ISSN:
0018-019X
Keywords:
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
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.
Additional Material:
1 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/hlca.19970800304
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