Synthesis of 1-indolyl substituted β-carboline natural products and discovery of antimalarial and cytotoxic activities

A series of 1-indolyl substituted β-carbolines including the natural products hyrtiosulawesine, pityriacitrin and pityriacitrin B were prepared via Pictet–Spengler condensation—oxidation strategy from the corresponding indolyl-acetaldehydes and substituted tryptamines. Efforts to prepare the C-1 met...

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Bibliographic Details
Published in:Tetrahedron 2014-08, Vol.70 (33), p.4910-4920
Main Authors: Liew, Lydia P.P., Fleming, Jessica M., Longeon, Arlette, Mouray, Elisabeth, Florent, Isabelle, Bourguet-Kondracki, Marie-Lise, Copp, Brent R.
Format: Article
Language:English
Subjects:
Aldehydes
Antimalarial
Biological
Biotechnology
Colon
Condensing
Eudistomin U
Hyrtiosulawesine
Natural products
Panels
Pictet–Spengler reaction
Pityriacitrin
Plasmodium falciparum
Tumours
β-Carboline
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Summary:A series of 1-indolyl substituted β-carbolines including the natural products hyrtiosulawesine, pityriacitrin and pityriacitrin B were prepared via Pictet–Spengler condensation—oxidation strategy from the corresponding indolyl-acetaldehydes and substituted tryptamines. Efforts to prepare the C-1 methylene-linked β-carboline analogues for structure–activity relationship studies were unsuccessful. Biological evaluation revealed two analogues (5 and 41) to exhibit weak inhibition of phospholipase A2 (IC50 171 and 131 μM, respectively), two to act as antioxidants (3 and 43), and 12 analogues with activity towards a chloroquine-resistant strain (FcB1) of Plasmodium falciparum (IC50 1.0–23 μM). Testing against a panel of 60 human tumour cell lines revealed a general lack of cytotoxic effect for most of the compounds with the exception of β-carboline 42 exhibiting modest antileukaemic activity towards the HL-60(TB) cell line (LC50 4.2 μM). In addition, two novel structures (30 and 32) resulting from aldol condensation followed by Pictet–Spengler cyclisation displayed cytotoxicity with pronounced subpanel specificities towards colon cancer (COLO 205 and HCC-2998) cell lines. [Display omitted]
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2014.05.068