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Semisynthesis and Screening of a Small Library of Pro‐Apoptotic Squamocin Analogues: Selection and Study of a Benzoquinone Hybrid with an Improved Biological Profile.
Author(s) -
Derbré Séverine,
Duval Romain,
Roué Gaël,
Garofano Aurelio,
Poupon Erwan,
Brandt Ulrich,
Susin Santos A.,
Hocquemiller Reynald
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500011
Subject(s) - quinone , apoptosis , biology , biochemistry , cytotoxicity , natural product , benzoquinone , programmed cell death , chemistry , stereochemistry , in vitro
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 (ΔΨ m ). 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.