3-Diarylethyne quinazolinones: a new class of senescence inducers

Abstract

A series of 3-diarylethyne quinazolinone compounds (4a–ad) were synthesized and evaluated for their cytotoxicity. They exhibited significant anticancer activity against MDA-MB-231, A549, MIAPaCa-2 and Colo-205 cancer cell lines and were highly effective in the MCF-7 cancer cell line with IC₅₀ values ranging from 2.27 to 3.88 μM. FACS analyses and BrdU assays revealed that there is G1 cell cycle arrest. Moreover, cells treated with these compounds show up-regulation of p53, p21, p16, TRF1 and POT1 and down-regulation of SKP2, TRF2 and tankyrase protein levels. To assess the senescence inducing ability of these compounds further, a senescence associated β-gal assay was performed. Interestingly, two of these compounds (4s and 4w) exhibited significant telomerase inhibition activity and inhibited tankyrase-1 protein, a protein partner associated with the sheltrin complexes of telomeres.