A prodrug approach toward cancer-related carbonic anhydrase inhibition

Area of Science:

• Medicinal Chemistry
• Carbohydrate Chemistry
• Enzyme Inhibitor Design

Background:

• Selective inhibition of cancer-associated carbonic anhydrase (CA) enzymes, specifically CA IX and XII, is a novel strategy for personalized cancer management.
• Targeting these extracellular enzymes offers a promising therapeutic avenue.

Purpose of the Study:

• To design and synthesize novel glycoconjugate primary sulfonamides targeting CA IX and XII.
• To evaluate the enzyme inhibition profiles and biopharmaceutical properties of these novel compounds.

Main Methods:

• Synthesis of 24 novel glycoconjugate primary sulfonamides via Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC).
• Variably acylated glycopyranosyl azides and ethynyl benzene sulfonamides were used as precursors.
• Determination of CA enzyme inhibition profiles, in vitro metabolic stability, plasma stability, and plasma protein binding.

Main Results:

• The synthesized compounds effectively bind to the extracellular catalytic domain of CA IX and XII.
• The study identified the influence of different acyl groups on key biopharmaceutical properties.
• A representative set of compounds exhibited favorable metabolic and plasma stability profiles.

Conclusions:

• Acyl group protected carbohydrate-based sulfonamides demonstrate potential as prodrugs.
• These compounds offer a promising approach for selectively targeting extracellular cancer-associated CA enzymes.
• Further development could lead to novel personalized cancer therapies.