged or fused). This review describes the syntheses of diverse asymmetric heterocycles with various membered rings (n = 3-9) followed by benzo or heteroannulated ones, for the period from 1996 to Dec. 2013. It details solution phase synthetic methodologies in which the naturally occurring α-amino acid is incorporated, totally or partially, into the final product.Organic & Biomolecular Chemistry 07/2014; · 3.49 Impact Factor