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Harnessing Nitric Oxide-Donating Benzofuroxans for Targeted Inhibition of Carbonic Anhydrase IX in Cancer
Silvia Bua1, Alessio Nocentini1, Alessandro Bonardi1
1NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy.
Abstract:
We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28, demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.
Insights
New benzofuroxan hybrids targeting human carbonic anhydrases (hCAs) show potent dual action. Compound 27 effectively reduced renal cancer cell growth and tumor size, with promising preclinical safety.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Human carbonic anhydrases (hCAs) IX and XII are validated targets in cancer therapy.
- Nitric oxide (NO)-donors offer therapeutic potential through various mechanisms.
- Hybrid molecules combining hCA inhibition and NO release are being explored for enhanced antitumor activity.
Purpose of the Study:
- To design and evaluate novel benzofuroxan-based hybrid derivatives as dual-acting inhibitors of hCA IX and XII.
- To assess the antitumor efficacy of these compounds in cancer cell lines and 3D tumor models.
- To investigate the molecular mechanisms underlying the antiproliferative effects of the lead compound.
Main Methods:
- Synthesis and characterization of benzofuroxan-based NO-donor hybrid derivatives.
- Enzyme inhibition assays for hCA IX and XII.
- In vitro antiproliferative assays against various cancer cell lines (e.g., A-498).
- Analysis of apoptosis, ferroptosis, reactive oxygen species (ROS), and gene expression.
- Three-dimensional spheroid culture models.
- In vivo toxicity studies in mice.
Main Results:
- Compounds 27 and 28 exhibited potent nanomolar inhibition of hCA IX and significant NO release.
- Compound 27 demonstrated significant antiproliferative effects, particularly against renal carcinoma A-498 cells.
- Compound 27 reduced CA IX and iron-regulatory protein expression, inducing apoptosis and ferroptosis via caspase activity and ROS increase.
- Compound 27 effectively reduced tumor spheroid size and viability in 3D models.
- In vivo studies showed good tolerability with no significant kidney function alterations.
Conclusions:
- Benzofuroxan-based NO-donor hybrids are effective dual-acting inhibitors of hCA IX.
- Compound 27 displays significant preclinical potential as an anticancer agent targeting renal cell carcinoma.
- The observed antitumor effects are mediated through induction of apoptosis and ferroptosis.
- These compounds warrant further preclinical development for cancer therapy.
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