Blebbistatin
Names
IUPAC name
3a-Hydroxy-6-methyl-1-phenyl-2,3-dihydropyrrolo[2,3-b]quinolin-4-one
Other names
(S)-Blebbistatin, (-)-Blebbistatin
Identifiers
3D model (JSmol)
UNII
  • CC1=CC2=C(C=C1)N=C3C(C2=O)(CCN3C4=CC=CC=C4)O
Properties
C18H16N2O2
Molar mass 292.338 g·mol−1
Appearance Yellow solid
10 μM
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Blebbistatin is a myosin inhibitor mostly specific for myosin II.[1][2] It is widely used in research to inhibit heart muscle myosin, non-muscle myosin II, and skeletal muscle myosin. Blebbistatin has been especially useful in optical mapping of the heart,[3] and its recent use in cardiac muscle cell cultures has improved cell survival time.[4][5] However, its adverse characteristics e.g. its cytotoxicity and blue-light instability or low solubility in water often make its application challenging.[6][7] Recently its applicability was improved by chemical design and its derivatives overcome the limitations of blebbistatin.[2][8] E.g. para-nitroblebbistatin and para-aminoblebbistatin are photostable, and they are neither cytotoxic nor fluorescent.[7][9]

Mode of action and biological effects

Blebbistatin inhibits myosin ATPase activity and this way acto-myosin based motility. It binds halfway between the nucleotide binding pocket and the actin binding cleft of myosin, predominantly in an actin detached conformation.[10] This type of inhibition relaxes the acto-myosin myofilaments and leads to several biological effects.

Blebbistatin inhibits the formation of blebs in melanoma cell culture,[11] hence its name. At a cellular level, blebbistatin also inhibits cytokinesis[11] and may also disrupt mitotic spindle formation.[12] Migration of cells can be either enhanced or inhibited depending on other conditions.[13] In neurons, blebbistatin was found to promote neurite outgrowth.[14] At the organ level blebbistatin stops the contraction of skeletal muscle[15] or heart muscle.[16] Blebbistatin has also been found to stabilize the super relaxed state in the myofilaments, where myosin heads are in a helical order and interact with each other but not with actin.[17][18][19]

Adverse characteristics

A number of physicochemical deficiencies hamper the use of blebbistatin as a chemical tool in particular applications.[2]

Photo-instability

Upon blue light illumination, blebbistatin becomes inactive and phototoxic due to changes in the structure of the compound accompanied by the generation of ROS [20][6][21]

Fluorescence

Blebbistatin is a relatively strong fluorophore. When dissolved in water, it absorbs at 420 nm and emits at 490 nm however in DMSO or when perfused through cardiac tissue, it absorbs around 430 nm and emits around 560 nm,[22] therefore at high concentrations its fluorescence interferes with GFP imaging or FRET experiments.[7] Reduction of the concentration of blebbistatin to 6.25 uM allows for FRET imaging in isolated adult mouse cardiac muscle cells.[5]

Cytotoxicity

Long-term incubation with blebbistatin results in cell damage and cytotoxicity, which are independent of the myosin inhibitory effect.

This photo-instability, phototoxicity and fluorescence makes in-vivo imaging of blebbistatin-treated samples impossible.

Myosin specificity

Blebbistatin is a potent inhibitor of nonmuscle myosin IIA and IIB, cardiac myosin, skeletal myosin and smooth muscle but does not inhibit myosin I, V and X.[23][24][25] The table below summarizes IC50 data of blebbistatin on different myosin isoforms.

