The Anticancer Activity for the Bumetanide-Based Analogs via Targeting the Tumor-Associated Membrane-Bound Human Carbonic Anhydrase-IX Enzyme

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.

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Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties

Pharmaceuticals ◽

10.3390/ph14070693 ◽

2021 ◽

Vol 14 (7) ◽

pp. 693

Author(s):

Kalyan K. Sethi ◽

KM Abha Mishra ◽

Saurabh M. Verma ◽

Daniela Vullo ◽

Fabrizio Carta ◽

...

Keyword(s):

Molecular Docking ◽

Carbonic Anhydrase ◽

Docking Studies ◽

Carbonic Anhydrases ◽

Molecular Docking Studies ◽

Structure Activity Relationships ◽

Structure Activity ◽

Carbonic Anhydrase I ◽

Human Carbonic Anhydrase ◽

Inhibition Studies

New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure–activity relationships (SAR) are rationalised with the help of molecular docking studies.

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Carbonic Anhydrase Inhibitors: Synthesis of Membrane-Impermeant Low Molecular Weight Sulfonamides Possessing in Vivo Selectivity for the Membrane-Bound versus Cytosolic Isozymes1

Journal of Medicinal Chemistry ◽

10.1021/jm990479+ ◽

2000 ◽

Vol 43 (2) ◽

pp. 292-300 ◽

Cited By ~ 95

Author(s):

Andrea Scozzafava ◽

Fabrizio Briganti ◽

Marc A. Ilies ◽

Claudiu T. Supuran

Keyword(s):

Molecular Weight ◽

Carbonic Anhydrase ◽

Low Molecular Weight ◽

Carbonic Anhydrase Inhibitors ◽

Membrane Bound

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In vivo effects of radioactive properties of Tl-201 on human carbonic anhydrase activity

10.1063/1.4981757 ◽

2017 ◽

Author(s):

Ali Sahin ◽

Murat Senturk

Keyword(s):

Carbonic Anhydrase ◽

Carbonic Anhydrase Activity ◽

Human Carbonic Anhydrase ◽

In Vivo Effects

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Preparation, Characterization, and Pharmacological Investigation of Withaferin-A Loaded Nanosponges for Cancer Therapy; In Vitro, In Vivo and Molecular Docking Studies

Molecules ◽

10.3390/molecules26226990 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6990

Author(s):

Hamid Saeed Shah ◽

Usman Nasrullah ◽

Sumera Zaib ◽

Faisal Usman ◽

Ajmal Khan ◽

...

Keyword(s):

Anticancer Activity ◽

Tumour Volume ◽

Docking Studies ◽

Withaferin A ◽

Target Cells ◽

Scanning Calorimetry ◽

Dapi Staining ◽

Anticancer Efficacy

The rapidly growing global burden of cancer poses a major challenge to public health and demands a robust approach to access promising anticancer therapeutics. In parallel, nanotechnology approaches with various pharmacological properties offer efficacious clinical outcomes. The use of new artificial variants of nanosponges (NS) as a transporter of chemotherapeutic drugs to target cells has emerged as a very promising tool. Therefore, in this research, ethylcellulose (EC) NS were prepared using the ultrasonication assisted-emulsion solvent evaporation technique. Withaferin-A (WFA), an active ingredient in Withania somnifera, has been implanted into the nanospongic framework with enhanced anticancer properties. Inside the polymeric structure, WFA was efficiently entrapped (85 ± 11%). The drug (WFA) was found to be stable within polymeric nanosponges, as demonstrated by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies. The WFA-NS had a diameter of 117 ± 4 nm and zeta potential of −39.02 ± 5.71 mV with a polydispersity index (PDI) of 0.419 ± 0.073. In addition, scanning electron microscopy (SEM) revealed the porous surface texture of WFA-NS. In vitro anticancer activity (SRB assay) results showed that WFA–NS exhibited almost twice the anticancer efficacy against MCF-7 cells (IC50 = 1.57 ± 0.091 µM), as quantified by flow cytometry and comet tests. Moreover, fluorescence microscopy with DAPI staining and analysis of DNA fragmentation revealed apoptosis as a mechanism of cancer cell death. The anticancer activity of WFA-NS was further determined in vivo and results were compared to cisplatin. The anticancer activity of WFA-NS was further investigated in vivo, and the data were consistent to those obtained with cisplatin. At Day 10, WFA-NS (10 mg/kg) significantly reduced tumour volume to 72 ± 6%, which was comparable to cisplatin (10 mg/kg), which reduced tumour volume to 78 ± 8%. Finally, the outcomes of molecular modeling (in silico) also suggested that WFA established a stable connection with nanosponges, generating persistent hydrophobic contacts (polar and nonpolar) and helping with the attractive delayed-release features of the formulation. Collectively, all the findings support the use of WFA in nanosponges as a prototype for cancer treatment, and opened up new avenues for increasing the efficacy of natural product-derived medications.

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