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Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation

Authors :
Emilie Anduran
Ashok Aspatwar
Nanda-Kumar Parvathaneni
Dennis Suylen
Silvia Bua
Alessio Nocentini
Seppo Parkkila
Claudiu T. Supuran
Ludwig Dubois
Philippe Lambin
Jean-Yves Winum
Source :
Molecules, Vol 25, Iss 10, p 2347 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

Hypoxia, a common feature of solid tumours’ microenvironment, is associated with an aggressive phenotype and is known to cause resistance to anticancer chemo- and radiotherapies. Tumour-associated carbonic anhydrases isoform IX (hCA IX), which is upregulated under hypoxia in many malignancies participating to the microenvironment acidosis, represents a valuable target for drug strategy against advanced solid tumours. To overcome cancer cell resistance and improve the efficacy of therapeutics, the use of bio-reducible prodrugs also known as Hypoxia-activated prodrugs (HAPs), represents an interesting strategy to be applied to target hCA IX isozyme through the design of selective carbonic anhydrase IX inhibitors (CAIs). Here, we report the design, synthesis and biological evaluations including CA inhibition assays, toxicity assays on zebrafish and viability assays on human cell lines (HT29 and HCT116) of new HAP-CAIs, harboring different bio-reducible moieties in nitroaromatic series and a benzenesulfonamide warhead to target hCA IX. The CA inhibition assays of this compound series showed a slight selectivity against hCA IX versus the cytosolic off-target hCA II and hCA I isozymes. Toxicity and viability assays have highlighted that the compound bearing the 2-nitroimidazole moiety possesses the lowest toxicity (LC50 of 1400 µM) and shows interesting results on viability assays.

Details

Language :
English
ISSN :
14203049
Volume :
25
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.8b3665cc17c46e1877cc22773b10067
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules25102347