d-Leucine modified Sansalvamide A analogs: photo-induced synthesis, target prediction, and antitumor potential study

Cyclic peptides show promise in cancer therapy but are hindered by low natural yields and poor metabolic stability. This study synthesized Sansalvamide A analogs (Compound 1-5) via Leucine configuration modification and green intramolecular photoinduced single-electron-transfer cyclization, which introduces antitumor isoindolinone into the skeleton to enhance the structural rigidity. In vitro MTT assay showed that cyclic peptides exhibit a certain degree of tumor cell inhibitory activity, among which Compound 5 (with multiple d-leucine modifications) exhibits relatively stronger activity. Target prediction and protein-protein interaction analysis identified BCL2 as a key hub target, a finding further confirmed by molecular docking, which demonstrated that Compound 5 exhibits high binding affinity to BCL2 through stable hydrogen bonds and hydrophobic interactions (alkyl, π-cation and π-sigma interactions). Meanwhile, JC-1 assay verified that Compound 5 can effectively reduce mitochondrial membrane potential, which in turn endows it with the potential to induce tumor cell apoptosis. In silico ADMET predictions further supported the practical application potential of Compound 5. This research has provided a useful guide for peptide-based drug-target design.