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- Title
The Anticancer Activity for the Bumetanide-Based Analogs via Targeting the Tumor-Associated Membrane-Bound Human Carbonic Anhydrase-IX Enzyme.
- Authors
Malebari, Azizah M.; Ibrahim, Tarek S.; Salem, Ibrahim M.; Salama, Ismail; Khayyat, Ahdab N.; Mostafa, Samia M.; El-Sabbagh, Osama I.; Darwish, Khaled M.
- Abstract
The membrane-bound human carbonic anhydrase (hCA) IX is widely recognized as a marker of tumor hypoxia and a prognostic factor within several human cancers. Being undetected in most normal tissues, hCA-IX implies the pharmacotherapeutic advent of reduced off-target adverse effects. We assessed the potential anticancer activity of bumetanide-based analogues to inhibit the hCA-IX enzymatic activity and cell proliferation of two solid cancer cell lines, namely kidney carcinoma (A-498) and bladder squamous cell carcinoma (SCaBER). Bumetanide analogues efficiently inhibit the target hCA-IX in low nanomolar activity (IC50 = 4.4–23.7 nM) and have an excellent selectivity profile (SI = 14.5–804) relative to the ubiquitous hCA-II isoform. Additionally, molecular docking studies provided insights into the compounds' structure–activity relationship and preferential binding of small-sized as well as selective bulky ligands towards the hCA-IX pocket. In particular, 2,4-dihydro-1,2,4-triazole-3-thione derivative 9c displayed pronounced hCA-IX inhibitory activity and impressive antiproliferative activity on oncogenic A-498 kidney carcinoma cells and is being considered as a promising anticancer candidate. Future studies will aim to optimize this compound to fine-tune its anticancer activity as well as explore its potential through in-vivo preclinical studies.
- Subjects
CARBONIC anhydrase; SQUAMOUS cell carcinoma; TUMOR markers; STRUCTURE-activity relationships; MOLECULAR docking; COBALT chloride
- Publication
Pharmaceuticals (14248247), 2020, Vol 13, Issue 9, p252
- ISSN
1424-8247
- Publication type
Article
- DOI
10.3390/ph13090252