Design concepts of half-sandwich organoruthenium anticancer agents based on bidentate bioactive ligands

Abstract

• Half-sandwich organoruthenium compounds are extensively investigated as cancer treatments. • Bidentate bioactive ligands with a wide variety of donor atom combinations are investigated. • Bidentate bioactive ligands endow in some Ru compounds multimodal anticancer activity. • The bioactivity of the organometallics is often determined by the bidentate ligands. • The complexes have been categorized into 5 structural design concepts. The small molecule anticancer agent cisplatin and its Pt(II) analogs carboplatin and oxaliplatin are widely used to treat a variety of tumorigenic diseases. Despite their structural simplicity, side effects and disadvantages, they are cornerstones of cancer chemotherapy. Several strategies have been pursued to enhance the activity and reduce the side effects of metal-based drugs, for example, to use bioactive ligands that equip them with novel modes of action, enhance delivery, allow for selective activation, create synergistic effects or improve tumor accumulation. Many of these strategies have been developed for or adapted in the design of half-sandwich organoruthenium compounds. For such compounds decorated with bioactive ligands that coordinate monodentately to the Ru center, we have identified five design concepts (Coord. Chem. Rev. 2021, 439, 213890): (i) the bioactive ligand coordinates directly to the Ru center or (ii) after functionalization with a coordinating group, (iii) the ligand(s) and the Ru center solely define the overall shape of the molecule, (iv) the bioactive ligand is released, and (v) the bioactive ligand acts as a vector to the tumor (cell). Herein, we use these five concepts and explore their application to half-sandwich organoruthenium anticancer compounds in which the bioactive ligand is coordinated to the Ru center through a bidentate chelating motif.