Synthesis and antiproliferative activity of unsaturated quinoline derivatives.
In our previous work Knoevenagel condensation of quinoline 2-, 3- and 4-carbaldehyde with malononitrile derivatives was used to produce a series of heteroarylidene malononitrile derivatives. Some of these heteroaromatic tyrphostins were potent inhibitors of the epidermal growth factor (EGF) receptor kinase. This work has now been extended by using 6-, 7-, and 8-quinolinecarbaldehyde to prepare 23 new quinoline-tyrphostins 1-23. Most of these compounds were moderately active against the MCF7 breast cancer cell line. The order of potency was 7- > 6 > 8-substituted quinoline, which indicates that increased activity of the 7-substituted quinolines is associated with electron deficiency at the 7-position in the quinoline ring. The most active compound, 12, formed from 7-quinolinecarbaldehyde and ethyl cyanoacetate, had an IC50 value of 2.3 microM. Compounds 1-23 showed similar IC50 values against the MCF7 and MCF7/ADR cell lines (the latter shows fourfold increased protein tyrosine kinase activity) except for the compounds 1 and 15 formed from 6-quinolinecarbaldehyde and malononitrile and 7-quinolinecarbaldehyde and cyanoacetamide, which showed a significant (11- and 42-fold, respectively) increase in potency against the MCF7/ADR cell line. Furthermore, no association was found between growth inhibition and inhibition of the EGFR protein tyrosine kinase (PTK), using a cell-free assay. In addition, new compounds were prepared from 2- and 4-quinolinecarbaldehyde with extended conjugation in the side chains (24-27) or with methoxypolyethoxyethyl esters in the side chain to increase water solubility (28 and 29). These compounds showed substantial cytotoxicity, with IC50 values in the range 1-25 microM, but similar values were observed against both cell lines. No association was found between inhibition of PTK and growth inhibition, again indicating that their mode of action may not be specific for the EGF receptor.
Montgomery
G J
GJ
Department of Chemistry, University of Glasgow, UK.
McKeown
P
P
McGown
A T
AT
Robins
D J
DJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020032:Tyrphostins / Q000138:chemical synthesis* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011804:Quinolines; D020032:Tyrphostins; D066246:ErbB Receptors