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 concentr… Show more
“…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.…”
Section: Resultsmentioning
confidence: 50%
“…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 .…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…[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.…”
A maleimide‐based acyclic enediyne with salicylaldiminato substituents at the alkyne termini was synthesized, which was further chelated with three kinds of metal‐ions, CuII, ZnII, and MgII, and form metalloenediynes. The cycloaromatization of this thermally inactive enediyne ligand was greatly accelerated through the coordination with metal ions. Specifically, the CuII‐metalloenediyne showed an extremely low onset temperature of 55 °C and underwent spontaneous cycloaromatization at ambient temperature to produce free radicals, followed by generation of reactive oxygen species in the physiological environment. The metalloenediyne exhibited excellent DNA cleavage ability and high cytotoxicity towards HeLa cells, with half‐maximal inhibitory concentration values comparable to many commercial antitumor agents. The combination of the electron‐withdrawing effect of the maleimide moiety at the ene position and metal coordination at the yne termini provides a new inspiration for designing and synthesizing highly efficient enediyne antitumor agents.
“…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.…”
Section: Resultsmentioning
confidence: 50%
“…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 .…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…[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.…”
A maleimide‐based acyclic enediyne with salicylaldiminato substituents at the alkyne termini was synthesized, which was further chelated with three kinds of metal‐ions, CuII, ZnII, and MgII, and form metalloenediynes. The cycloaromatization of this thermally inactive enediyne ligand was greatly accelerated through the coordination with metal ions. Specifically, the CuII‐metalloenediyne showed an extremely low onset temperature of 55 °C and underwent spontaneous cycloaromatization at ambient temperature to produce free radicals, followed by generation of reactive oxygen species in the physiological environment. The metalloenediyne exhibited excellent DNA cleavage ability and high cytotoxicity towards HeLa cells, with half‐maximal inhibitory concentration values comparable to many commercial antitumor agents. The combination of the electron‐withdrawing effect of the maleimide moiety at the ene position and metal coordination at the yne termini provides a new inspiration for designing and synthesizing highly efficient enediyne antitumor agents.
Great efforts have been dedicated to studying the thermal-induced Myers-Saito cyclization (MSC) of enyneallene as the resulting diradicals hold significant potential in various fields, especially in antitumor applications. Besides abstracting hydrogen from DNA backbone and further inducing tumor cell death, the diradicals might react through multiple pathways and lose their efficiency in antitumor applications. The in-depth understanding of the reaction pattern of these highly reactive diradical intermediates will provide clear guidelines for the design of new enyne-allene with high antitumor potency. Herein, we report detailed studies to reveal the reaction mechanism of ketal-conjugated enediynes, which are hydrolyzed and tautomerized into enyne-allene structures in acidic condition and produce diradicals through MSC. Further 1,3-hydrogen atom transfer (HAT)/6-endo cyclization to yield pyran-type product or 5endo cyclization/1,4-HAT to yield furan-type product were confirmed and rationalized through computational studies. The proposed reaction pathways were further verified with deuterium labeling experiments. Based on these new findings, a new enediyne with asymmetric structure and tertbutyl group to block the HAT process was synthesized, which demonstrated much higher cytotoxicity against the HeLa cell line with a half inhibition concentration (IC 50 value) down to submicromolar level.
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