Development and Biological Evaluation of a Photoactivatable Small Molecule Microtubule-Targeting Agent.

Autor: Döbber A; School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany., Phoa AF; School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia., Abbassi RH; School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia., Stringer BW; QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia., Day BW; QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia., Johns TG; Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative, Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia.; Monash University, Wellington Road, Clayton, VIC 3800, Australia., Abadleh M; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany., Peifer C; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany., Munoz L; School of Medical Sciences and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2017 Mar 15; Vol. 8 (4), pp. 395-400. Date of Electronic Publication: 2017 Mar 15 (Print Publication: 2017).
DOI: 10.1021/acsmedchemlett.6b00483
Abstrakt: Photoremovable protecting groups added to bioactive molecules provide spatial and temporal control of the biological effects. We present synthesis and characterization of the first photoactivatable small-molecule tubulin inhibitor. By blocking the pharmacophoric OH group on compound 1 with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photocaged prodrug 2 that had no effect in biological assays. Short UV light exposure of the derivative 2 or UV-irradiation of cells treated with 2 resulted in fast and potent inhibition of tubulin polymerization, attenuation of cell viability, and apoptotic cell death, implicating release of the parent active compound. This study validates for the first time the photoactivatable prodrug concept in the field of small molecule tubulin inhibitors. The caged derivative 2 represents a novel tool in antitubulin approaches.
Databáze: MEDLINE
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