Synthesis of tripeptides as potent Yersinia protein tyrosine phosphatase inhibitors.
We report the synthesis of a series of monoanionic phosphotyrosyl (pTyr) mimetic-containing tripeptides based on 'Fmoc-Glu(OBn)-Xxx-Leu-amide' (where Xxx = pTyr mimetic) and their N-terminally modified derivatives. The inhibitory potencies of compounds were tested against YopH and human PTP1B enzymes. Several compounds exhibited noteworthy activity against both YopH and PTP1B. Among the N-terminally modified analogues, 5-methylindole derivative 30 was found to be the best moiety to replace base-labile Fmoc group. A mode of binding with YopH is proposed for tripeptides 21, 30, and 31.
Lee
Kyeong
K
Laboratory of Medicinal Chemistry, NCI, NIH, NCI-Frederick, Frederick, MD 21702, USA.
Boovanahalli
Shanthaveerappa K
SK
Nam
Ky-Youb
KY
Kang
Sang-Uk
SU
Lee
Mijeoung
M
Phan
Jason
J
Wu
Li
L
Waugh
David S
DS
Zhang
Zhong-Yin
ZY
No
Kyoung Tai
KT
Lee
Jung Jun
JJ
Burke
Terrence R
TR
D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D015007:Yersinia / Q000201:enzymology*
D001425:Bacterial Outer Membrane Proteins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia