856925-72-9Relevant academic research and scientific papers
Dynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage
Li, Ming-De,Wong, Nai-Kei,Xiao, Jia,Zhu, Ruixue,Wu, Liangliang,Dai, Sheng-Yao,Chen, Feng,Huang, Guanheng,Xu, Liang,Bai, Xiaoyu,Geraskina, Margarita R.,Winter, Arthur H.,Chen, Xuebo,Liu, Yingxia,Fang, Weihai,Yang, Dan,Phillips, David Lee
, p. 15957 - 15968 (2018)
Development 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.
Discovery of (S)-3′-hydroxyblebbistatin and (S)-3′-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties
Verhasselt, Sigrid,Roman, Bart I.,De Wever, Olivier,Van Hecke, Kristof,Van Deun, Rik,Bracke, Marc E.,Stevens, Christian V.
, p. 2104 - 2118 (2017/03/11)
In search of myosin II inhibitors with superior research tool properties, a chemical optimization campaign of the blebbistatin scaffold was conducted in this paper. (S)-Blebbistatin is the best known small-molecule inhibitor of myosin II ATPase activity. Unfortunately, as a research tool this compound has several deficiencies: it is photolabile and (photo)toxic, has low water solubility, and its (fluorescent) precipitates interfere in (fluorescence) readouts. In view of obtaining tool compounds with improved properties, both enantiomers of a series of D-ring modified polar analogs were prepared. We identified (S)-3′-hydroxyblebbistatin (S)-2 and (S)-3′-aminoblebbistatin (S)-3 as two myosin II inhibitors with a 30-fold higher water solubility than (S)-blebbistatin. These molecules furthermore do not cause interference in (fluorescence) readouts. (S)-2 and (S)-3 thus are superior alternatives to (S)-blebbistatin as research tools to study myosin II.
Improved synthesis and comparative analysis of the tool properties of new and existing D-ring modified (S)-blebbistatin analogs
Verhasselt, Sigrid,Roman, Bart I.,Bracke, Marc E.,Stevens, Christian V.
, p. 85 - 103 (2017/05/10)
(S)-Blebbistatin is a widely used research tool to study myosin II, an important regulator of many motility based diseases. Its potency is too low to be of clinical relevance, but identification of analogs with enhanced potency could deliver leads for tar
Absolute stereochemical assignment and fluorescence tuning of the small molecule tool, (-)-blebbistatin
Lucas-Lopez, Cristina,Patterson, Stephen,Blum, Till,Straight, Aaron F.,Toth, Judit,Slawin, Alexandra M. Z.,Mitchison, Timothy J.,Sellers, James R.,Westwood, Nicholas J.
, p. 1736 - 1740 (2007/10/03)
(-)-Blebbistatin (1), a recently discovered small molecule inhibitor of the ATPase activity of non-muscle myosin II has been prepared from methyl 5-methylanthranilate (6) in three steps. This flexible synthetic route has also been used to prepare a nitro
