Unraveling the Anticancer Activity of Sunitinib Derivatives Through Modifications in Solvent-Exposed Regions:...

This study modified the solvent-exposed region of sunitinib by replacing its diethylaminoethyl tail with linear and heterocyclic amines, guided by lipophilicity, steric, and electronic considerations to enhance the anticancer activity and selectivity. Sunitinib and its 20 derivatives, including 14 new compounds (4a, 4c, 4d, 4g-4i, 5a, 5b, 7a-7e, and 8) and 6 known compounds (4b, 4e-4f, 5c-5d, and 6), were successfully synthesized. The cytotoxic effects of sunitinib and its derivatives were evaluated against three human cancer cell lines (HeLa, SH-SY5Y, and HepG2) and one normal cell line (L929) using the MTT assay. Sunitinib exhibited the strongest cytotoxicity toward SH-SY5Y neuroblastoma cells, with an IC₅₀ of 3.88 µM. Among the derivatives, compound 5b showed the highest potency with an IC₅₀ of 4.28 µM against SH-SY5Y. Compound 6 displayed the highest selectivity index (SI ≥ 5) for HeLa, indicating good selectivity toward cancer over normal cells. Overall, these results suggest that targeted modification of the solvent-exposed region in sunitinib can improve anticancer activity without toxicity against normal cell lines, with compound 5b emerging as a promising lead for further development, particularly against neuroblastoma. The solvent-exposed region is strategic for drug development, allowing modifications that improve affinity, selectivity, solubility, and pharmacokinetics without disrupting ligand-protein interactions.