species myosin isoform or muscle type assay type IC50
Dictyostelium discoideum myosin II motor domain basal ATPase 2.96 ± 0.45 μM,[7] 4.4 ± 0.3 μM,[9] 4.9 μM[23]
Dictyostelium discoideum myosin II motor domain actin activated ATPase 3.9 ± 0.3 μM[9]
Rabbit skeletal muscle II basal ATPase 0.50 μM,[23] 0.3 ± 0.03 μM,[9] 0.41 ± 0.03 μM [7]
Rabbit skeletal muscle II actin activated ATPase 0.11 ± 0.009 μM[9]
Porcine b-cardiac muscle basal ATPase 1.2 μM[23]
Scallop striated muscle basal ATPase 2.3 μM[23]
Human nonmuscle IIA basal ATPase 5.1 μM[23]
Chicken nonmuscle IIB basal ATPase 1.8 μM[23]
Human nonmuscle IIA actin activated ATPase 3.58 μM[26]
Human nonmuscle IIB actin activated ATPase 2.30 μM[26]
Mouse nonmuscle IIC actin activated ATPase 1.57 μM[26]
Turkey smooth muscle basal ATPase 79.6 μM[23]
Acanthamoeba myosin II basal ATPase 83 μM[23]
Rat myosin 1B basal ATPase >150 μM[23]
Acanthamoeba myosin IC basal ATPase >150 μM[23]
Mouse myosin V basal ATPase >150 μM[23]
Bovine myosin X basal ATPase >150 μM[23]
smooth muscle myosin IIA heavy-chain actin activated ATPase 3 μM[24]
smooth muscle myosin IIB heavy-chain actin activated ATPase 3 μM[24]
Rabbit femoral, renal and saphenous artery tonic contraction 5 μM[24]
Chicken gizzard contraction 20 μM[24]
Chicken gizzard smooth muscle HMM basal ATPase 15 ± 0.6 μM[27]
Chicken gizzard smooth muscle actin activated ATPase 6.47 μM[26]
Rat bladder contraction 100% inhibition at 15 μM[28]
Mouse intact paced cardiac papillary muscle contraction 1.3 μM[29]
Mouse Ca2+-activated, permeabilized cardiac papillary muscle contraction 2.8 μM[29]
Rat skinned cardiac trabeculae Ca2+ activated force 0.38 ± 0.03 μM[15]
Rat native demembranated right ventricular trabeculae isometric force development 3.17 ± 0.43 μM[30]
Drosophila nonmuscle myosin-2 actin activated ATPase no inhibition[31]
Drosophila nonmuscle myosin-2 M466I mutation actin activated ATPase 36.3 ± 4.1 μM[31]
Drosophila cardiac tubes heart wall motion 100 μM resulted in full inhibition[32]
Starfish nonmuscle myosin-2 oocyte cytokinesis effective at 300 μM[33]
C. elegans nonmuscle myosin-2 acto-myosin colocalization microscopy effective at 100 μM [34]
C. elegans nonmuscle myosin-2 ventral enclosure effective at 100 μM[35]
Podocoryna carnea (cnidarian) nonmuscle myosin-2 stolon tip pulsations and gastrovascular flow effective at 255 μM[36]

Derivatives

The main aims of the structure-activity relationship work on the blebbistatin scaffold are the improvement of the physicochemical properties and the ATPase inhibitory potency, for use as chemical or pharmacological tools. Several analogs with superior properties have been developed, and guidelines for their optimal use have been described.[2][8]

para-Nitroblebbistatin

2D structure of para-nitroblebbistatin

A non-fluorescent, non-phototoxic, non-cytotoxic derivative developed in 2014.[7] Its myosin inhibitory properties are similar to those of blebbistatin (for rabbit skeletal muscle myosin S1 IC50=0.4 μM, for Dictyostelium discoideum myosin II motor domain IC50=2.3 μM, for human β-cardiac myosin subfragment 1 IC50=13 μM,[37] for heavy meromyosin fragment of chicken skeletal muscle myosin IC50=0.4 μM[37]). It has been successfully used in fluorescent imaging experiments involving myosin IIA-GFP expressing live dendritic cells[38]

para-Aminoblebbistatin

2D structure of para-aminoblebbistatin

A water-soluble blebbistatin derivative developed in 2016,[9] its high water solubility (~400 uM) enables in vivo research applications. Para-aminoblebbistatin is a slightly weaker myosin inhibitor than blebbistatin (for rabbit skeletal muscle myosin S1 IC50=1.3 μM, for Dictyostelium discoideum myosin II motor domain IC50=6.6 μM with only 90% maximal inhibition), it is non-fluorescent, photostable, neither cytotoxic nor phototoxic.

