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Medicinal chemistry and use of myosin II inhibitor (S)-blebbistatin and its derivatives

Bart Roman (UGent) , Sigrid Verhasselt (UGent) and Christian Stevens (UGent)
(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(21). p.9410-9428
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Abstract
(S)-Blebbistatin, a chiral tetrahydropyrroloquinolinone, is a widely used and well-characterized ATPase inhibitor selective for myosin II. The central role of myosin II in many normal and pathological biological processes has been revealed with the aid of this small molecule. The first part of this manuscript provides a summary of myosin II and (S)-blebbistatin literature from a medicinal chemist's perspective. The second part of this perspective deals with the physicochemical deficiencies that trouble the use of (S)-blebbistatin in advanced biological settings: low potency and solubility, fluorescence interference, (photo)toxicity, and stability issues. A large toolbox of analogues has been developed in which particular shortcomings have been addressed. This perspective provides a necessary overview of these developments and presents guidelines for selecting the best available analogue for a given application. As the unmet need for high-potency analogues remains, we also propose starting points for medicinal chemists in search of nanomolar myosin II inhibitors.
Keywords
SMOOTH-MUSCLE MYOSIN, SMALL-MOLECULE TOOL, NONMUSCLE MYOSIN, BLEBBISTATIN INHIBITION, GLIOMA INVASION, MOTOR DOMAIN, CANCER-CELLS, LIGHT-CHAIN, BLUE-LIGHT, CONTRACTION

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Citation

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MLA
Roman, Bart, Sigrid Verhasselt, and Christian Stevens. “Medicinal Chemistry and Use of Myosin II Inhibitor (S)-blebbistatin and Its Derivatives.” JOURNAL OF MEDICINAL CHEMISTRY 61.21 (2018): 9410–9428. Print.
APA
Roman, B., Verhasselt, S., & Stevens, C. (2018). Medicinal chemistry and use of myosin II inhibitor (S)-blebbistatin and its derivatives. JOURNAL OF MEDICINAL CHEMISTRY, 61(21), 9410–9428.
Chicago author-date
Roman, Bart, Sigrid Verhasselt, and Christian Stevens. 2018. “Medicinal Chemistry and Use of Myosin II Inhibitor (S)-blebbistatin and Its Derivatives.” Journal of Medicinal Chemistry 61 (21): 9410–9428.
Chicago author-date (all authors)
Roman, Bart, Sigrid Verhasselt, and Christian Stevens. 2018. “Medicinal Chemistry and Use of Myosin II Inhibitor (S)-blebbistatin and Its Derivatives.” Journal of Medicinal Chemistry 61 (21): 9410–9428.
Vancouver
1.
Roman B, Verhasselt S, Stevens C. Medicinal chemistry and use of myosin II inhibitor (S)-blebbistatin and its derivatives. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(21):9410–28.
IEEE
[1]
B. Roman, S. Verhasselt, and C. Stevens, “Medicinal chemistry and use of myosin II inhibitor (S)-blebbistatin and its derivatives,” JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 21, pp. 9410–9428, 2018.
@article{8565155,
  abstract     = {(S)-Blebbistatin, a chiral tetrahydropyrroloquinolinone, is a widely used and well-characterized ATPase inhibitor selective for myosin II. The central role of myosin II in many normal and pathological biological processes has been revealed with the aid of this small molecule. The first part of this manuscript provides a summary of myosin II and (S)-blebbistatin literature from a medicinal chemist's perspective. The second part of this perspective deals with the physicochemical deficiencies that trouble the use of (S)-blebbistatin in advanced biological settings: low potency and solubility, fluorescence interference, (photo)toxicity, and stability issues. A large toolbox of analogues has been developed in which particular shortcomings have been addressed. This perspective provides a necessary overview of these developments and presents guidelines for selecting the best available analogue for a given application. As the unmet need for high-potency analogues remains, we also propose starting points for medicinal chemists in search of nanomolar myosin II inhibitors.},
  author       = {Roman, Bart and Verhasselt, Sigrid and Stevens, Christian},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keywords     = {SMOOTH-MUSCLE MYOSIN,SMALL-MOLECULE TOOL,NONMUSCLE MYOSIN,BLEBBISTATIN INHIBITION,GLIOMA INVASION,MOTOR DOMAIN,CANCER-CELLS,LIGHT-CHAIN,BLUE-LIGHT,CONTRACTION},
  language     = {eng},
  number       = {21},
  pages        = {9410--9428},
  title        = {Medicinal chemistry and use of myosin II inhibitor (S)-blebbistatin and its derivatives},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.8b00503},
  volume       = {61},
  year         = {2018},
}

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