Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/116006
Title: Combination of betulinic acid fragments and carbonic anhydrase inhibitors : a new drug targeting approach
Author(s): Bache, MatthiasLook up in the Integrated Authority File of the German National Library
Heise, Niels ValentinLook up in the Integrated Authority File of the German National Library
Thiel, Andreas
Funtan, AnneLook up in the Integrated Authority File of the German National Library
Seifert, FranziskaLook up in the Integrated Authority File of the German National Library
Petrenko, Marina
Güttler, Antje
Brandt, Sarah
Müller, ThomasLook up in the Integrated Authority File of the German National Library
Vordermark, DirkLook up in the Integrated Authority File of the German National Library
Thondorf, IrisLook up in the Integrated Authority File of the German National Library
Csuk, RenéLook up in the Integrated Authority File of the German National Library
Paschke, ReinhardLook up in the Integrated Authority File of the German National Library
Issue Date: 2024
Type: Article
Language: English
Abstract: Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and bicarbonate. It is a membrane-bound protein with an extracellular catalytic center that is predominantly overexpressed in solid hypoxic tumors. Sulfamates and sulfonamides, for example acetazolamide (AZA), have been used to inhibit hCA IX in order to improve the response to solid hypoxic tumors. In the present study, we propose a new drug targeting approach by attaching the natural cytotoxic substances betulin and betulinic acid (BA) via a linker to sulfonamides. The conjugate was designed with different spacer lengths to accumulate at the target site of hCA IX. Computational and cell biological studies suggest that the length of the linker may influence hCA IX inhibition. Cytotoxicity tests of the newly synthesized bifunctional conjugates 3, 5, and 9 show effective cytotoxicity in the range of 6.4 and 30.1 µM in 2D and 3D tumor models. The hCA IX inhibition constants of this conjugates, measured using an in vitro enzyme assay with p-nitrophenyl acetate, were determined in a low µM-range, and all compounds reveal a significant inhibition of hypoxia-induced CA activity in a cell-based assay using the Wilbur–Anderson method. In addition, the cells respond with G1 increase and apoptosis induction. Overall, the dual strategy to produce cytotoxic tumor therapeutics that inhibit tumor-associated hCA IX was successfully implemented.
URI: https://opendata.uni-halle.de//handle/1981185920/117961
http://dx.doi.org/10.25673/116006
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Journal Title: Pharmaceutics
Publisher: MDPI
Publisher Place: Basel
Volume: 16
Issue: 3
Original Publication: 10.3390/pharmaceutics16030401
Appears in Collections:Open Access Publikationen der MLU

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