Synthesis of Modified Tripeptides and Tetrapeptides as potential bisubstrate inhibitors of the epidermal growth factor receptor protein tyrosine kinase |
| |
Authors: | Grard Ross Urs Squin Helmut Mett Pascal Furet Peter Traxler Heinz Fretz |
| |
Institution: | Gérard Rossé,Urs Séquin,Helmut Mett,Pascal Furet,Peter Traxler,Heinz Fretz |
| |
Abstract: | 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(OtBu)-Tyr-Leu-OBzl ( 5 ) and Ac-Glu(OtBu)-Tyr-Leu-Arg(Pmc)-NH2 ( 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, N6-(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 IC50 value of 33 μM. |
| |
Keywords: | |
|
|