Structure-Activity Relationships in a Series of 5-[(2,5-Dihydroxybenzyl)amino]salicylate Inhibitors of EGF-Receptor-Associated Tyrosine Kinase: Importance of Additional Hydrophobic Aromatic Interactions

Abstract

Potent inhibitors of EGF-dependent protein tyrosine kinase (PTK) activity were synthesized in a series of 5-[(2,5-dihydroxybenzyl)amino]salicylates. Several of these compounds inhibited EGF-dependent DNA synthesis in ER 22 cells with IC50 < 1 microM. In this series of PTK inhibitors, the role of the salicylate moiety as a potential divalent ion chelator was tested and found to be nonessential in all cases. The length and ramification of the substituting carboxyl group were investigated to improve cellular bioavailability, and this analysis provided compounds with increased inhibitory effect on EGF-induced DNA synthesis. Salicylates esterified with long hydrophobic chains were shown to be noncompetitive inhibitors of ATP, in contrast to the free acid and methyl salicylate. Moreover, all the tested inhibitors were shown to be noncompetitive inhibitors of the peptide substrate. Structure-activity relationships allowed us to suspect a hydrophobic pocket in the tyrosine kinase domain, preferentially interacting with aromatic rings. Finally, the selectivity of the best inhibitors was tested against other kinases, and they were found to be selective for tyrosine kinase. They were also shown to be good inhibitors of EGF-receptor autophosphorylation.

A Concise Synthesis of Triazole Analogues of Lavendustin A via Click Chemistry Approach and Preliminary Evaluation of Their Antiparasitic Activity Against Trypanosoma cruzi

“…In this case, 7 b was first reacted with salicylaldehyde in acid conditions to provide the N ‐benzylideneaniline derivative 8 a , in 92 % of yield after recrystallization in MeOH [16] . Next, this latter was easily reduced with NaBH 4 to give 9 a in 90 % of yield after purification on a short silica gel chromatography column [5u] . Ultimately, the overall yields were similar among the two evaluated pathways, but the first one was chosen considering saved time and more affordable costs (see Supporting Information).…”

“…Concerning the synthetic approaches envisioning lavendustin derivatives, the main investigations were focused on analogues of the pharmacophoric subunit ( e. g . 3 e [5j] ), which were achieved from reductive amination [5i,j, ° ,q,s] or by Schiff base formation and subsequent reduction [5g,r,t,u,w] . When required, the resulting N ‐benzylanilines could be easily alkylated to provide N,N ‐disubstituted anilines [5a,b,d,f] ( e. g .…”

“…Regarding the effects of derivatization on the carboxylic acid group, the more lipophilic lavendustin esters [5 ° ,u,w,z] ( e. g . 2 a , b , [5u,z] Figure 1) and N ‐alkylamides [5u,h,j] derivatives ( e. g . 3 c ‐ e , Figure 2) displayed better cellular permeability in intact cells, contributing to good bioactivities, mainly as anticancer agents.…”

Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase

“…To further explore the available chemical space, a small array of analogues of compound 1 were synthesised from the literature compound 11 21 by coupling to the 5-NH 2 position with commercially available acid chlorides (Scheme 1). After deprotection of the hydroxamic acid, the majority of compounds showed decreased inhibitory activity compared with 1 (Table 2).…”

Design, Synthesis, and Biological Evaluation of Aminoboronic Acids as Growth‐Factor Receptor Inhibitors of EGFR and VEGFR‐1 Tyrosine Kinases

“…The active pharmacophore 1 of lavendustin is composed of two aromatic rings linked by a methyleneamino chain and it was previously synthesized from 3‐aminosalicylic acid and 2,5‐dihydroxybenzaldehyde by reductive amination 12b. A series of aminoboronic acid analogues 5 – 8 was synthesized from various anilines 2 a – d and aldehydes 3 a – e in the presence of NaCNBH 3 in MeOH at room temperature or NaBH 4 in EtOH after the formation of the imine 4 (Scheme…”