Synthesis and Evaluation of New Hsp90 Inhibitors Based on a 1,4,5-Trisubstituted 1,2,3-Triazole Scaffold

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• 作者：Maurizio Taddei ; Serena Ferrini ; Luca Giannotti ; Massimo Corsi ; Fabrizio Manetti ; Giuseppe Giannini ; Loredana Vesci ; Ferdinando M. Milazzo ; Domenico Alloatti ; Mario B. Guglielmi ; Massimo Castorina ; Maria L. Cervoni ; Marcella Barbarino ; Rosanna Foder脿 ; Valeria Carollo ; Claudio Pisano ; Silvia Armaroli ; Walter Cabri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2258-2274
• 全文大小：840K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.