Fluorescent p53 helix mimetics pairing anticancer and bioimaging properties

Abstract

Fluorescent therapeutic molecules offer a unique platform to study cellular uptake and biological pathways of drug candidates. Inhibition of the p53–HDM2 protein complex with the reactivation of the p53 pathway leading to apoptosis is a promising way to overcome the barriers and challenges in cancer therapeutic design. Although p53 helix mimetics based on the ‘hotspots’ design using either helical or non-helical backbones are known, cell-permeable and biocompatible inherently fluorescent helix mimetics have not yet been described. We report theragnostic helix mimetics featuring both therapeutic and bioimaging properties in a cancer cell model for the first time. The solvatochromic phthalimide unit in the scaffold functions as a site to append the hotspot mimicking residues, helps in the intramolecular hydrogen bonding mediated pre-organization of side chains on one face, and importantly, exhibits intrinsic fluorescence. The design of the mimetics, synthesis, conformational studies, and molecular docking results are discussed. In vitro cytotoxicity studies were carried out on four cell lines: U87MG (human glioblastoma), A549 (human non-small cell lung cancer), MDA-MB-231 (human triple-negative breast cancer) and HEK293 (non-cancerous cell line). The molecules showed anticancer activity in the micromolar range. The fluorescence properties provided valuable insights into their cellular permeability, distribution, and selectivity towards cancer cells and can shed light on their mechanisms of action.