Sugar amino acids and related molecules: some recent developments

To meet the growing demands for the development of new molecular entities for discovering new drugs and materials, organic chemists have started working on many new concepts that can help to assimilate knowledge-based structural diversities more efficiently than ever before. Emulating the basic principles followed by Nature to build its vast repertoire of biomolecules, organic chemists are developing many novel multifunctional building blocks and using them to create 'nature-like' and yet unnatural organic molecules. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl, amino and hydroxyl termini provide an excellent opportunity to organic chemists to create structural diversities akin to Nature's molecular arsenal. In recent years, sugar amino acids have been used extensively in the area of peptidomimetic studies. Advances made in the area of combinatorial chemistry can provide the necessary technological support for rapid compilations of sugar amino acidbased libraries exploiting the diversities of their carbohydrate frameworks and well-developed solid-phase peptide synthesis methods. This perspective article chronicles some of the recent applications of various sugar amino acids, furan amino acids, pyrrole amino acids etc. and many other related building blocks in wide-ranging peptidomimetic studies

TBK1 regulates regeneration of pancreatic β-cells

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells

β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-cell regeneration enhancer was a cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), which, acting through the cAMP-dependent protein kinase A (PKA), stimulated β-cell-specific proliferation by increasing cyclic AMP (cAMP) levels and mechanistic target of rapamycin (mTOR) activity. A combination of PIAA and cilostamide, an inhibitor of β-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced β-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1β-cells and β-cells in mammalian islets including human islets with elevation in cAMP levels and insulin secretion. PIAA improved glycemic control in streptozotocin (STZ)-induced diabetic mice with increases in β-cell proliferation, β-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKKε suppression in expanding functional β-cell mass

Diastereoselective opening of trisubstituted epoxy alcohols: application in the synthesis of (+)-prelactone C

A novel method developed by us for the synthesis of chiral 2-methyl-1,3-diols by radical-mediated diastereoselective opening of trisubstituted epoxy alcohols at the more substituted carbon was the key step in the synthesis of (+)-prelactone C (1)

Synthesis of (+)-prelactone B

Radical-mediated opening of a trisubstituted epoxy alcohol using cp2TiCl was followed by diastereoselective reduction of the resulting product with a centrally located methylene group, flanked on both sides by two chiral hydroxyl-bearing carbons, to build all the three chiral centers of (+)-prelactone B 1 in their desired stereochemistries leading to the total synthesis of the molecule

Cyclic trimer of 5-(aminomethyl)-2-furancarboxylic acid as a novel synthetic receptor for carboxylate recognition

A novel 18-membered cyclic oligopeptide 1 based on 5-(aminomethyl)-2-furancarboxylic acid (2), is developed as an excellent receptor for carboxylate binding having an association constant of 8.64×103 M-1 for tetrabutylammonium acetate in CD3CN. The synthesis of 1 was achieved by a high-yielding cyclotrimerization reaction of the unfunctionalized furan amino acid 2

Preferential polymerization of 5-(aminomethyl)-2-furancarboxylic acid (AMFC) into a cyclic tripeptide

Theoretical justification for the preferential formation of an 18-membered cyclic oligopeptide 1 based on 5-(aminomethyl)-2-furancarboxylic acid (AMFC, 2), is attempted using ab initio quantum chemical calculations. The free energy values obtained from Hessian calculations show that while the formation of the higher order cyclized oligopeptides [HN-H2C-(furan)-CO]n with n = 3,4, is energetically favorable, the formation of the cyclic dipeptide 3 is thermodynamically unfavorable. Inclusion of the solvent in calculations enhances this preference further. A plausible explanation for this is the proximity of repulsive charges on the furan O atoms in the dimer 3. Details of geometric parameters and Mulliken charges support this possibility. The repulsion is enhanced, as low frequency modes of nuclear motion that bring these O atoms closer are active at room temperature

Sugar amino acids in designing new molecules

Emulating the basic principles followed by Nature to build its vast repertoire of biomolecules, organic chemists are developing many novel multifunctional building blocks and using them to create 'nature-like' and yet unnatural organic molecules. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl, amino and hydroxyl termini provide an excellent opportunity to organic chemists to create structural diversities akin to Nature's molecular arsenal. This article describes some of our works on various sugar amino acids and many other related building blocks, like furan amino acids, pyrrole amino acids etc. used in wide-ranging peptidomimetic studies

Cyclic trimers of chiral furan amino acids

Chiral furan amino acids were synthesized as novel peptide building blocks. Cyclooligomerization of these monomers by a single-step process led to the selective formation of chiral C3-symmetric cyclic trimers, which were studied for their structures and properties, like anion binding and antimicrobial activities