Synthesis and Cytotoxic Activity of Self‐Assembling Squalene Conjugates of 3‐[(Pyrrol‐2‐yl)methylidene]‐2,3‐dihydro‐1H‐indol‐2‐one Anticancer Agents

Abstract

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.

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

“…Preparation of nanoassemblies from GemSQ and GemSQ- d 6 : In a similar manner to the procedure published [ 19 ] the prodrugs based nanoparticle suspensions (2 mg·mL −1 ) were prepared in a single step by dropwise addition of an ethanol solution (4 mg·mL −1 ) in milli-Q water (1 mL) under vigorous stirring (500 rpm). Formation of NAs occurred immediately.…”

“…More notably, squalenoylation of adenosine and the subsequent formation of NAs, allowed prolonged circulation of this nucleoside, providing neuroprotection in mice with induced focal cerebral ischemia and in rats undergoing spinal cord injury [ 16 ]. Interestingly, the “squalenisation platform” initially developed with highly hydrophilic therapeutics has been further extended to hydrophobic drugs such as beta-lactam antibiotics [ 17 ], paclitaxel [ 18 ], indolinone kinase inhibitors [ 19 ] or doxorubicin [ 20 ].…”

Self-assembly drug conjugates for anticancer treatment

“…An innovative self-delivery system in which drugs can be delivered by themselves without any carrier was developed by Huang et al An amphiphilic drug-drug conjugate, consisting of the hydrophilic anticancer drug irinotecan (19) and hydrophobic anticancer drug chlorambucil (20) has been synthesized and demonstrated to be able to self-assemble in water to form NPs with a diameter of about 88 nm. As a result of the presence of an ester bond between the two drugs, the amphiphilic conjugate was able to release both the compounds after the hydrolysis of this bond in the tumor cells [43].…”

“…The NPs obtained by the covalent linkage of these compounds with squalene were biologically evaluated on human umbilical vein endothelial cells (HUVECs), demonstrating that squalenoyl-sunitinib conjugate NPs showed notable cytotoxicity whereas semaxanib NPs were not active [19]. In addition, sunitinib NPs showed moderate cytotoxic activity against Mia Paca2 pancreatic cancer cells.…”

“…The water-soluble drug irinotecan (19), a camptothecin derivative and a potent DNA topoisomerase I inhibitor, and the water-insoluble chlorambucil (20), a DNA alkylating anticancer drug, were used to form an amphiphilic conjugate by an esterification reaction [43]. The NPs obtained were biologically evaluated using MCF-7 and HeLa cell lines.…”