DNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid neocryptolepine

Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Crypto-lepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can int ercalate into DNA and stimulates DNA cleavage by human topoisomerase II, In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orient ation of the indole unit with respect to the quinoline moiety, The biochemi cal and physicochemical results presented here indicate that neocryptolepin e also intercalates into DNA, preferentially at GC-rich sequences, but exhi bits a reduced affinity for DNA compared with cryptolepine, The two alkaloi ds interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer, The data provide a molecular basis to account for the reduced c ytotoxicity of neocryptolepine compared with the parent drug.