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Title

Epidithiodiketopiperazines : strain-promoted thiol-mediated cellular uptake at the highest tension
Authors
Zong, Lili
Bartolami, Eline
Abegg, Daniel
Adibekian, Alexander
Sakai, Naomi
Matile, Stefan
Published in ACS Central Science. 2017, vol. 3, no. 5, p. 449-453
Abstract The disulfide dihedral angle in epidithiodiketopiperazines (ETPs) is near 0°. Application of this highest possible ring tension to strain-promoted thiol-mediated uptake results in efficient delivery to the cytosol and nucleus. Compared to the previous best asparagusic acid (AspA), ring-opening disulfide exchange with ETPs occurs more efficiently even with nonactivated thiols, and the resulting thiols exchange rapidly with nonactivated disulfides. ETP-mediated cellular uptake is more than 20 times more efficient compared to AspA, occurs without endosomal capture, depends on temperature, and is “unstoppable” by inhibitors of endocytosis and conventional thiol-mediated uptake, including siRNA against the transferrin receptor. These results suggest that ETP-mediated uptake not only maximizes delivery to the cytosol and nucleus but also opens the door to a new multitarget hopping mode of action.
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Article (Published version) (2.8 MB) - public document Free access
Structures
Faculté des sciences / Section de chimie et biochimie / Département de chimie organique
Research groups Groupe Matile
Groupe Adibekian
Citation
(ISO format) 		ZONG, Lili et al. Epidithiodiketopiperazines : strain-promoted thiol-mediated cellular uptake at the highest tension. In: ACS Central Science, 2017, vol. 3, n° 5, p. 449-453. doi: 10.1021/acscentsci.7b00080 https://archive-ouverte.unige.ch/unige:95404

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Deposited on : 2017-07-12

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