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.

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The paper describes a new general synthesis of α‐substituted δ‐carbolines based on key steps such as metalation, cross‐coupling and cyclization.

Based on how the mushroom Lactarius vellereus converts an inactive precursor into the cytotoxic dialdehyde isovelleral (1) via a cyclic enol ether, as part of a binary chemical defense system that protects the fruit bodies against parasites, a synthetic way to obtain analogous dialdehydes masked in the same way has been developed. As isovelleral analogues (e.g. 2 and 3) possess extremely potent cytotoxic activity, but display low selectivity as their biological activity is linked to their reactivity, suitably masked isovelleraloids that are converted to the corresponding dialdehyde under specific conditions, may constitute a way to utilize these potent compounds. Specifically, compounds 4 and 5, biomimetic precursors of the isovelleral analogues 2 and 3, but trapped as the stable methyl acetals, have been prepared.