Journal
JOURNAL OF NATURAL PRODUCTS
Volume 83, Issue 6, Pages 1829-1845Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.9b01224
Keywords
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Funding
- Cancer Research UK
- Medical Research Council [MC_ U105663141, MC_UU_00015/2]
- AstraZeneca
- EU [2013-IEF-626191]
- EPSRC [EP/P020291/1]
- Royal Society
- EPSRC [EP/P020291/1] Funding Source: UKRI
- MRC [MC_U105663141, MC_UU_00015/2] Funding Source: UKRI
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Prostate cancer is one of the leading causes of cancer-related death in men. The identification of new therapeutics to selectively target prostate cancer cells is therefore vital. Recently, the rotenoids rotenone (1) and deguelin (2) were reported to selectively kill prostate cancer cells, and the inhibition of mitochondrial complex I was established as essential to their mechanism of action. However, these hydrophobic rotenoids readily cross the blood-brain barrier and induce symptoms characteristic of Parkinson's disease in animals. Since hydroxylated derivatives of 1 and 2 are more hydrophilic and less likely to readily cross the blood-brain barrier, 29 natural and unnatural hydroxylated derivatives of 1 and 2 were synthesized for evaluation. The inhibitory potency (IC50) of each derivative against complex I was measured, and its hydrophobicity (Slog(10)P) predicted. Amorphigenin (3), dalpanol (4), dihydroamorphigenin (5), and amorphigenol (6) were selected and evaluated in cell-based assays using C4-2 and C4-2B prostate cancer cells alongside control PNT2 prostate cells. These rotenoids inhibit complex I in cells, decrease oxygen consumption, and selectively inhibit the proliferation of prostate cancer cells, leaving control cells unaffected. The greatest selectivity and antiproliferative effects were observed with 3 and 5. The data highlight these molecules as promising therapeutic candidates for further evaluation in prostate cancer models.
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