New synthesis of benzo-delta-carbolines, cryptolepines, and their salts: in vitro cytotoxic, antiplasmodial, and antitrypanosomal activities of delta-carbolines, benzo-delta-carbolines, and cryptolepines.

摘要

The paper describes, in its first part, a new synthesis of benzo-delta-carbolines, cryptolepines, and their salts. The strategy is based on the association between halogen-dance and hetero-ring cross-coupling. It is fully convergent and regioselective with interesting overall yields from 27% to 70%. A halogen-dance mechanism in quinoline series is also proposed. The formal synthesis of potential antimalarial compounds and the first total synthesis of 11-isopropylcryptolepine are also described. In the second part, cytotoxic activity against mammalian cells and activities against Plasmodium falciparum and Trypanosoma cruzi of benzo-delta-carbolines and delta-carbolines were evaluated in vitro to study the structure-activity relationships. For benzo-delta-carbolines, methylation at N-5 increases the cytotoxic and antiparasitic activities. A further alkylation on C-11 generally increases the cytotoxic activity but not the antiparasitic activity, cryptolepine and 11-methylcryptolepine being the most active on both parasites. Taking advantage of the fluorescence of the indoloquinoline chromophore, cryptolepine was localized by fluorescence microscopy in parasite DNA-containing structures suggesting that these compounds act through interaction with parasite DNA as proposed for cryptolepine on melanoma cells. For delta-carbolines, methylation at N-1 is essential for the antimalarial activity. 1-Methyl-delta-carboline specifically accumulates in the intracellular parasite. It has weak cytotoxic activity and can be considered as a potential antimalarial compound.