Synthesis of saccharin-glycoconjugates targeting carbonic anhydrase using a one-pot cyclization/deprotection strategy

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Carbonic anhydrase IX (CA IX) is a significant biomarker and therapeutic target in various cancers, crucial for tumor cell growth.
• Simple cyclic sulfonamides like saccharin (SAC) exhibit limited selectivity towards CA IX.
• Previous derivatization of SAC using a "tail-approach" enhanced selectivity but faced synthetic challenges.

Purpose of the Study:

• To develop an improved synthetic strategy for highly selective CA IX inhibitors.
• To overcome limitations in existing synthetic protocols for saccharin-based CA IX inhibitors.
• To synthesize and evaluate novel galactosyl and glucosyl conjugates as potential CA IX inhibitors.

Main Methods:

• Developed an alternative synthetic route for CA IX inhibitors.
• Implemented a "one pot" deprotection/cyclization as the final synthetic step.
• Synthesized new galactosyl and glucosyl conjugates of modified saccharin.

Main Results:

• The new synthetic approach avoids problematic deprotection steps.
• Achieved high selectivity (>1000-fold) for CA IX over other carbonic anhydrase isoforms.
• New galactosyl and glucosyl conjugates demonstrated low to mid nM inhibition of CA IX.

Conclusions:

• The developed "one pot" method offers a more efficient synthesis of potent CA IX inhibitors.
• These novel conjugates represent promising candidates for targeted cancer therapy development.
• The high isoform selectivity is critical for minimizing off-target effects in clinical applications.