title: Sulfur incorporation generally improves Ricin inhibition in pterin-appended glycine-phenylalanine dipeptide mimics.
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.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wiget
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Manzano
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Pruet
authors.forename: Grace
authors.initials: G
authors.lastname: Gao
authors.forename: Ryota
authors.initials: R
authors.lastname: Saito
authors.forename: Arthur F
authors.initials: AF
authors.lastname: Monzingo
authors.forename: Karl R
authors.initials: KR
authors.lastname: Jasheway
authors.forename: Jon D
authors.initials: JD
authors.lastname: Robertus
authors.forename: Eric V
authors.initials: EV
authors.lastname: Anslyn
mesh_terms: D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011622:Pterins / Q000737:chemistry*; D012276:Ricin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*; D013854:Thioamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D011622:Pterins; D013854:Thioamides; D013455:Sulfur; C029660:glycylphenylalanine; D012276:Ricin; D013890:Thiourea