Azidoblebbistatin

A photoreactive myosin inhibitor developed in 2012.[39] A permanent inhibition of myosin may be achieved by covalently crosslinking the inhibitor azidoblebbistatin to its target by photoaffinity labeling (PAL). Briefly, upon UV illumination, the aryl-azide moiety in azidoblebbistatin forms a reactive nitrene.[40] This reaction is utilized to form covalent link between the inhibitor and myosin.

Azidoblebbistatin is also sensitive to two-photon irradiation, i.e. the covalent crosslink may also be generated by two-photon excitation microscope, therefore azidoblebbistatin is suitable for molecular tattooing.[41]

(S)-Nitroblebbistatin

This derivative was developed in 2005 to increase the photostability and decrease the fluorescence of blebbistatin.[42] (S)-nitro-blebbistatin is indeed stable to prolonged irradiation at 450-490 nm and has been successfully used in fluorescent live cell imaging.[43] However its affinity to myosin significantly decreased with the nitro-substitution (for nonmuscle myosin IIA, the IC50 = 27 μM).[42] In many cases due to the low solubility, it is not possible to achieve full inhibition of myosin with (S)-nitro-blebbistatin. It is effective for FRET imaging of isolated adult mouse cardiac muscle cells.[5]

(+)-Blebbistatin

(+)-Blebbistatin (or (R)-blebbistatin) is the inactive enantiomer of blebbistatin[1] which inhibits the ATPase activity by maximum 10%.[44] In research, it is useful compound for control treatment, to check the non-myosin related toxic effects of blebbistatin.

Other derivatives

The blebbistatin scaffold has been modified in several ways to optimize myosin isoform specificity or to improve the inhibitory properties and to map the structure-activity relationship. Major steps in the optimization include the work of Lucas-Lopez et al. from 2008[45] and the works of Verhasselt et al. from 2017.[46][47][48][49] The latter studies also include modifications of the A- and C-rings of the scaffold.

para-Chloroblebbistatin

A photostable, non-fluorescent, phototoxic derivative. Its fluorescence is less than 1% of that of blebbistatin myosin inhibitory properties are similar to those of blebbistatin. It is even more phototoxic than blebbistatin.[7]

