Sulfur incorporation generally improves Ricin inhibition in pterin-appended glycine-phenylalanine dipeptide mimics.
Bioorg Med Chem Lett
; 23(24): 6799-804, 2013 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-24432385
ABSTRACT
Several 7-aminoamido-pterins were synthesized to evaluate the electronic and biochemical subtleties observed in the 'linker space' when N-{N-(pterin-7-yl)carbonylglycyl}-l-phenylalanine 1 was bound to the active site of RTA. The gylcine-phenylalanine dipeptide analogs included both amides and thioamides. Decarboxy gly-phe analog 2 showed a 6.4-fold decrease in potency (IC50 = 128 µM), yet the analogous thioamide 7 recovered the lost activity and performed similarly to the parent inhibitor (IC50 = 29 µM). Thiourea 12 exhibited an IC50 nearly six times lower than the oxo analog 13. All inhibitors showed the pterin head-group firmly bound in their X-ray structures yet the pendants were not fully resolved suggesting that all pendants are not firmly bound in the RTA linker space. Calculated log P values do not correlate to the increase in bioactivity suggesting other factors dominate.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pterinas
/
Ricina
/
Enxofre
/
Dipeptídeos
/
Inibidores Enzimáticos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article