Selenium-analogs based on natural sources as cancer-associated carbonic anhydrase isoforms IX and XII inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Carbonic anhydrase (CA) isoforms IX and XII are overexpressed in various cancers.
• Inhibiting these tumor-associated CA isoforms can lead to significant antitumor and antimetastatic effects.
• Organoselenium compounds, particularly selenols, are effective inhibitors of CA due to selenium's favorable binding properties.

Purpose of the Study:

• To synthesize and evaluate novel selenoesters as potential inhibitors of carbonic anhydrase isoforms.
• To investigate the efficacy of selenoesters incorporating NSAIDs and natural product fragments against CA I, II, IX, and XII.
• To identify selective inhibitors for tumor-associated CA isoforms IX and XII.

Main Methods:

• Synthesis of two series of selenoesters (compounds 1a-19a and 1b-19b).
• Evaluation of synthesized compounds against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII.
• Structure-activity relationship analysis to identify key inhibitory features.

Main Results:

• Selenoesters combining NSAIDs with natural product fragments were developed.
• Indomethacin and flufenamic acid analogs showed selectivity for the tumor-associated CA isoform IX.
• Inhibition was observed in the low micromolar range for specific analogs.

Conclusions:

• Selenoesters represent a promising class of non-classical inhibitors for tumor-associated carbonic anhydrase isoforms.
• The combination of NSAIDs and natural product fragments in selenoesters yields potent and selective CA IX inhibitors.
• These findings support the development of organoselenium compounds as novel cancer therapeutics.