4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor-Associated Carbonic Anhydrase Isoforms IX
Alessio Nocentini1, Elena Trallori2, Srishti Singh3
1NEUROFARBA Dept., Sezione di Scienze Farmaceutiche , Università degli Studi di Firenze , Via Ugo Schiff 6 , 50019 Sesto Fiorentino Florence , Italy.
Abstract:
Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB-231, and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation toward the development of hypoxia-activated antitumor CAIs.
Insights
New carbonic anhydrase inhibitors (CAIs) show increased antiproliferative action in hypoxic cancer cells. These hypoxia-activated CAIs are a promising step toward developing novel cancer therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Human carbonic anhydrases (CA) IX and XII are overexpressed in tumors, responding to hypoxia and acidity.
- Hypoxia enhances oxido-reductase activity, enabling selective activation of bioreductive prodrugs.
Purpose of the Study:
- To develop novel, selective inhibitors of carbonic anhydrase IX and XII (CA IX/XII).
- To create hypoxia-activated antitumor carbonic anhydrase inhibitors (CAIs) based on SLC-0111 analogues.
Main Methods:
- Synthesis of ureido-substituted benzenesulfonamides with a nitro-aromatic moiety.
- Screening for inhibition of human carbonic anhydrases (hCA) I, II, IX, and XII.
- X-ray crystallography to rationalize inhibitory activity.
- Assessment of cancer cell viability under normoxic and hypoxic conditions.
Main Results:
- Novel CA IX/XII inhibitors were synthesized, showing increased antiproliferative activity under hypoxia.
- Six X-ray crystallographies provided insights into the compounds' inhibitory mechanisms against CA II and IX/mimic.
- Compounds demonstrated effects on the viability of HT-29, MDA-MB-231, and PC-3 cancer cell lines.
Conclusions:
- The developed compounds represent a new class of hypoxia-activated antitumor carbonic anhydrase inhibitors.
- These findings initiate the development of targeted cancer therapies exploiting tumor hypoxia.
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