Semisynthetic studies identify mitochondria poisons from botanical dietary supplements—Geranyloxycoumarins from Aegle marmelos

Abstract

Bioassay-guided isolation and subsequent structure elucidation 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 1.10 μg mL−1, respectively). Insufficient material and chemical instability 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 by semisynthesis. The unsaturated C-6′ linoleic acid ester derivative 14 that was structurally most similar to 1 and 2, inhibited HIF-1 activation with comparable potency (IC50 0.92 μM). The octanoyl (11) and undecanoyl (12) ester derivatives also suppressed HIF-1 activation (IC50 values 3.1 and 0.87 μM, respectively). Mechanistic studies revealed that these geranyloxycoumarin derivatives disrupt mitochondrial respiration, primarily at complex I. Thus, these compounds may inhibit HIF-1 activation by suppressing mitochondria-mediated hypoxic signaling. One surprising observation was that, while less potent, the purported cancer chemopreventive agent auraptene (8) was found to act as a mitochondrial poison that disrupts HIF-1 signaling in tumors.

Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation

“…Because auraptene is an inhibitor of mitochondrial complex I [ 11 ], it may be a candidate for the regulation of energy metabolism in RCC. To assess whether mitochondrial oxidative phosphorylation (OXPHOS) in RCC is affected by auraptene, RCC4 cells were incubated with 100 μM auraptene or DMSO (vehicle control) for 24 h and the effects on basal OCR were determined using an XF-24 analyzer.…”

“…Auraptene, a natural compound initially isolated and purified from citrus fruit, is known as a mitochondrial complex I inhibitor [ 11 ]. In rodent models, auraptene has shown inhibitory effects on mammary and oral carcinogenesis and metastasis of melanoma through modulation of metabolism-related processes, such as hypoxic signaling [ 12 – 14 ].…”

Auraptene Mitigates Parkinson’s Disease-Like Behavior by Protecting Inhibition of Mitochondrial Respiration and Scavenging Reactive Oxygen Species

“…It has previously been reported that AUR affects mitochondrial complex I and inhibits mitochondrial respiration in RCC4 renal cell carcinoma cells [8,11]. In this context, effects of AUR on mitochondrial oxygen consumption rate (OCR), shown in Figure 1C,D, are somewhat counterintuitive.…”

“…Auraptene (AUR) is a 7-geranyloxylated coumarin isolated from citrus fruit [8]. Natural compounds such as AUR might generally be expected to offer advantages of safety and minimal adverse effects [9]; notably, AUR is able to cross the blood-brain barrier [10].…”

Toxins in Botanical Dietary Supplements: Blue Cohosh Components Disrupt Cellular Respiration and Mitochondrial Membrane Potential

“…13,32 Protoliminoids and other constituents found in Bael tree ( Aegle marmelos ) products act as mitochondrial poisons that disrupt the ETC and interfere with global protein translation through an endoplasmic reticulum (ER)-stress activated signaling pathway. 21,33 These A. marmelos studies further indicate that even auraptene (a purported cancer chemopreventative agent) potentially may act as a mitochondrial poison. One of the major challenges for the identification of botanical dietary supplement-induced mitochondrial toxicity is that these products are often consumed in conjunction with clinically approved drugs, which may also produce off-target effects on the mitochondria.…”