Nitrostyrene Derivatives of Adenosine 5′‐Glutarates Modified with an Alkyl Spacer and their inhibitory activity on epidermal growth factor receptor protein tyrosine kinase

Abstract

B-Nitrostyrene derivatives of adenosine 5'-glutarates are potent and selective bisubstrate-type inhibitors of the epidermal growth factor receptor protein tyrosine kinase (EGF-R PTK). In an attempt to improve the inhibitory activity, this type of compounds was modified with alkyl spacers of varying length between the nitrostyrene and the glutaryl units. The spacers consisted of 1, 3,4, and 5 atoms to give compounds of the benzyl, oxyethyl, oxypropyl, and oxybutyl series, respectively (Schemes 1 and 2). Adenosine 5'-esters were prepared in the benzyl and oxypropyl series only. Compared to the compounds in the parent series without spacer (ICs0 = 0.7-12 p~) , most of the modified compounds inhibited the EGF-R PTK only marginally or were inactive (K5, 2 100 VM). The only exceptions were the free acids 19 and 20 with IC,, values of ca. 5 PM. It is noteworthy that esterification of these two hydrogen glutarates with either MeOH or adenosine yielded inactive compounds, which is in contrast to the corresponding substances without spacers.

Synthesis of Modified Tripeptides and Tetrapeptides as potential bisubstrate inhibitors of the epidermal growth factor receptor protein tyrosine kinase

“…The additional OH group may enhance the complexation of bivalent metal ions. Subtle changes in the length of the spacer unit or in the way it is attached to the tyrosine mimic also greatly influence the inhibitory activity as was shown in our earlier reports [19] [20]. In this respect, the adipoyl moiety of 28 is quite a long and flexible spacer, which might be one of the reasons why 28 proved to be inactive.…”

Phosphotyrosyl Mimetics in the Development of Signal Transduction Inhibitors

“…As seen in Figure 2B, such inhibitors may mimic various points in the catalytic process of phosphoryl transfer. Analogues, such as 2 having formal ATP-like moieties tethered to Tyr equivalents, 15 are intended as bisubstrate inhibitors. Others containing abbreviated phosphorylmimicking groups, such as 3, 16 4, 17 and 5, 18 may be viewed either as transition-state analogues or as end-product inhibitors.…”