Self‐Delivery Nanoparticles of Amphiphilic Acyclic Enediynes for Efficient Tumor Cell Suppression

Abstract

Summary of main observation and conclusion Four acyclic maleimide‐based enediyne compounds with different hydrophilicity were synthesized through Sonogashira reaction to reveal a self‐delivery antitumor drug platform. As proved by ESR analysis, the enediyne compounds undergo Bergman‐like cyclization and generate diradical intermediates at physiological temperature, which are able to induce DNA‐cleavage through the abstraction of H atoms from the sugar‐phosphate backbones. When the critical aggregation concentration is reached in water, the amphiphilic enediyne compounds self‐assemble into nanoparticles and possess the self‐delivery ability to be facilely admitted by tumor cells, resulting in greatly improved cytotoxicity (IC50 down to 10 μmol·L–1) and much higher tumor cell apoptosis rate (up to 86.6%) in comparison with either the hydrophilic or the lipophilic enediyne compound. The enhanced endocytosis of the amphiphilic enediyne compounds was further confirmed through confocal laser scanning microscopy analysis. The unveiled relationship between the hydrophilicity of enediyne drugs and their therapeutic efficacy will provide a guideline for the design of new self‐delivery drugs employed in medicinal applications.

Coordination‐Accelerated Radical Formation from Acyclic Enediynes for Tumor Cell Suppression

“…Meanwhile, the charge separation assistance in the metal‐ion‐catalyzed Bergman cyclization should not be excluded as well . Nevertheless, this study confirmed that the metalloenediyne EDY‐Cu is highly reactive towards spontaneous cycloaromatization at physiological temperature to produce free diradicals, endowing it with the ability of DNA cleavage and tumor cell suppression as discussed below.…”

“…We also found that the cycloaromatization activities of the enediyne compounds could be regulated by simply adjusting the functional groups at the alkyne termini in order to realize the generation of free diradicals at low temperature . These maleimide‐based enediynes showed strong DNA‐cleavage and tumor cell suppression activities . Furthermore, substituent modifications at the maleimide moiety were applied in tailored synthesis of enediyne compounds employed in drug conjugates and drug delivery .…”

“…These maleimide‐based enediynes showed strong DNA‐cleavage and tumor cell suppression activities . Furthermore, substituent modifications at the maleimide moiety were applied in tailored synthesis of enediyne compounds employed in drug conjugates and drug delivery . By combining the electron‐withdrawing effect of maleimide moiety at the ene position and the metal coordination at alkyne termini, herein, we propose a new strategy for the synthesis of highly reactive metalloenediyne.…”

“…[14b,c, 15] Furthermore,s ubstituent modifications at the maleimidem oiety were applied in tailored synthesis of enediyne compounds employed in drug conjugates [16] and drug delivery. [15,17] By combining the electron-withdrawinge ffect of maleimide moiety at the ene positiona nd the metal coordination at alkyne termini, herein, we propose an ew strategy for the synthesis of highly reactive metalloenediyne. The enediyne compound with salicylaldiminato groupss howedl ow cycloaromatization activity and no DNA-cleavage ability.O nt he contrary,o nce chelated with metal ions at the alkyne termini, the thermalr eaction was accelerated as demonstrated by differential scanning calorimetry (DSC) experiment.…”