Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1, 2, 4]triazolo[1, 5-a]pyrimidines. Issue 12 (1st July 2018)

• Record Type: Journal Article
• Authors: Oukoloff, Killian; Kovalevich, Jane; Cornec, Anne-Sophie; Yao, Yuemang; Owyang, Zachary A.; James, Michael; Trojanowski, John Q.; Lee, Virginia M.-Y.; Smith, Amos B.; Brunden, Kurt R.; Ballatore, Carlo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 12(2018)
• Page Start: 2180
• Page End: 2183
• Publication Date: 2018-07-01
• Subjects: Triazolopyrimidine -- Microtubule stabilization -- Photoaffinity labeling -- CNS drug discovery; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.05.010
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Microtubule (MT)-active triazolopyrimidines can preserve or disrupt MT integrity. A series of photoactivatable derivatives was designed, synthesized and evaluated. Selected photoactivatable candidate probes have been identified. Such probes may be used in photoaffinity labeling studies. Abstract: The [1, 2, 4]triazolo[1, 5- a ]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.