Semisynthesis and screening of a small library of pro-apoptotic squamocin analogues: selection and study of a benzoquinone hybrid with an improved biological profile.
Acetogenins of Annonaceae, including squamocin (1), exert spectacular cytotoxicity and the most potent inhibition of NADH:ubiquinone oxidoreductase known so far. Cell death induced by these natural products was identified as apoptosis and was thought to be linked to alterations in mitochondrial function. Quinone-squamocin hybrid compounds were semisynthesized and evaluated for their pro-apoptotic properties with a screening method based on dissipation of the mitochondrial transmembrane potential (DeltaPsim). Herein, we report a short one-step synthesis of a squamocin carboxylic acid analogue. For the first time on a natural product, the radical decarboxylation and quinone addition reaction has enabled preparation of a library of squamocin-quinone hybrids and four other analogues. Squamoquinone, tenfold more potent than squamocin as an inducer of apoptosis, emerged as a promising compound, as it induces apoptosis through a mitochondrial caspase-dependent pathway.
Derbré
Séverine
S
Laboratoire de Pharmacognosie associé au CNRS (BioCIS, UMR 8076), Université Paris-Sud 11, Centre d'Etudes Pharmaceutiques, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry CEDEX, France.
Duval
Romain
R
Roué
Gaël
G
Garofano
Aurelio
A
Poupon
Erwan
E
Brandt
Ulrich
U
Susin
Santos A
SA
Hocquemiller
Reynald
R
D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D015394:Molecular Structure
D016227:Benzoquinones; D005663:Furans; D007783:Lactones; C059660:squamocin