Characterization of novel alpha-Mangostin and Paeonol derivatives with cancer-selective cytotoxicity

: alpha-Mangostin and Paeonol have shown anti-cancer and anti-inflammatory properties, however these two natural compounds have no clinical value because of their low solubility and low membrane permeability. In this study, we screened chemically synthesized derivatives from these two natural compounds as potential novel chemicals that increase cancer cell cytotoxicity over non-transformed human cells. We found that two derivative compounds, named α-Mangostin-1 (aMan1) and Paeonol-1 (Pae1) more efficiently and more specifically induced cytotoxicity in HCT116, HT29, and SW48 colorectal cancer (CRC) cell lines than the parental compounds. Both aMan1 and Pae1 arrested HCT116 cells in G1 phase and HT29 and SW48 cells in G2/M phase of the cell cycle. Both aMan1 and Pae1 induced apoptosis in human CRC cells, through a Caspase-dependent mechanism. aMan1 and Pae1 induced selective transcriptional responses in CRC cells involving genes related to metabolic stress and DNA damage response signaling pathways. Finally, experiments on primary colon organoids showed that both derivatives were able to kill cancer-derived organoids without affecting the viability of organoids derived from healthy tissue, where the parental compounds and the currently used chemotherapeutic drug Irinotecan failed. In conclusion, our findings expand the knowledge of natural compound derivatives as anticancer agents and open new avenues of research in the derivation of lead compounds aimed at developing novel chemotherapeutic drugs for CRC treatment that selectively target cancer, but not healthy cells.