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Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity
Hakan Aslan1,2, Gioele Renzi2, Andrea Angeli2
1Department of Chemistry, Faculty of Science and Arts, Sinop University Sinop Turkey hakaslan@gmail.com.
Abstract:
In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (10-17a-b) and similar derivatives (20-21) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme-inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (23) emerged. The surprisingly potent inhibitory activity of 23 for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer.
Insights
Researchers developed novel compounds targeting carbonic anhydrases IX and XII, crucial in hypoxic tumors. These inhibitors show potent activity and selectivity, offering promising avenues for new anticancer drug discovery.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Biochemistry
Background:
- Carbonic anhydrases (CAs), particularly isoforms IX and XII, are overexpressed in hypoxic tumors, making them significant pharmacological targets for cancer therapy.
- The development of novel anticancer agents necessitates the rapid synthesis of diverse compound libraries.
- One-pot reactions like the Biginelli reaction are valuable for efficient compound synthesis.
Purpose of the Study:
- To synthesize and evaluate novel benzenesulfonamide-bearing Biginelli products and derivatives as inhibitors of carbonic anhydrases IX and XII.
- To investigate the selectivity of these compounds against cancer-relevant CA isoforms over physiologically important ones.
- To elucidate the binding interactions of potent inhibitors with carbonic anhydrases through structural studies.
Main Methods:
- Synthesis of Biginelli products and related derivatives incorporating the benzenesulfonamide moiety.
- Enzyme inhibition assays using the stopped-flow technique to assess activity against carbonic anhydrase isoforms.
- Crystallography and molecular docking simulations to understand enzyme-inhibitor interactions.
- Chemical similarity screening to identify novel lead compounds.
Main Results:
- Several synthesized Biginelli products and derivatives demonstrated potent inhibition of carbonic anhydrases IX and XII in the nanomolar range.
- Compounds exhibited promising selectivity over carbonic anhydrase isoforms I and II.
- A diphenylpyrimidine derivative (23) showed significant inhibitory activity and strong antiproliferative effects on triple-negative breast cancer and glioblastoma cell lines.
- Structural studies provided insights into the binding modes within the enzyme-inhibitor complex.
Conclusions:
- Novel benzenesulfonamide-containing compounds are effective inhibitors of carbonic anhydrases IX and XII.
- The diphenylpyrimidine derivative (23) represents a promising lead compound for anticancer drug development targeting carbonic anhydrases.
- These findings reinforce the critical role of carbonic anhydrases in cancer progression and therapeutic targeting.
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