Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex

Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53+/+ colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53-/- SW480; the lung cancer cell line p53-/- H1299; mouse embryonic fibroblasts (MEF) p53+/+ and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53+/+ cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.