New synthesis of benzo-δ-carbolines, cryptolepines, and their salts: In vitro cytotoxic, antiplasmodial, and antitrypanosomal activities of δ-carbolines, benzo-δ-carbolines, and cryptolepines

Erwan Arzel, P. Rocca*, P. Grellier, M. Labaeïd, F. Frappier, F. Guéritte, C. Gaspard, F. Marsais, A. Godard, G. Quéguiner

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    133 Scopus citations

    Abstract

    The paper describes, in its first part, a new synthesis of benzo-δ-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-δ-carbolines and δ-carbolines were evaluated in vitro to study the structure-activity relationships. For benzo-δ-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 δ-carbolines, methylation at N-1 is essential for the antimalarial activity. 1-Methyl-δ-carboline specifically accumulates in the intracellular parasite. It has weak cytotoxic activity and can be considered as a potential antimalarial compound.

    Original languageEnglish (US)
    Pages (from-to)949-960
    Number of pages12
    JournalJournal of Medicinal Chemistry
    Volume44
    Issue number6
    DOIs
    StatePublished - Mar 15 2001

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery

    Fingerprint Dive into the research topics of 'New synthesis of benzo-δ-carbolines, cryptolepines, and their salts: In vitro cytotoxic, antiplasmodial, and antitrypanosomal activities of δ-carbolines, benzo-δ-carbolines, and cryptolepines'. Together they form a unique fingerprint.

    Cite this