Hydroxylated 2-(5'-salicyl)naphthalenes as protein-tyrosine kinase inhibitors

Abstract

The salicyl group figures prominently in several potent protein-tyrosine kinase (PTK) inhibitors, including the fermentation product lavendustin A (3), the salicylsulfonyl nitrostyryl 30, and our recently reported salicyl-containing stilbene 7. Taking compound 7 and the isomeric 8 as lead structures, bicyclic nuclei 9-12 were prepared as conformationally constrained mimetics in which the hydroxyphenyl rings of 7 and 8 are held coplanar with the stilbene ethylene bridge. A similar approach with styryl-based PTK inhibitors of structure 1 previously yielded analogues 2 with enhanced potency. In the present case, however, the resulting salicyl-containing bicyclics exhibited extremely poor inhibitory potency when examined against autophosphorylation of immunoprecipitated p56lck PTK preparations. The implications of these results are discussed as they relate to the potential ways in which salicyl-containing stilbenes may be oriented relative to styryl-based inhibitors of type 1 and to an emerging class of potent aryl-substituted bicyclic inhibitors exemplified by compound 31.

Novel Antiproliferative Agents Derived from Lavendustin A

“…These findings suggested that a high degree of flexibility with regard to the relative spatial positions of the two aromatic ring systems might be important for high antiproliferative activity. Higher flexibility might also be the reason for the superior activity of the (2,5-dimethoxyphenyl)ethyl (12,13) and (2,5-dimethoxybenzyl)oxy (7,8) versus (2,5-dimethoxybenzyl)amino (4,5) analogs. In the benzylamino compounds, a preferred conformational arrangement of the molecule could be expected due to potential interaction of the amino function with the 2-methoxy group.…”

The effect of tyrosine kinase inhibitors on IgE-mediated histamine release from human lung mast cells and basophils

“…We followed up these investigations by assessing the effects of a further two drugs, ST638 and lavendustin C. Both of these inhibitors are reported to be more potent against receptor associated tyrosine kinases and will only inhibit src tyrosine kinases at concentrations above 10 M and 18 M respectively [28,29]. In our hands, ST638 (1 to 10 M) caused a significant inhibition of anti-IgE induced histamine release from human basophils.…”

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

“…4 [5a] and 6 [5b] ). In addition, similar non‐aminated analogues like 3 a‐d [5e,h,k] could be accessed either from cross‐couplings [5e,h, ° ,p] or by Wittig‐type [5h,x] reactions. In the field of combinatorial chemistry, a series of anticancer lavendustin analogues linked by a triazole ring ( e. g .…”