Synthesis and structure-activity studies of a series of [(hydroxybenzyl)amino]salicylates as inhibitors of EGF receptor-associated tyrosine kinase activity

Chen, Huixiong; Boiziau, Janine; Parker, Fabienne; Maroun, Rachid C.; Tocqué, Bruno; Roques, Bernárd P.; Garbay‐Jaureguiberry, Christiane

doi:10.1021/jm00077a014

Cited by 33 publications

(29 citation statements)

References 11 publications

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“…Stilbene derivatives 10 and 11 were synthesized by Wittig reaction from (2,5-dimethoxybenzyl)triphenylphosphonium bromide and 5-formylsalicylic acid methyl ester and separated by silica gel chromatography. Unprotected 5-formylsalicylic acid methyl ester could be used successfully only when lithium diisopropylamide (LDA) in tetrahydrofuran, prepared from a highly concentrated solution of n-butyllithium (10 deprotonate the phosphonium salt in the Wittig reaction. The use of other bases or a higher percentage of hexane in the solvent mixture (from the preparation of LDA using less concentrated solutions of n-butyllithium) gave substantially lower yields of products, probably due to insufficient solubility of the phenolate intermediate.…”

Section: Chemistrymentioning

confidence: 99%

Novel Antiproliferative Agents Derived from Lavendustin A

Nußbaumer¹,

Ap²,

Cammisuli³

et al. 1994

J. Med. Chem.

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The active partial structure of the potent tyrosine kinase inhibitor lavendustin A was derivatized in the search for novel agents against cellular proliferation. The antiproliferative potential of the new derivatives was determined using the human keratinocyte cell line HaCaT as the primary test system. Whereas the lavendustin A partial structure is ineffective in inhibiting cell proliferation, esterification of its carboxylic acid function leads to measurable antiproliferative activity. Additional O-methylation of the 2,5-dihydroxyphenyl moiety yields activity in the micromolar range. Further substantial increases in activity are achieved by replacing the nitrogen with oxygen and carbon within the 2,5-dimethoxyphenyl series (but not within the 2,5-dihydroxyphenyl analogs) leading to 5-[2-(2,5-dimethoxyphenyl) ethyl]-2-hydroxybenzoic acid methyl ester (13) as the most potent analog identified to date. These increases in antiproliferative activity are paralleled, however, by the disappearance of activity against the epidermal growth factor receptor-associated tyrosine kinase, suggesting another mechanism of action.

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Section: Chemistrymentioning

confidence: 99%

Novel Antiproliferative Agents Derived from Lavendustin A

Nußbaumer¹,

Ap²,

Cammisuli³

et al. 1994

J. Med. Chem.

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“…Addition of S or N nucleophiles to compound 2 did not increase the inhibitory potency. In contrast, a slight decrease of activity was observed (compounds [16][17][18][19]. Nevertheless, some of these derivatives showed interesting cellular properties.…”

Section: Biological Evaluation and Discussionmentioning

confidence: 96%

[(Alkylamino)methyl]acrylophenones: Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor Protein Tyrosine Kinase

Traxler¹,

Trinks²,

Buchdunger³

et al. 1995

J. Med. Chem.

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[(Alkylamino)methyl]acrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as the benzyloxy or (benzoylsulfonyl)oxy group in the 4-position, represent a novel class of inhibitors of the epidermal growth factor (EGF) receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. The most active compounds inhibited the EGF receptor protein tyrosine kinase from A431 cell membranes with IC50 values of < 0.5 microM. Derivatives with a benzyloxy substituent in the 4-position of the aromatic ring inhibited both the EGF receptor kinase and the proliferation of an EGF-dependent mouse epidermal keratinocyte cell line (BALB/MK) but were only marginally active in the inhibition of the cellular EGF-dependent tyrosine phosphorylation. Compound 18 inhibited ligand-induced tyrosine phosphorylation and BALB/MK cell proliferation with IC50 values of approximately 100 and 1.21 microM, respectively, and showed antitumor activity in vivo in a nude mouse model. However, the discrepancy between the IC50 values for antiproliferative activity and cellular tyrosine phosphorylation as well as the relatively low tolerability in animals suggests a second site of action of this class of inhibitors. Nevertheless, [(alkylamino)methyl]acrylophenones and (alkylamino)propiophenones may prove to be interesting tools for studying the action of tyrosine kinases.

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“…A group of these drugs involves strongly hydrophobic polycyclic compounds [16,31] classified further according to their chemical structures. QSAR studies have been performed to predict their efficiency to help the planning of more active derivatives [32,33]. A comparative cell-based strategy for the discovery of selective tyrosine kinase inhibitors has been worked out by Stratowa et al [34].…”

Section: Discussionmentioning

confidence: 99%