Synthesis and biological evaluation of C-ring nitro-substituted dehydroabietylamine analogs: in vitro cytotoxicity, DNA affinity, and molecular docking studies

Abstract

In pursuit of more effective anticancer treatments, we developed a series of innovative dehydroabietylamine (DHAA) derivatives, with particular emphasis on introducing nitro modifications to the C-ring based on incorporating C-18 Schiff base heterocyclic structures. We evaluated the cytotoxic effects of these compounds in vitro against a panel of human tumor cell lines – MCF-7 (breast cancer), A549 (lung cancer), HeLa (cervical cancer), and HepG2 (liver cancer) - as well as the non-malignant cell line HUVEC (human umbilical vein endothelial cells). DHAA derivatives L¹⁵ and L²⁰, with C-ring 14-nitro substitution based on C-18 Schiff base heterocyclic modification, showed higher cytotoxic activity against HeLa and A549 cells, respectively, while demonstrating significantly lower cytotoxicity to non-malignant HUVEC cells. Meantime the mechanism of cytotoxicity of DHAA derivatives was preliminarily investigated. The result suggested that inducing cell apoptosis might be the primary mechanism. The interaction between DHAA derivatives and HS-DNA was studied using absorption spectral analysis and ethidium bromide (EB) fluorescence displacement experiments, the results exhibited that the binding of DHAA derivatives to DNA was in the intercalative mode. The molecular docking study demonstrated that DHAA derivatives exhibited a strong binding affinity to DNA, facilitated by carbon‑hydrogen interactions and π-donor hydrogen bonds. The structure-activity relationship discussion implied that introduction of the nitro-group, especially the 14-nitro group, significantly improved the cytotoxicity of DHAA. The significant cytotoxicity and high selectivity exhibited by compounds L¹⁵ and L²⁰ suggested their potential as promising antitumor medicines.