References

  1. 1 2 Straight AF, Cheung A, Limouze J, Chen I, Westwood NJ, Sellers JR, Mitchison TJ (March 2003). "Dissecting temporal and spatial control of cytokinesis with a myosin II Inhibitor". Science. 299 (5613): 1743–7. Bibcode:2003Sci...299.1743S. doi:10.1126/science.1081412. PMID 12637748. S2CID 38625401.
  2. 1 2 3 4 Roman BI, Verhasselt S, Stevens CV (June 2018). "Medicinal Chemistry and Use of Myosin II Inhibitor ( S)-Blebbistatin and Its Derivatives". Journal of Medicinal Chemistry. 61 (21): 9410–9428. doi:10.1021/acs.jmedchem.8b00503. PMID 29878759.
  3. ↑ Swift LM, Asfour H, Posnack NG, Arutunyan A, Kay MW, Sarvazyan N (November 2012). "Properties of blebbistatin for cardiac optical mapping and other imaging applications". Pflügers Archiv. 464 (5): 503–12. doi:10.1007/s00424-012-1147-2. PMC 3586237. PMID 22990759.
  4. ↑ Kabaeva Z, Zhao M, Michele DE (April 2008). "Blebbistatin extends culture life of adult mouse cardiac myocytes and allows efficient and stable transgene expression". American Journal of Physiology. Heart and Circulatory Physiology. 294 (4): H1667–74. doi:10.1152/ajpheart.01144.2007. PMID 18296569.
  5. 1 2 3 Reddy GR, West TM, Jian Z, Jaradeh M, Shi Q, Wang Y, Chen-Izu Y, Xian g YK (2018-09-21). "Illuminating cell signaling with genetically encoded FRET biosensors in adult mouse cardiomyocytes". The Journal of General Physiology. 150 (11): 1567–1582. doi:10.1085/jgp.201812119. PMC 6219686. PMID 30242036.
  6. 1 2 Kolega J (July 2004). "Phototoxicity and photoinactivation of blebbistatin in UV and visible light". Biochemical and Biophysical Research Communications. 320 (3): 1020–5. doi:10.1016/j.bbrc.2004.06.045. PMID 15240150.
  7. 1 2 3 4 5 6 7 Képiró M, Várkuti BH, Végner L, Vörös G, Hegyi G, Varga M, Málnási-Csizmadia A (July 2014). "para-Nitroblebbistatin, the non-cytotoxic and photostable myosin II inhibitor". Angewandte Chemie. 53 (31): 8211–5. doi:10.1002/anie.201403540. PMID 24954740.
  8. 1 2 Rauscher AÁ, Gyimesi M, Kovács M, Málnási-Csizmadia A (September 2018). "Targeting Myosin by Blebbistatin Derivatives: Optimization and Pharmacological Potential". Trends in Biochemical Sciences. 43 (9): 700–713. doi:10.1016/j.tibs.2018.06.006. PMID 30057142.
  9. 1 2 3 4 5 6 Várkuti BH, Képiró M, Horváth IÁ, Végner L, Ráti S, Zsigmond Á, Hegyi G, Lenkei Z, Varga M, Málnási-Csizmadia A (May 2016). "A highly soluble, non-phototoxic, non-fluorescent blebbistatin derivative". Scientific Reports. 6: 26141. Bibcode:2016NatSR...626141V. doi:10.1038/srep26141. PMC 4886532. PMID 27241904.
  10. ↑ Kovács M, Tóth J, Hetényi C, Málnási-Csizmadia A, Sellers JR (August 2004). "Mechanism of blebbistatin inhibition of myosin II". The Journal of Biological Chemistry. 279 (34): 35557–63. doi:10.1074/jbc.M405319200. hdl:10831/92817. PMID 15205456.
  11. 1 2 Cheung A, Dantzig JA, Hollingworth S, Baylor SM, Goldman YE, Mitchison TJ, Straight AF (January 2002). "A small-molecule inhibitor of skeletal muscle myosin II". Nature Cell Biology. 4 (1): 83–8. doi:10.1038/ncb734. PMID 11744924. S2CID 32475661.
  12. ↑ Rosenblatt J, Cramer LP, Baum B, McGee KM (April 2004). "Myosin II-dependent cortical movement is required for centrosome separation and positioning during mitotic spindle assembly". Cell. 117 (3): 361–72. doi:10.1016/s0092-8674(04)00341-1. PMID 15109496.
