Design and Synthesis of Cryptostyline I Derivatives: Cytotoxic Activity and Molecular Docking Insights

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 alkaloids 17 , 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 compounds 17 , 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.