Synthesis and Cytotoxic Activity of Self-Assembling Squalene Conjugates of 3-[(Pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one Anticancer Agents
Squalenoyl conjugates of semaxanib and sunitinib, two potent antiangiogenic (pyrrolyl)methylidenyl‐substituted oxindole multitarget tyrosine kinase inhibitors, were synthesized with a hemiaminal‐based pH‐sensitive linker. The prodrugs were prepared according to a three‐step sequence involving (i) N‐alkylation with chloromethoxy‐triisopropylsilane; (ii) desilylation; and (iii) acylation with trisnorsqualenic acid. These squalenoyl prodrugs were found to self‐assemble into nanoassemblies in aqueous media without the need for any surfactant. The nanosized aggregates were characterized by dynamic light scattering and transmission electron microscopy, and appeared to be stable in water for several days, as determined by particle‐size measurement. In vitro biological studies showed that squalenoyl sunitinib nanoassemblies are notably cytotoxic against the human umbilical vein endothelial cell line (HUVEC), which is involved in the tumor vessel formation.