  13. ↑ Kamimura M, Scheideler O, Shimizu Y, Yamamoto S, Yamaguchi K, Nakanishi J (June 2015). "Facile preparation of a photoactivatable surface on a 96-well plate: a versatile and multiplex cell migration assay platform". Physical Chemistry Chemical Physics. 17 (21): 14159–67. Bibcode:2015PCCP...1714159K. doi:10.1039/c5cp01499a. PMID 25959431. S2CID 22216223.
  14. ↑ Yu P, Santiago LY, Katagiri Y, Geller HM (March 2012). "Myosin II activity regulates neurite outgrowth and guidance in response to chondroitin sulfate proteoglycans". Journal of Neurochemistry. 120 (6): 1117–28. doi:10.1111/j.1471-4159.2011.07638.x. PMC 3296867. PMID 22191382.
  15. 1 2 Farman GP, Tachampa K, Mateja R, Cazorla O, Lacampagne A, de Tombe PP (March 2008). "Blebbistatin: use as inhibitor of muscle contraction". Pflügers Archiv. 455 (6): 995–1005. doi:10.1007/s00424-007-0375-3. PMID 17994251. S2CID 20503064.
  16. ↑ Fedorov VV, Lozinsky IT, Sosunov EA, Anyukhovsky EP, Rosen MR, Balke CW, Efimov IR (May 2007). "Application of blebbistatin as an excitation-contraction uncoupler for electrophysiologic study of rat and rabbit hearts". Heart Rhythm. 4 (5): 619–26. doi:10.1016/j.hrthm.2006.12.047. PMID 17467631.
  17. ↑ Zhao FQ, Padrón R, Craig R (October 2008). "Blebbistatin stabilizes the helical order of myosin filaments by promoting the switch 2 closed state". Biophysical Journal. 95 (7): 3322–9. Bibcode:2008BpJ....95.3322Z. doi:10.1529/biophysj.108.137067. PMC 2547462. PMID 18599626.
  18. ↑ Xu S, White HD, Offer GW, Yu LC (May 2009). "Stabilization of helical order in the thick filaments by blebbistatin: further evidence of coexisting multiple conformations of myosin". Biophysical Journal. 96 (9): 3673–81. Bibcode:2009BpJ....96.3673X. doi:10.1016/j.bpj.2009.01.049. PMC 2711421. PMID 19413972.
  19. ↑ Wilson C, Naber N, Pate E, Cooke R (October 2014). "The myosin inhibitor blebbistatin stabilizes the super-relaxed state in skeletal muscle". Biophysical Journal. 107 (7): 1637–46. Bibcode:2014BpJ...107.1637W. doi:10.1016/j.bpj.2014.07.075. PMC 4190596. PMID 25296316.
  20. ↑ Sakamoto T, Limouze J, Combs CA, Straight AF, Sellers JR (January 2005). "Blebbistatin, a myosin II inhibitor, is photoinactivated by blue light". Biochemistry. 44 (2): 584–8. doi:10.1021/bi0483357. PMID 15641783.
  21. ↑ Mikulich A, Kavaliauskiene S, Juzenas P (July 2012). "Blebbistatin, a myosin inhibitor, is phototoxic to human cancer cells under exposure to blue light". Biochimica et Biophysica Acta (BBA) - General Subjects. 1820 (7): 870–7. doi:10.1016/j.bbagen.2012.04.003. PMID 22507270.
  22. ↑ Swift LM, Asfour H, Posnack NG, Arutunyan A, Kay MW, Sarvazyan N (November 2012). "Properties of blebbistatin for cardiac optical mapping and other imaging applications". Pflügers Archiv. 464 (5): 503–12. doi:10.1007/s00424-012-1147-2. PMC 3586237. PMID 22990759.
  23. 1 2 3 4 5 6 7 8 9 10 11 12 13 Limouze J, Straight AF, Mitchison T, Sellers JR (2004-01-01). "Specificity of blebbistatin, an inhibitor of myosin II". Journal of Muscle Research and Cell Motility. 25 (4–5): 337–41. doi:10.1007/s10974-004-6060-7. PMID 15548862. S2CID 22355306.
  24. 1 2 3 4 5 Eddinger TJ, Meer DP, Miner AS, Meehl J, Rovner AS, Ratz PH (February 2007). "Potent inhibition of arterial smooth muscle tonic contractions by the selective myosin II inhibitor, blebbistatin". The Journal of Pharmacology and Experimental Therapeutics. 320 (2): 865–70. doi:10.1124/jpet.106.109363. PMID 17132816. S2CID 28556955.
  25. ↑ Yumoto M, Watanabe M (2013). "Blebbistatin, a myosin II inhibitor, suppresses Ca(2+)-induced and "sensitized"-contraction of skinned tracheal muscles from guinea pig". Journal of Smooth Muscle Research = Nihon Heikatsukin Gakkai Kikanshi. 49: 89–98. doi:10.1540/jsmr.49.89. PMC 5137305. PMID 24662474.
