Semisynthetic studies identify mitochondrial poisons from botanical dietary supplements – Aegle marmelos geranyloxycoumarins

Bioassay-guided isolation of a Bael tree Aegle marmelos lipid extract yielded two unstable acylated geranyloxycoumarin mixtures (1 – 2), six geranyloxycoumarins (3 – 8), (+)-9'-isovaleroxylariciresinol (9), and dehydromarmeline (10). In a T47D cell-based reporter assay, 1 and 2 potently inhibited hypoxia-induced HIF-1 activation (IC₅₀ values 0.18 and 1.10µg mL^-1, respectively). Insufficient material prevented full delineation of the fatty acyl side chain olefin substitution patterns in 1 and 2. Therefore, five fatty acyl geranyloxycoumarin ester derivatives (11 - 15) were prepared from marmin (3) and commercial fatty acyl chlorides. Derivative 14 potently inhibited HIF-1 activation (IC₅₀ 0.92µM). The octanoyl (11) and undecanoyl (12) ester derivatives also suppressed HIF-1 activation (IC₅₀ values 3.1 and 0.87µM, respectively). These geranyloxycoumarin derivatives disrupt mitochondrial respiration at complex I. One surprising observation was that, while less potent, the purported cancer chemopreventative agent auraptene (8) acts as a mitochondrial poison.