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Article: Dynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage

TitleDynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage
Authors
Issue Date2018
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html
Citation
Journal of the American Chemical Society, 2018, v. 140 n. 46, p. 15957-15968 How to Cite?
AbstractDevelopment of versatile, chemically tunable photocages for photoactivated chemotherapy (PACT) represents an excellent opportunity to address the technical drawbacks of conventional photodynamic therapy (PDT) whose oxygen-dependent nature renders it inadequate in certain therapy contexts such as hypoxic tumors. As an alternative to PDT, oxygen free mechanisms to generate cytotoxic reactive oxygen species (ROS) by visible light cleavable photocages are in demand. Here, we report the detailed mechanisms by which the small molecule blebbistatin acts as a one-photon blue light-gated or two-photon near-infrared light-gated photocage to directly release a hydroxyl radical (•OH) in the absence of oxygen. By using femtosecond transient absorption spectroscopy and chemoselective ROS fluorescent probes, we analyze the dynamics and fate of blebbistatin during photolysis under blue light. Water-dependent photochemistry reveals a critical process of water-assisted protonation and excited state intramolecular proton transfer (ESIPT) that drives the formation of short-lived intermediates, which surprisingly culminates in the release of •OH but not superoxide or singlet oxygen from blebbistatin. CASPT2//CASSCF calculations confirm that hydrogen bonding between water and blebbistatin underpins this process. We further determine that blue light enables blebbistatin to induce mitochondria-dependent apoptosis, an attribute conducive to PACT development. Our work demonstrates blebbistatin as a controllable photocage for •OH generation and provides insight into the potential development of novel PACT agents. © 2018 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/279292
ISSN
2017 Impact Factor: 14.357
2015 SCImago Journal Rankings: 7.123
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, M-
dc.contributor.authorWong, NK-
dc.contributor.authorXiao, J-
dc.contributor.authorZhu, R-
dc.contributor.authorWu, L-
dc.contributor.authorDai, SY-
dc.contributor.authorChen, F-
dc.contributor.authorHuang, G-
dc.contributor.authorXu, L-
dc.contributor.authorBai, X-
dc.contributor.authorGeraskina, MR-
dc.contributor.authorWinter, AH-
dc.contributor.authorChen, X-
dc.contributor.authorLiu, Y-
dc.contributor.authorFang, W-
dc.contributor.authorYang, D-
dc.contributor.authorPhillips, DL-
dc.date.accessioned2019-10-25T02:23:35Z-
dc.date.available2019-10-25T02:23:35Z-
dc.date.issued2018-
dc.identifier.citationJournal of the American Chemical Society, 2018, v. 140 n. 46, p. 15957-15968-
dc.identifier.issn0002-7863-
dc.identifier.urihttp://hdl.handle.net/10722/279292-
dc.description.abstractDevelopment of versatile, chemically tunable photocages for photoactivated chemotherapy (PACT) represents an excellent opportunity to address the technical drawbacks of conventional photodynamic therapy (PDT) whose oxygen-dependent nature renders it inadequate in certain therapy contexts such as hypoxic tumors. As an alternative to PDT, oxygen free mechanisms to generate cytotoxic reactive oxygen species (ROS) by visible light cleavable photocages are in demand. Here, we report the detailed mechanisms by which the small molecule blebbistatin acts as a one-photon blue light-gated or two-photon near-infrared light-gated photocage to directly release a hydroxyl radical (•OH) in the absence of oxygen. By using femtosecond transient absorption spectroscopy and chemoselective ROS fluorescent probes, we analyze the dynamics and fate of blebbistatin during photolysis under blue light. Water-dependent photochemistry reveals a critical process of water-assisted protonation and excited state intramolecular proton transfer (ESIPT) that drives the formation of short-lived intermediates, which surprisingly culminates in the release of •OH but not superoxide or singlet oxygen from blebbistatin. CASPT2//CASSCF calculations confirm that hydrogen bonding between water and blebbistatin underpins this process. We further determine that blue light enables blebbistatin to induce mitochondria-dependent apoptosis, an attribute conducive to PACT development. Our work demonstrates blebbistatin as a controllable photocage for •OH generation and provides insight into the potential development of novel PACT agents. © 2018 American Chemical Society.-
dc.languageeng-
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html-
dc.relation.ispartofJournal of the American Chemical Society-
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in [JournalTitle], copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/page/policy/articlesonrequest/index.html].-
dc.titleDynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage-
dc.typeArticle-
dc.identifier.emailDai, SY: sydai@hku.hk-
dc.identifier.emailBai, X: xybai89@hku.hk-
dc.identifier.emailYang, D: yangdan@hku.hk-
dc.identifier.emailPhillips, DL: phillips@hku.hk-
dc.identifier.authorityYang, D=rp00825-
dc.identifier.authorityPhillips, DL=rp00770-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/jacs.8b10235-
dc.identifier.pmid30269478-
dc.identifier.scopuseid_2-s2.0-85056525546-
dc.identifier.hkuros308135-
dc.identifier.volume140-
dc.identifier.issue46-
dc.identifier.spage15957-
dc.identifier.epage15968-
dc.identifier.isiWOS:000451496800055-
dc.publisher.placeUnited States-

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