Coumarin-Thiourea Hybrids: Structural Features Governing CA Inhibition and Antiproliferative Effects

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Tumor-associated carbonic anhydrase (CA) isoforms IX and XII are overexpressed in hypoxic tumors, making them promising anticancer targets.
• Coumarins are recognized for their biological activities and act as effective CA inhibitors, particularly as suicide inhibitors.

Purpose of the Study:

• To design and synthesize novel hybrid compounds combining a coumarin core with an N-arylthioureido scaffold.
• To investigate the influence of structural variations on CA inhibition and antiproliferative activity.
• To identify potent and selective inhibitors of CA IX and XII for anticancer applications.

Main Methods:

• Synthesis of substituted coumarins via Pechmann condensation.
• Introduction of the N-arylthioureido motif using aryl isothiocyanates.
• Evaluation of carbonic anhydrase inhibition (Ki values) and antiproliferative activity (GI50 values).
• Assessment of selectivity indexes (SI) compared to acetazolamide.
• Label-free three-dimensional holotomographic microscopy to study cellular effects.

Main Results:

• The lead compound, a dimethylated coumarin with a pentyl linker and N-(p-tolyl)thioureido group, demonstrated potent inhibition of CA IX and XII in the low to mid-nanomolar range.
• The lead compound exhibited selectivity indexes superior to acetazolamide.
• Significant antiproliferative activity was observed in the low micromolar range against both drug-sensitive and multidrug-resistant cancer cell lines.
• Holotomographic microscopy revealed the compound induces slow apoptosis, leading to cell death over approximately 20 hours.

Conclusions:

• The designed coumarin-based hybrid compounds are effective inhibitors of tumor-associated carbonic anhydrases IX and XII.
• The lead compound displays promising anticancer potential due to its potent and selective inhibition and antiproliferative effects.
• These findings highlight the therapeutic promise of targeting CA IX and XII with novel coumarin derivatives for cancer treatment.