Synthesis and in Vitro and in Vivo Antitumor Activity of 2-Phenylpyrroloquinolin-4-ones

In our search for potential new anticancer drugs, we designed and synthesized a series of tricyclic compounds containing the antimitotic 2-phenylazaflavone chromophore fused to a pyrrole ring in a pyrroloquinoline structure. Compounds <BO>8</BO>, <BO>18</BO>,<BO> 19</BO>,<BO> 22</BO>,<BO> 23</BO>, <BO>25 </BO>and <BO>26</BO>, when tested against a panel of fourteen human tumor cell lines, showed poor in vitro cytotoxic activity, whereas <BO>20</BO>,<BO> 21 </BO>and<BO> 24</BO> showed significant activity (IC<INF>50</INF> 0.7 to 50 μM). Steroid hormone-sensitive ovary, liver, breast and adrenal gland adenocarcinoma cell lines displayed the highest sensitivity (IC<INF>50</INF> 0.7 to 8 μM). Compound <BO>24 </BO>blocked cells in the G<INF>2</INF>/M phase of the cell cycle and induced a significant increase in apoptotis. Compounds <BO>20</BO>, <BO>21</BO> and <BO>24</BO> proved to alter microtubule assembly and stability, displaying a cytoplasmic microtubule network similar to that caused by Vincristine. In vivo, administration of compound <BO>24</BO> to Balb/c mice inhibited the growth of a syngenic hepatocellular carcinoma.