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Synthesis and Cytotoxic Activity of Self‐Assembling Squalene Conjugates of 3‐[(Pyrrol‐2‐yl)methylidene]‐2,3‐dihydro‐1 H ‐indol‐2‐one Anticancer Agents
Author(s) -
Buchy Eric,
Valetti Sabrina,
Mura Simona,
Mougin Julie,
Troufflard Claire,
Couvreur Patrick,
Desmaële Didier
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201403088
Subject(s) - chemistry , prodrug , hemiaminal , linker , oxindole , conjugate , cytotoxicity , in vitro , stereochemistry , human umbilical vein endothelial cell , combinatorial chemistry , squalene , biochemistry , umbilical vein , mathematical analysis , mathematics , computer science , catalysis , operating system
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.