Mitochondrion
has emerged as one of the unconventional targets
in next-generation cancer therapy. Hence, small molecules targeting
mitochondria in cancer cells have immense potential in the next-generation
anticancer therapeutics. In this report, we have synthesized a library
of hydrazide–hydrazone-based small molecules and identified
a novel compound that induces mitochondrial outer membrane permeabilization
by inhibiting antiapoptotic B-cell CLL/lymphoma 2 (Bcl-2) family proteins
followed by sequestration of proapoptotic cytochrome c. The new small molecule triggered programmed cell death (early and
late apoptosis) through cell cycle arrest in the G2/M phase and caspase-9/3
cleavage in HCT-116 colon cancer cells, confirmed by an array of fluorescence
confocal microscopy, cell sorting, and immunoblotting analysis. Furthermore,
cell viability studies have verified that the small molecule rendered
toxicity to a panel of colon cancer cells (HCT-116, DLD-1, and SW-620),
keeping healthy L929 fibroblast cells unharmed. The novel small molecule
has the potential to form a new understudied class of mitochondria
targeting anticancer agent.
AIEgens = Aggregation-induced-emission luminogens.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.
The presence of the same proteins at different sub-cellular locations with completely different functions adds to the complexity of signalling pathways in cancer.
Iron-catalyzed dehydrogenative cross-coupling of carbonyl compounds with aliphatic peroxide was developed under mild conditions. A library of linear alkylated and arylated peroxides are synthesized in good to excellent yield. This method is highly selective and general for a range of biologically important derivatives of 2-oxindole, barbituric acid, and 4-hydroxy coumarin with a good functional group tolerance and without the cleavage of the peroxide bond. This peroxidation reaction is upscalable to grams and also synthesizable in continuous flow with increased safety in short duration. Mechanistic investigation reveals Fe-(II) undergoes redox type process to generate the radical intermediates, which subsequently recombine selectively to form the stable peroxides. The potential of peroxides is evaluated by cell viability assay and found to exhibit the good anticancer activity with minimum IC= 5.3 μM.
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