Bosca Mayans, F.; Sastre Navarro, GI.; Andreu, JM.; Jornet, D.; Tormos Faus, RE.; Miranda Alonso, MÁ. (2015). Drug-tubulin interactions interrogated by transient absorption spectroscopy. RSC Advances. 5(61):49451-49458. doi:10.1039/C5RA05636E.
Por favor, use este identificador para citar o enlazar este ítem: http://hdl.handle.net/10251/88053
Title:
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Drug-tubulin interactions interrogated by transient absorption spectroscopy
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Author:
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Bosca Mayans, Francisco
Sastre Navarro, German Ignacio
Andreu, José María
Jornet, David
Tormos Faus, Rosa Esperanza
Miranda Alonso, Miguel Ángel
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UPV Unit:
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Universitat Politècnica de València. Instituto Universitario Mixto de Tecnología Química - Institut Universitari Mixt de Tecnologia Química
Universitat Politècnica de València. Departamento de Química - Departament de Química
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Issued date:
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Abstract:
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[EN] Colchicine (COL) is a bioactive molecule with antitumor properties. When COL binds to tubulin (TU), it inhibits microtubule assembly dynamics. We have investigated COL-TU interactions using laser flash photolysis (LFP) ...[+]
[EN] Colchicine (COL) is a bioactive molecule with antitumor properties. When COL binds to tubulin (TU), it inhibits microtubule assembly dynamics. We have investigated COL-TU interactions using laser flash photolysis (LFP) technique and performing fully flexible molecular dynamics simulations. Excitation of COL at 355 nm in aqueous medium did not lead to any transient absorption spectrum. By contrast, in the presence of TU a transient peaking at lambda(max) ca. 420 nm was registered and assigned as triplet excited COL complexed with TU ((COL)-C-3*@TU). In aerated medium, the lifetime was tau ca. 160 mu s and the quantum yield was 0.138. Likewise, when the bicyclic COL analog MTC was submitted to LFP in the presence of TU, (MTC)-M-3@TU* was detected with a lifetime of ca. 62 ms and a quantum yield of 0.296, Aqueous solutions of MTC did not produce any signal in the microsecond timescale. The triplet energy of MTC was obtained by means of emission measurements and found to be ca. 200 kJ mol(-1), a value that matches with that previously reported for COL (188 kJ mol(-1)). Molecular dynamic simulations, both with the ground and triplet excited state, reveal a strong interaction between COL and TU to give stabilized complexes with restricted mobility inside the protein binding site. These results demonstrate that LFP is a useful methodology to study the binding of COL derivatives to TU and open a new way to evaluate the interactions of non-fluorescent anticancer drugs with this protein.
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Subjects:
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Colchicine site inhibitors
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Fluorescence stopped-flow
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Molecular-dynamics
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Anticancer drugs
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Binding-site
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Analogs
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Ring
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Complex
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Lumicolchicines
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Polymerization
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Copyrigths:
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Reserva de todos los derechos
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Source:
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RSC Advances. (issn:
2046-2069
)
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DOI:
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10.1039/C5RA05636E
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Publisher:
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Royal Society of Chemistry
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Publisher version:
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http://doi.org/10.1039/c5ra05636e
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Project ID:
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MICINN/CTQ2010-19909
GV/PROMETEOII/2013/005
CAM/S2010/BMD-2353
MICINN/BFU2011-23416
MICINN/SEV 2012-0267
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Thanks:
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Financial support from the Spanish Government (grants CTQ2010-19909; BFU2011-23416 and SEV 2012-0267), the Generalitat Valenciana (Prometeo II/2013/005) and Comunidad de Madrid (S2010/BMD-2353) is gratefully acknowledged. ...[+]
Financial support from the Spanish Government (grants CTQ2010-19909; BFU2011-23416 and SEV 2012-0267), the Generalitat Valenciana (Prometeo II/2013/005) and Comunidad de Madrid (S2010/BMD-2353) is gratefully acknowledged. G.S. thanks ASIC-UPV for computing time.
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Type:
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Artículo
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