Coumarins-lipophilic cations conjugates: Efficient mitocans targeting carbonic anhydrases

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• Cancer progression is linked to carbonic anhydrases IX and XII.
• Developing selective antiproliferative agents is crucial for effective cancer therapy.
• Mitochondriotropic agents can enhance drug delivery to cancer cells.

Purpose of the Study:

• To design and synthesize novel mitochondriotropic agents targeting carbonic anhydrases IX and XII.
• To evaluate the inhibitory activity and selectivity of these compounds against cancer-related carbonic anhydrases.
• To assess the in vitro antiproliferative effects and mechanisms of action in tumor cell lines.

Main Methods:

• Conjugation of coumarin with lipophilic cations (triphenylphosphonium salts, guanidinium).
• Enzyme inhibition assays for carbonic anhydrases IX, XII, and cytosolic isoforms.
• In vitro antiproliferative assays on tumor and MDR cell lines.
• Docking and molecular dynamics simulations for interaction analysis.
• Live cell microscopy to determine mechanisms of action.

Main Results:

• Compounds showed potent, selective inhibition of carbonic anhydrases IX and XII (nM range).
• Increased tether length improved antiproliferative potency (sub-micromolar range) and tumor cell selectivity (S.I. >357).
• Phosphonium salts exhibited chemoresistance via P-glycoprotein efflux, while guanidines induced apoptosis; phosphonium salts depolarized mitochondria.

Conclusions:

• Novel mitochondriotropic agents effectively target carbonic anhydrases IX and XII.
• The designed compounds demonstrate significant antiproliferative activity and selectivity against cancer cells.
• Distinct mechanisms of action (cytostatic vs. apoptotic) were observed for phosphonium salts and guanidines, offering potential for tailored cancer therapies.