Synthesis of modified tripeptides and tetrapeptides as potential bisubstrate inhibitors of the epidermal growth factor receptor protein tyrosine kinase

Abstract

The synthesis of a series of bisubstrate inhibitors of the epidermal growth factor receptor protein kinase (EGF-R PTK) consisting of small peptides 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)-NH2 (8; Pmc = 2,2,5,7,8-pentamethylchroman-6-sulfonyl) were prepared by standard peptide chemistry, 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, and finally coupled with the 5'-OH group of 2',3'-O-isopropylideneadenosine. In addition, N6-[(benzyloxy)carbonyl]-2',3'-O-isopropylideneadenosine 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.