  26. 1 2 3 4 Zhang HM, Ji HH, Ni T, Ma RN, Wang A, Li XD (August 2017). "Characterization of Blebbistatin Inhibition of Smooth Muscle Myosin and Nonmuscle Myosin-2". Biochemistry. 56 (32): 4235–4243. doi:10.1021/acs.biochem.7b00311. PMID 28714309.
  27. ↑ Wang HH, Tanaka H, Qin X, Zhao T, Ye LH, Okagaki T, Katayama T, Nakamura A, Ishikawa R, Thatcher SE, Wright GL, Kohama K (May 2008). "Blebbistatin inhibits the chemotaxis of vascular smooth muscle cells by disrupting the myosin II-actin interaction". American Journal of Physiology. Heart and Circulatory Physiology. 294 (5): H2060–8. doi:10.1152/ajpheart.00970.2007. PMID 18296570. S2CID 7063637.
  28. ↑ Zhang X, Seftel A, DiSanto ME (2011-10-07). "Blebbistain, a myosin II inhibitor, as a novel strategy to regulate detrusor contractility in a rat model of partial bladder outlet obstruction". PLOS ONE. 6 (10): e25958. Bibcode:2011PLoSO...625958Z. doi:10.1371/journal.pone.0025958. PMC 3189232. PMID 22016792.
  29. 1 2 Dou Y, Arlock P, Arner A (September 2007). "Blebbistatin specifically inhibits actin-myosin interaction in mouse cardiac muscle". American Journal of Physiology. Cell Physiology. 293 (3): C1148–53. doi:10.1152/ajpcell.00551.2006. PMID 17615158.
  30. ↑ Kampourakis T, Zhang X, Sun YB, Irving M (January 2018). "Omecamtiv mercabil and blebbistatin modulate cardiac contractility by perturbing the regulatory state of the myosin filament". The Journal of Physiology. 596 (1): 31–46. doi:10.1113/jp275050. PMC 5746517. PMID 29052230.
  31. 1 2 Heissler SM, Chinthalapudi K, Sellers JR (April 2015). "Kinetic characterization of the sole nonmuscle myosin-2 from the model organism Drosophila melanogaster". FASEB Journal. 29 (4): 1456–66. doi:10.1096/fj.14-266742. PMC 4396609. PMID 25636739.
  32. ↑ Viswanathan MC, Kaushik G, Engler AJ, Lehman W, Cammarato A (January 2014). "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function". Circulation Research. 114 (2): e6–17. doi:10.1161/CIRCRESAHA.114.302028. PMC 4526186. PMID 24221941.
  33. ↑ Bischof J. "The Molecular Mechanism of Surface Contraction Waves in the Starfish Oocyte" (PDF). The Heidelberg Document Repository.
  34. ↑ Kachur TM, Audhya A, Pilgrim DB (February 2008). "UNC-45 is required for NMY-2 contractile function in early embryonic polarity establishment and germline cellularization in C. elegans". Developmental Biology. 314 (2): 287–99. doi:10.1016/j.ydbio.2007.11.028. PMID 18190904.
  35. ↑ Wernike D. "Studying Ventral Enclosure during C. elegans Epidermal Morphogenesis" (PDF). Concordia University Spectrum Research Repository. Retrieved 31 July 2018.
  36. ↑ Connally N, Anderson CP, Bolton JE, Bolton EW, Buss LW (2015-11-25). "The Selective Myosin II Inhibitor Blebbistatin Reversibly Eliminates Gastrovascular Flow and Stolon Tip Pulsations in the Colonial Hydroid Podocoryna carnea". PLOS ONE. 10 (11): e0143564. Bibcode:2015PLoSO..1043564C. doi:10.1371/journal.pone.0143564. PMC 4659590. PMID 26605798.
  37. 1 2 Tang W, Blair CA, Walton SD, Málnási-Csizmadia A, Campbell KS, Yengo CM (2017). "Modulating Beta-Cardiac Myosin Function at the Molecular and Tissue Levels". Frontiers in Physiology. 7: 659. doi:10.3389/fphys.2016.00659. PMC 5220080. PMID 28119616.
