New cryptostyline I derivatives were synthesized and structurally characterized by NMR, MS, and X-ray analysis. Their cytotoxicity was evaluated against cancer and normal cell lines, revealing structure–activity relationships. Selected derivatives modulated lipid peroxidation in CCRF-CEM cells. Molecular docking with P-gp and ADMET analysis provided insights into interactions, pharmacokinetics, and toxicity.

Abstract

In the search for new alkaloid-based cytotoxic agents, new cryptostyline I derivatives were synthesized. The structures of the obtained compounds were elucidated by NMR and mass spectrometry. The structures of the alkaloids17, 19, and 23 were also determined by x-ray diffraction analysis on single crystals. The cytotoxicity of the new cryptostyline I derivatives was assessed against cancer cell lines – HeLa, HEp-2, HBL-100, and CCRF-CEM—as well as on primary skin fibroblast cultures. It was found that the manifestation of cytotoxicity is influenced by the presence in the isoquinoline structure of a bromine atom in the C-ring and a pentyl (or octyl═nonyl) group on the nitrogen atom. The ability of the synthesized tetrahydroisoquinoline derivatives with high cytotoxicity to affect the levels of primary (diene conjugates [DC] and triene conjugates [TC]) and secondary (malondialdehyde [MDA]) lipid peroxidation (LPO) products in the CCRF-CEM cell line was also investigated. For Molecular Modelling, P-gp was selected as hypothetical molecular target and compounds17, 19, 20, and 23 were docked to the prepared protein. For the best-ranked docking poses, the interactions with the protein were calculated. Furthermore, a computational ADMET analysis was conducted to evaluate pharmacokinetics and toxicity parameters for the examined compounds.