Novel diarylamides and diarylureas with N-substitution dependent activity against medulloblastoma.

Abstract Medulloblastoma – highly aggressive and heterogeneous tumours of the cerebellum – account for 15–20% of all childhood brain tumours, and are the most common high-grade childhood embryonal tumour of the central nervous system. Herein, potent in vitro anticancer activity against two established medulloblastoma cell lines of the sonic hedgehog subgroup, namely DAOY (p53 mutant) and ONS-76 (p53 wild type), has been achieved. A number of first-generation diarylamides and diarylureas were evaluated and activity is likely to be, in-part, conformation-dependent. The most active compound from this first-generation set of compounds, 1-naphthyl derivative 4b, was selected and a second-generation of compounds were optimised and tested for activity against the medulloblastoma cell lines. This process resulted in drug-like compounds with up to sixty times the activity (sub-micromolar) of the first-generation – thus providing potent new leads for further study.