Cationic, amphipathic
host defense peptides represent a promising group of agents to be developed for anticancer applications. Poly-
N-substituted glycines, or
peptoids, are a class of biostable,
peptidomimetic scaffold that can display a great diversity of side chains in highly tunable sequences via facile solid-phase synthesis. Herein, we present a library of anti-proliferative
peptoids that mimics the cationic, amphipathic structural feature of the
host defense peptides and explore the relationships between the structure, anticancer activity and selectivity of these
peptoids. Several
peptoids are found to be potent against a broad range of
cancer cell lines at low-micromolar concentrations including
cancer cells with multidrug resistance (MDR), causing cytotoxicity in a concentration-dependent manner. They can penetrate into cells, but their cytotoxicity primarily involves plasma membrane perturbations. Furthermore,
peptoid 1, the most potent
peptoid synthesized, significantly inhibited
tumor growth in a human
breast cancer xenotransplantation model without any noticeable acute adverse effects in mice. Taken together, our work provided important structural information for designing
host defense peptides or their mimics for anticancer applications. Several cationic, amphipathic
peptoids are very attractive for further development due to their high solubility, stability against
protease degradation, their broad, potent cytotoxicity against
cancer cells and their ability to overcome multidrug resistance.