Novel dual-mode antitumor chlorin-based derivatives as potent photosensitizers and histone deacetylase inhibitors for photodynamic therapy and chemotherapy.

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy. [Display omitted] • The dual-mode cytotoxic chlorin-based derivatives as PSs and HDACIs were synthesized. • HDAC inhibitory activities of target compounds were investigated. • Photo-cytotoxicity and dark-cytotoxicity for target compounds were evaluated. • Compound 15e exhibited the strongest PDT and chemotherapy efficacies. • Dual-mode cytotoxic mechanism of compound 15e was further studied. [ABSTRACT FROM AUTHOR]