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.
A Cu-catalyzed radical annulation/C3-functionalization cascade of tryptamine derivatives with aryl ethylene is reported. The mild catalytic system enables the facile construction of 3a-benzoylmethylpyrrolidino[2,3- b]indolines with excellent chemo- and regioselectivities. Remarkably, this novel method utilizes earth-abundant and inexpensive cupric salt as the catalyst and air as the co-oxidant, rendering the process highly environmentally friendly and atom economic. Presumably, the reaction proceeds through Cu-initiated formation of pyrrolidino[2,3- b]indolines radical intermediate I, which is successively trapped by aryl ethylene and O to form the product. An O-labeling experiment and several control experiments were designed to support the mechanistic proposal.
Condition-controlled divergent oxidative coupling reactions
between
indole/tryptamine derivatives and β-arylacrylic acids with the
catalysis of copper(II) have been developed. Specifically, a formal
Michael addition/dehydration sequence between indoles and β-arylacrylic
acids occurred in the presence of catalytic CuBr2 in CH3CN under air, thus affording highly functionalized 2,3-dihydro-1H-pyrrolo[1,2-a]indoles. In contrast, upon
changing the oxidant to
t
BuOOH and the
solvent to DCM, the reaction course switched to the unprecedented
oxidative coupling/cyclization cascade to give the tetracyclic pyrrolo[2,3-b]indolines selectively.
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