Design, synthesis and in Vitro activity of anticancer styrylquinolines. The p53 Independent Mechanism of Action

A group of styrylquinolines were synthesized and tested for their anti-proliferative activity. Anti-proliferative activity was evaluated against the human colon carcinoma cell lines that had a normal expression of the p53 protein (HCT116 p53+/+) and mutants with a disabled TP53 gene (HCT116 p53-/-) and against the GM 07492 normal human fibroblast cell line. A SAR study revealed the importance of Cl and OH as substituents in the styryl moiety. Several of the compounds that were tested were found to have a marked anti-proliferative activity that was similar to or better than doxorubicin and were more active against the p53 null than the wild type cells. The cellular localization tests and caspase activity assays suggest a mechanism of action through the mitochondrial pathway of apoptosis in a p53-independent manner. The activity of the styrylquinoline compounds may be associated with their DNA intercalating ability

Caspase-3/7 activities on the HCT116 cell lines.

<p>Caspase-3/7 activities on the HCT116 cell lines.</p

Selective hydrolysis of styrylquinolines.

<p>For example, compare <b>2b</b>, <b>3b</b> and <b>18b</b>.</p

Tubulin level (a) and PARP cleavage (b) in HCT-116 cells for 6b (0, 10, 20, 40 μM) and 17b (0, 10, 20, 40, μM).

<p>Tubulin level (a) and PARP cleavage (b) in HCT-116 cells for 6b (0, 10, 20, 40 μM) and 17b (0, 10, 20, 40, μM).</p

Quinolines and analogs with a marked anticancer activity.

<p>Quinolines and analogs with a marked anticancer activity.</p

Synthesis of the compounds that were studied.

<p>Synthesis of the compounds that were studied.</p

<i>In vitro</i> staining of HCT116 cells treated with 6b (CH I.) and MitoTracker Orange CMTMRos dye (CH II.).

<p><i>In vitro</i> staining of HCT116 cells treated with 6b (CH I.) and MitoTracker Orange CMTMRos dye (CH II.).</p

Anti-cancer activity of the studied compounds (ND—not determined).

<p>Results are expressed as mean ± SD of at least three independent experiments. IC₅₀ values below 10 μM are bolded.</p><p>Anti-cancer activity of the studied compounds (ND—not determined).</p

Absorption spectra of 2c, 3c, 5b, 6b, CP-31398 and doxorubicin without CT-DNA (solid line) and with CT-DNA (dotted line).

<p>Absorption spectra of 2c, 3c, 5b, 6b, CP-31398 and doxorubicin without CT-DNA (solid line) and with CT-DNA (dotted line).</p

Activity (as—logIC₅₀) vs logP of the compounds that were tested.

<p>Activity (as—logIC₅₀) vs logP of the compounds that were tested.</p