Metals in Cancer Research: Beyond Platinum Metallodrugs

Abstract

The discovery of the medicinal properties of platinum complexes has fueled the design and synthesis of new anticancer metallodrugs endowed with unique modes of action (MoA). Among the various families of experimental antiproliferative agents, organometallics have emerged as ideal platforms to control the compounds' reactivity and stability in a physiological environment. This is advantageous to efficiently deliver novel prodrug activation strategies, as well as to design metallodrugs acting only via noncovalent interactions with their pharmacological targets. Noteworthy, another justification for the advance of organometallic compounds for therapy stems from their ability to catalyze bioorthogonal reactions in cancer cells. When not yet ideal as drug leads, such compounds can be used as selective chemical tools that benefit from the advantages of catalytic amplification to either label the target of interest (e.g., proteins) or boost the output of biochemical signals. Examples of metallodrugs for the so-called "catalysis in cells" are considered in this Outlook together with other organometallic drug candidates. The selected case studies are discussed in the frame of more general challenges in the field of medicinal inorganic chemistry.

Figure 1

Structure of cisplatin (A) and its molecular structure (B) as determined by single-crystal X-ray diffraction (SC-XRD) taken from CCDC entry CUKRAB02. (C and E) Structures of Ru(II) compounds in clinical trials. (D) Molecular structure of BOLD-100 as determined by SC-XRD taken as an excerpt from the CCDC entry UFIDUJ. SC-XRD structures realized with Mercury (version 2023.2.0).

Figure 2

(A) Structure of the monocarbonyl Ru(II) kinase inhibitor Λ-OS1 with the staurosporin-inspired binding domain in violet; (B) structure of the cyclometalated Pt(II) complex [Pt(C^∧N^∧N)(NHC₂Bu)]PF₆ (Pt1a; HC^∧N^∧N = 6-phenyl-2,2′-bipyridine; NHC^2Bu = N-butyl substituted heterocyclic carbene); (C) molecular structure of Pt1a as determined by SC-XRD, taken from the CCDC entry IPIYIQ (ellipsoids shown at 30% probability, hydrogen atoms omitted for clarity). (D) Structure of the Au(I) NHC complex AuTMX₂ and (E) molecular structure of the AuTMX₂ cation as determined by SC-XRD, taken from the CCDC entry YENBAW. SC-XRD structures realized with Mercury (version 2023.2.0). (F) Noncovalent adduct of AuTMX₂ with the promoter G4 structure cKit-1 calculated by multiple collective variable (CV) metadynamics. G4s color scheme: sugar backbone = turquoise, DNA bases = blue, potassium ions = purple spheres. Compound AuTMX₂ in stick representation, color scheme: carbon = turquoise, nitrogen = blue, oxygen = red, hydrogen = white, Au(I) = yellow sphere. Figure generated with VMD software.

Figure 3

(A) Representative examples of organometallic Ru(II) complexes studied for transfer hydrogenation (TH) reactions in cancer cells. (B) Cartoon representation of the TH reactions leading to 1,4-NADH oxidation in cells catalyzed by organometallic Ru(II) compounds in the presence of molecular O₂. (D) Scheme of the reaction of Au(III) cyclometalated compounds, featuring C^∧N-type ligands, with cysteine or selenocysteine residues. Following the formation of a coordination adduct of the Au(III) center with the amino acid (Cys or Sec), the reaction can proceed toward C–S cross-coupling via reductive elimination in physiological conditions.