  38. ↑ Chabaud M, Heuzé ML, Bretou M, Vargas P, Maiuri P, Solanes P, Maurin M, Terriac E, Le Berre M, Lankar D, Piolot T, Adelstein RS, Zhang Y, Sixt M, Jacobelli J, Bénichou O, Voituriez R, Piel M, Lennon-Duménil AM (June 2015). "Cell migration and antigen capture are antagonistic processes coupled by myosin II in dendritic cells". Nature Communications. 6: 7526. Bibcode:2015NatCo...6.7526C. doi:10.1038/ncomms8526. PMC 4491822. PMID 26109323.
  39. ↑ Képiró M, Várkuti BH, Bodor A, Hegyi G, Drahos L, Kovács M, Málnási-Csizmadia A (June 2012). "Azidoblebbistatin, a photoreactive myosin inhibitor". Proceedings of the National Academy of Sciences of the United States of America. 109 (24): 9402–7. Bibcode:2012PNAS..109.9402K. doi:10.1073/pnas.1202786109. PMC 3386077. PMID 22647605.
  40. ↑ "Photoreactive Crosslinker Chemistry". Thermo Fischer Scientific.
  41. ↑ Képiró M, Várkuti BH, Rauscher AA, Kellermayer MS, Varga M, Málnási-Csizmadia A (April 2015). "Molecular tattoo: subcellular confinement of drug effects". Chemistry & Biology. 22 (4): 548–558. doi:10.1016/j.chembiol.2015.03.013. PMID 25892202.
  42. 1 2 Lucas-Lopez C, Patterson S, Blum T, Straight AF, Toth J, Slawin AM, Mitchison TJ, Sellers JR, Westwood NJ (2005-05-01). "Absolute Stereochemical Assignment and Fluorescence Tuning of the Small Molecule Tool, (–)-Blebbistatin". European Journal of Organic Chemistry. 2005 (9): 1736–1740. doi:10.1002/ejoc.200500103.
  43. ↑ Ponsaerts R, D'hondt C, Bultynck G, Srinivas SP, Vereecke J, Himpens B (November 2008). "The myosin II ATPase inhibitor blebbistatin prevents thrombin-induced inhibition of intercellular calcium wave propagation in corneal endothelial cells". Investigative Ophthalmology & Visual Science. 49 (11): 4816–27. doi:10.1167/iovs.07-1533. PMID 18614806.
  44. ↑ Lucas-Lopez C. "Supportin information for the article "Absolute Stereochemical Assignment and Fluorescence Tuning of the Small Molecule Tool, (–)-Blebbistatin"" (PDF).
  45. ↑ Lucas-Lopez C, Allingham JS, Lebl T, Lawson CP, Brenk R, Sellers JR, Rayment I, Westwood NJ (June 2008). "The small molecule tool (S)-(-)-blebbistatin: novel insights of relevance to myosin inhibitor design". Organic & Biomolecular Chemistry. 6 (12): 2076–84. doi:10.1039/b801223g. PMC 3758137. PMID 18528569.
  46. ↑ Verhasselt S, Roman BI, De Wever O, Van Hecke K, Van Deun R, Bracke ME, Stevens CV (March 2017). "Discovery of (S)-3'-hydroxyblebbistatin and (S)-3'-aminoblebbistatin: polar myosin II inhibitors with superior research tool properties". Organic & Biomolecular Chemistry. 15 (9): 2104–2118. doi:10.1039/c7ob00006e. hdl:1854/LU-8514040. PMID 28220174.
  47. ↑ Verhasselt S, Roman BI, Bracke ME, Stevens CV (August 2017). "Improved synthesis and comparative analysis of the tool properties of new and existing D-ring modified (S)-blebbistatin analogs". European Journal of Medicinal Chemistry. 136: 85–103. doi:10.1016/j.ejmech.2017.04.072. hdl:1854/LU-8519711. PMID 28486210.
  48. ↑ Verhasselt S, Stevens CV, Van den Broecke T, Bracke ME, Roman BI (July 2017). "Insights into the myosin II inhibitory potency of A-ring-modified (S)-blebbistatin analogs" (PDF). Bioorganic & Medicinal Chemistry Letters. 27 (13): 2986–2989. doi:10.1016/j.bmcl.2017.05.008. hdl:1854/LU-8519713. PMID 28512027.
  49. ↑ Roman BI, Verhasselt S, Mangodt CW, De Wever O, Stevens CV (July 2018). "Synthesis of C-ring-modified blebbistatin derivatives and evaluation of their myosin II ATPase inhibitory potency". Bioorganic & Medicinal Chemistry Letters. 28 (13): 2261–2264. doi:10.1016/j.bmcl.2018.05.041. PMID 29807794.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.