Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients.
A regiospecific
synthesis of naphtho[2,1-b]benzofurans
with a substituent at the C6 position was achieved via intramolecular
6-endo-dig electrophilic cyclization under acidic conditions to construct
the central aromatic C ring. Screening of the synthesized compounds
using a high-content imaging system enabled us to discover novel dual
state emissive compounds 2{1,6}, 2{1,8}, and 2{4,3}, which are highly emissive with blue emission in their solid states
as well as in solution states in most solvents. In addition, the compounds 2{4,3}, 2{4,12}, and 2{5,13} were found to be the
most cell permeable in HeLa cells for live cell imaging with negligible
phototoxicity.
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