Expanding the Chemical Space of Allyl Palladates with Anticancer Properties

Abstract

Allyl palladates are emerging as promising anticancer agents due to their unique mechanisms of action, including thioredoxin reductase inhibition and immunogenic cell death activation. However, their lack of selectivity toward cancer cells has hindered their therapeutic potential. Herein, a library of ten novel allyl palladates featuring diverse azolium ligands is synthesized via a solvent-free approach, including 1) ring-expanded azolium salts; 2) azolium salts functionalized with phosphonium, thioether, selenoether, or sulfoxide groups; 3) 12-membered cyclic alkyl groups; or 4) bulky or methoxy-functionalized aryl groups. The newly synthesized compounds are tested against A2780, A2780cis, and U87 cancer cell lines, as well as MRC-5 non-cancerous cells. Results reveal a general excellent cytotoxicity (in the micromolar or submicromolar range), with allyl palladates 2c–d showing the greatest activity but limited selectivity. Compounds 2f and 2h, however, demonstrate improved selectivity toward cancer cells, highlighting the influence of thioether and selenoether functional groups.