- Asymmetric synthesis, biological activity and molecular docking studies of some unsaturated α-amino acids, derivatives of glycine, allylglycine and propargylglycine
-
New enantiomerically enriched unsaturated tailor-made amino acids have been obtained. As a starting amino acid synthon for the asymmetric synthesis of tailor-made unsaturated amino acids, Ni(II) square-planar complexes of Schiff's bases of propargylglycine, allylglycine and glycine with chiral auxiliary (S)-2-N-(N’-benzylprolyl)-aminobenzophenone ((S)-BPB) were used. The Cα-alkylation of propargylglycine, allylglycine and glycine moieties resulted in the asymmetric synthesis of novel (S)-α-propargylglycine, (S)-α-allylglycine and glycine derivatives containing an aromatic group in the side chain (de 80–95,5%). After purification and cleavage of the metal complexes, the amino acids were isolated in high enantiomeric purity (ee >99%). Of the obtained seven tailor-made amino acids four showed inhibitory activity to collagenase G. The amino acid with an acetylene bond in the side chain (IC50 = 1.29 ± 0.02 mM) had the best result. Molecular docking showed that the amino acids with activity to collagenase G contained hydrogen and π-π bonds with the enzyme.
- Hayriyan, Liana A.,Karapetyan, Ani J.,Minasyan, Ella V.,Mkrtchyan, Anna F.,Paloyan, Ani M.,Panosyan, Henrik A.,Poghosyan, Artavazd S.,Saghyan, Ashot S.,Sahakyan, Lusine Yu.,Sargsyan, Armen S.,Tovmasyan, Anna S.,Tsaturyan, Avetis H.
-
-
- Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)
-
The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.
- Chien, Huan-Chieh,Colas, Claire,Finke, Karissa,Springer, Seth,Stoner, Laura,Zur, Arik A.,Venteicher, Brooklynn,Campbell, Jerome,Hall, Colton,Flint, Andrew,Augustyn, Evan,Hernandez, Christopher,Heeren, Nathan,Hansen, Logan,Anthony, Abby,Bauer, Justine,Fotiadis, Dimitrios,Schlessinger, Avner,Giacomini, Kathleen M.,Thomas, Allen A.
-
supporting information
p. 7358 - 7373
(2018/08/06)
-