1. Academic Validation
  2. Structure-activity relationships of triazole-benzodioxine inhibitors of cathepsin X

Structure-activity relationships of triazole-benzodioxine inhibitors of cathepsin X

  • Eur J Med Chem. 2020 May 1;193:112218. doi: 10.1016/j.ejmech.2020.112218.
Urša Pečar Fonović 1 Damijan Knez 2 Martina Hrast 2 Nace Zidar 2 Matic Proj 2 Stanislav Gobec 2 Janko Kos 3
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia. Electronic address: ursa.pecarfonovic@ffa.uni-lj.si.
  • 2 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia.
  • 3 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia; Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia.
Abstract

Cathepsin X is a cysteine Carboxypeptidase that is involved in various physiological and pathological processes. In particular, highly elevated expression and activity of Cathepsin X has been observed in cancers and neurodegenerative diseases. Previously, we identified compound Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) as a potent and specific reversible Cathepsin X inhibitor. Here, we have explored the effects of chemical variations to Z9 of either benzodioxine or triazol moieties, and the importance of the central ketomethylenethio linker. The ketomethylenethio linker was crucial for Cathepsin X inhibition, whereas changes of the triazole heterocycle did not alter the inhibitory potencies to a greater extent. Replacement of benzodioxine moiety with substituted benzenes reduced Cathepsin X inhibition. Overall, several synthesized compounds showed similar or improved inhibitory potencies against Cathepsin X compared to Z9, with IC50 values of 7.1 μM-13.6 μM. Additionally, 25 inhibited prostate Cancer cell migration by 21%, which is under the control of Cathepsin X.

Keywords

1,2,4-Triazole; Anticancer drugs; Cathepsin X; Triazole-benzodioxine inhibitors.

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