Abstract
Induction of apoptosis is a common chemotherapeutic mechanism to kill cancer cells The thiazole system has been reported over the past decades as a building block for the preparation of anticancer agents. A novel series of 2-arylalkylamino-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)-thiazole derivatives designed as dual inhibitors of tubulin and cyclin-dependent kinases (CDKs) were synthesized and evaluated for their antiproliferative activity in vitro against two cancer cell lines and, for selected highly active compounds, for interactions with tubulin and cyclin-dependent kinases and for cell cycle and apoptosis effects. Structure-activity relationships were elucidated for various substituents at the 2-position of the thiazole skeleton. Among the synthesized compounds, the most active analogues were found to be the p-chlorobenzylamino derivative 8e as well as the p-chloro and p-methoxyphenethylamino analogues 8f and 8k, respectively, which inhibited the growth of U-937 and SK-MEL-1 cancer cell lines with IC50 values ranging from 5.7 to 12.2 μM. On U-937 cells, the tested compounds 8f and 8k induced apoptosis in a time and concentration dependent manner. These two latter molecules did not affect tubulin polymerization (IC50 > 20 μM) nor CDK activity at a single concentration of 10 μM, suggesting alternative targets than tubulin and CDK for the compounds.
Highlights
Several efforts were made for the discovery of new small molecules that target both tubulin and cyclin-dependent kinases (CDKs), which are involved in regulating the cell cycle, promoting tumor cell proliferation and apoptosis [5,6]
In structure-activity relationship studies, we examined the effects of electron-withdrawing groups (EWGs) or electron-releasing groups (ERGs) at the phenyl moiety (Figure 1)
1, summarize we summarize the antiproliferative activity of 2-arylalkylamino-4the 15 novel In Table the antiproliferative activity of the
Summary
A form of programmed cell death, plays a critical role in normal cell development and is a highly controlled mechanism that regulates the selective removal of damaged and dysfunctional cells [1]. Miller and co-workers discovered two novel classes of simple synthetic molecules based on a 4-(3,4,5-trimethoxybenzoyl)thiazole molecular skeleton, characterized by the presence of an aryl or an anilino moiety at the 2-position of the thiazole ring and corresponding to conjugates with general structures 4 and 5, respectively. These conjugates showed nanomolar antiproliferative activity against cancer cell lines by inhibiting tubulin polymerization [13,14].
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