Synthesis, analysis and biological evaluation of novel indoloquinoline cryptolepine analogues as potential antitumour agents

This project investigated the development of novel anticancer agents with good efficacy and selectivity. Cryptolepine is an alkaloid found in the roots of West African climbing shrub species including Cryptolepis triangu- laris and Cryptolepis sanguinolenta. Cryptolepine is 5-methyl-1oH-indolo [3, 2-b]quinolone, and was first identified as an antimalarial agent, but also acts as an anti-cancer agent by intercalating into DNA and also inhibiting topoi- somerase ll and other key enzymes. Studies elsewhere have shown the mode of action of cryptolepine in vitro appears to be unaffected by drug re- sistance mechanisms identified. In this project a number Cryptolepine ana- logues have been made, modifying key positions in order to enhance DNA binding. The aim of this study was to attach halogens (F, Cl, Br and I) and alkyl amino or amido side chains at the 11-position and then test these mole- cules for anticancer activity. It was anticipated that these nitrogen containing side chains might interact with the sugar-phosphate backbone of DNA to give improved binding and hence interfering with topoisomerase II and related enzymes such as helicase and hence enhancing cytotoxicity. Fluorescence microscopy was used to investigate whether the derivatives reach the cell nucleus. In conclusion, these studies have shown that novel amino- and halogenated cryptolepine analogues have greater in vitro cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents.