The mode of action of cryptolepine, a potential antitumoral agent extracted from a West African liana, has been revealed by scientists in Spain and the UK. The alkaloid, which was traditionally used in local medicine to ward off malaria, colic, and stomach ulcers, is obtained from the Criptolepis sanguinolenta vine by chopping it up and making a bitter-tasting tea known as ‘nibima’ or Ghana quinine. However, interest in its antitumoral properties has grown since it was found to kill melanoma (Biochemistry 1998; 37: 5136–46) and leukaemia cells in vitro (Eur J Pharmacol 2000; 409: 9–18).
Although known to bind to DNA and inhibit synthesis and transcription, cryptolepine's exact mode of action has remained unclear. Now, John Lisgarten (Birkbeck College, London, UK) and Miquel Coll and colleagues (Instituto de Biología Molecular de Barcelona, Spain) have shown, using X-ray diffraction performed at the synchrotrons in Grenoble (France) and Hamburg (Germany), that the compound intercalates between bases in the DNA in a previously unknown way (Nature Struct Biol2002; 9: 57–60). Perpendicular intercalators, eg doxorubicin and daunomycin, attach between alternating CG sites and their aromatic structures slice between the DNA bases with their longitudinal axes oriented perpendicular to Watson-Crick hydrogen bonds. Parallel intercalators, such as acridine and actinomycin, also attach between different consecutive bases, but their longitudinal axes lie parallel to the DNA's hydrogen bonds. Cryptolepine is also a parallel intercalator, but it inserts differently. Says Coll, “This is the first intercalator known to get between two identical consecutive bases: CC or GG”. This ability is due to the asymmetry of cryptolepine's four aromatic rings, which enables the molecule to stack perfectly between the CC on one DNA strand and the GG on the other.
Coauthor Juan Aymami (Univer-sitat Politècnica de Catalunya, Spain) told TLO, “It is very encouraging that cryptolepine has been found to work in vitro against tumour cells resistant to other drugs. With this new information on its mode of action we might be able to design new compounds that are more refined and perhaps more specific”.
Although research on its antitumoral activity is fairly new, and clinical trials will not be carried out for some time, the fact that cryptolepine has been used as an antimalarial agent by West Africans for centuries suggests that its toxicity might be tolerable. Ongoing studies investigating the use of cryptolepine analogues as potential antimalarial agents (J Med Chem 2001; 44: 3187–94) may eventually yield important cytotoxicity data.