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Synthesis of Modified Tripeptides and Tetrapeptides as potential bisubstrate inhibitors of the epidermal growth factor receptor protein tyrosine kinase
Author(s) -
Rossé Gérard,
Séquin Urs,
Mett Helmut,
Furet Pascal,
Traxler Peter,
Fretz Heinz
Publication year - 1997
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19970800304
Subject(s) - chemistry , tripeptide , stereochemistry , moiety , autophosphorylation , tyrosine , peptide , epidermal growth factor , adenosine , enzyme , protein kinase a , receptor , biochemistry
The synthesis of a series of bisubstrate inhibitors of the epidermal growth factor receptor protein kinase (EGF‐R PTK) consisting of small pep tides linked covalently to adenosine via appropriate triphosphate substitutes is described. Boc‐Glu(O t Bu)‐Tyr‐Leu‐OBzl ( 5 ) and Ac‐Glu(O t Bu)‐Tyr‐Leu‐Arg(Pmc)‐NH 2 ( 8 ; Pmc = 2,2,5,7,8‐pentamethylchroman‐6‐sulfonyl) were prepared by standard peptide chemistry, ( Scheme 1 ), then modified at the OH group of tyrosine either with adipic anhydride or with 4‐(chlorosulfonyl)benzoic acid, 4‐(chlorosulfonyl)‐2‐hydroxybenzoic acid, or benzene‐1,4‐disulfonyldichloride ( Scheme 2 ), and finally coupled with the 5′‐OH group of 2′,3′‐ O ‐isopropylideneadenosine ( Scheme 3 ). In addition, N 6 ‐[(benzyloxy)carbonyl]‐2′,3′‐ O ‐isopropylidene‐adenosine 5′‐(hydrogenhexanedioate) ( 26 ), an ATP substitute, was coupled with the morpholide of 5 ( Scheme 4 ). Removal of the protecting groups gave the bisubstrate analogs 23, 24 , and 28. The compounds synthesized were tested as inhibitors of the EGF‐R PTK. The most active bisubstrate‐type inhibitor was 24 , composed of the tripeptide sequence H‐Glu‐Tyr‐Leu‐OBzl, the 2‐hydroxy‐4‐sulfonylbenzoyl moiety, and adenosine; it showed an IC 50 value of 33 μM.