Synthesis and SAR of [1,2,4]Triazolo[1,5-a]pyrimidines, a Class of Anticancer Agents with a Unique Mechanism of Tubulin Inhibition

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• 作者：Nan Zhang ; Semiramis Ayral-Kaloustian ; Thai Nguyen ; Jay Afragola ; Richard Hernandez ; Judy Lucas ; James Gibbons ; Carl Beyer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：January 25, 2007
• 年：2007
• 卷：50
• 期：2
• 页码：319 - 327
• 全文大小：140K
• 年卷期：v.50,no.2(January 25, 2007)
• ISSN：1520-4804

文摘

The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol,or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been establishedfor optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylaminogroup is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at thepositions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to thetriazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followedby a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this seriesof triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, butdid not bind competitively with paclitaxel.¹ Instead, they inhibit the binding of vincas to tubulin. Selectedcompounds were studied further, and it was shown that these compounds were able to overcome resistanceattributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumorgrowth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orallyor intravenously.