Inhibition of autophagy has been widely viewed as a promising
strategy
for anticancer therapy. However, few effective and specific autophagy
inhibitors have been reported. Herein, we described the design, synthesis,
and biological characteristics of new analogues of strigolactones
(SLs), an emerging class of plant hormones, against colorectal cancers.
Among them, an enantiopure analogue 6 exerted potent
and selective cytotoxicity against colorectal cancer cells, but not
normal human colon mucosal epithelial cells, which were further confirmed
by the plate colony formation assay. Moreover, it significantly inhibited
tumor growth in an HCT116 xenograft mouse model with low toxicity.
Mechanistically, it is associated with selective induction of cell
apoptosis and cell cycle arrest. Remarkably, 6 acted
as a potent autophagy/mitophagy inhibitor by selectively increasing
the autophagic flux while blocking the autophagosome–lysosome
fusion in HCT116 cells. This study features stereo-defined SLs as
novel autophagy inhibitors with high cancer cell specificity, which
paves a new path for anticolorectal cancer therapy.
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