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Facilitating Myers-Saito Cyclization through Acid-Triggered Tautomerization for the Development of Maleimide-Based Antitumor Agents

Abstract

Enyne-allene compounds undergo Myers-Saito cyclization at physiological temperature to generate diradical intermediates that are capable of inducing DNA damage and cell death. The high reactivity of enyne-allene however limits their promising prospect as anticancer agents due to the spontaneous cyclization during storage and delivery. Regulating the cyclization process by taking advantage of the characteristics of tumor cellular microenvironment, such as employing the low pH value to activate the cyclization process, is thus of essential importance. In this work, a novel enediyne (EDY) system with locked carbonyl groups was specifically designed and synthesized. Unlocking the protected carbonyl groups in the presence of acid would facilitate the rearrangement of propargyl moiety into allene group, enabling the formation of enyne-allene structure and occurrence of Myers-Saito cyclization. The pH-dependent diradical generation and DNA-cleavage ability of the designed EDY system were confirmed by electron paramagnetic resonance analysis and DNA gel electrophoresis. A promising cytotoxicity against Hela cells with half inhibition concentrations (IC50) as low as 1.4 M was obtained, which was comparable to many commercially applied anticancer drugs. Further in vitro experiments revealed that this EDY system induced intracellular DNA damage and subsequently resulted in S-phase arrest and cytotoxicity through programmed apoptosis.

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Supplementary files

Article information


Submitted
17 Nov 2019
Accepted
28 Jan 2020
First published
30 Jan 2020

J. Mater. Chem. B, 2020, Accepted Manuscript
Article type
Paper

Facilitating Myers-Saito Cyclization through Acid-Triggered Tautomerization for the Development of Maleimide-Based Antitumor Agents

H. Lu, H. Ma, B. Li, M. Zhang, H. Chen, Y. Wang, X. Li, Y. Ding and A. Hu, J. Mater. Chem. B, 2020, Accepted Manuscript , DOI: 10.1039/C9TB02589H

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