Methylation and demethylation of histone are important epigenetic processes that control numerous transcriptional activities. Histone lysine demethylase 4 (KDM4) is a member of the Jumonji domain 2 (JDJM2) family which is overexpressed in tumors including prostate cancer. We have previously identified 8-hydroxyquinolin-based compounds like B3 that showed high potency and selectivity on inhibiting KDM4B. In an attempt to improve their biological activities, we have designed a large number of novel B3 analogs with structural modification of the 3-phenylpropylamine moiety with various aminoacyl N-alkylamide. This modification not only increased structural diversity of the alkyl chain but also provided an efficient solid-phase synthetic route. 183 compounds were synthesized with Fmoc solid-phase synthesis employing the aminomethylated polystyrene resin along with a backbone amide linker. Then MTT assays were performed on these compounds with a 4 days treatment of 1 um concentration. Among numerous analogs synthesized and tested, A16 that contains Trp showed the strongest cell growth inhibition on prostate cancer cells (22RV1), showing a potential of the synthetic strategy to achieve strong biological activity.

Design and synthesis of potent histone lysine demethylase inhibitors containing 8-hydroxyquinoline

ACS Spring Meeting 2021

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