Rh(iii)-Catalyzed substituent enabled alkylation and alkenylation of 1,4-naphthoquinones with maleimides under acidic and basic conditions is described.
The rhodium(III)-catalyzed direct C−H addition and annulation of benzimidates and aldimines with β-(trifluoromethyl)-α,β-unsaturated ketones is described. This protocol provides the facile and efficient formation of various trifluoromethyl-containing indenamines or aminoindanes in moderate to high yields.I ndenes and indanes are very important carbocyclic derivatives that are found in various natural products and pharmaceutically active molecules. 1 Moreover, they find application in organometallics and material science. 2 In particular, aminoindene/indane derivatives have shown important biological activities, 3 such as glutamate receptor antagonist, calcium antagonist, and anti-Parkinson. In addition, trifluoromethyl-containing indane acts as a selective CB2 ligand (Figure 1). 4
A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a–r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC50 = 2.04 μM) and 15r (IC50 = 0.85 μM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC50 = 5.31 μM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G0/G1 phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 μM and 1 μM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, β-catenin, TAB-182, β-actin, AXIN-2, and NF-κB markers that are involved in the β-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.
A library of pyridine-based 1,2,4-triazolo-tethered indole
conjugates
were designed, synthesized, and evaluated for anti-proliferative activity
against a panel of six human cancer cell lines. All the synthesized
conjugates (14a–q) were found to
be effective against the HT-29 cell line. Particularly conjugates 14a, 14n, and 14q exhibited promising
cytotoxicity, with IC50 values of 1 μM, 2.4 μM,
and 3.6 μM, respectively, compared to the standard 5-fluorouracil
(IC50 = 5.31 μM). Cell cycle arrest at the G0/G1
phase was observed with these compounds, the mitochondrial membrane
potential was interrupted, and the total ROS production was enhanced.
Western blot and immunofluorescence experiments illustrated that these
compounds inhibit the expression of markers that are involved in β-catenin
and PI3K pathways. Molecular dynamics simulations demonstrated that
compound 14a has major hydrophobic interactions and few
H-bonding interactions with both PI3K and tankyrase proteins.
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