Preclinical Anticancer Activity of an Electron‐Deficient Organoruthenium(II) Complex

• Published in: ChemMedChem Vol. 15; no. 11; pp. 982 - 987
• Main Authors: Soldevila‐Barreda, Joan J., Azmanova, Maria, Pitto‐Barry, Anaïs, Cooper, Patricia A., Shnyder, Steven D., Barry, Nicolas P. E.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 04.06.2020
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis - drug effects; Biotechnology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cisplatin; Colon; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Cymene; Cytotoxicity; Dose-Response Relationship, Drug; Drug development; Drug Screening Assays, Antitumor; electron-deficient; Electrons; half-sandwich complexes; hollow fibre assay; Humans; In vivo methods and tests; in vivo evaluation; Lung cancer; metallodrugs; Mice; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Non-small cell lung carcinoma; Organoruthenium complexes; p53 Protein; Platinum; Reactive Oxygen Species - metabolism; Ruthenium; Ruthenium - chemistry; Ruthenium - pharmacology; Ruthenium compounds; Structure-Activity Relationship; Tumor cell lines; Xenografts; Xenotransplantation; in vivo evaluation; half-sandwich complexes; metallodrugs; hollow fibre assay; electron-deficient
• DOI: 10.1002/cmdc.202000096
• ISSN: 1860-7179; 1860-7187

Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt‐resistance mechanisms. Electron‐deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron‐deficient organoruthenium complex [(p‐cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53+/+ and HCT116 p53−/−), and non‐small cell lung H460 cancer cell lines. It shows no cross‐resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53‐independent. In vivo evaluation in the hollow‐fibre assay across a panel of cancer cell types and subcutaneous H460 non‐small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow‐up, this work is the first preclinical study of electron‐deficient half‐sandwich complexes and highlights their promise as anticancer drug candidates. Anticancer evaluation: Although electron‐deficient, [(p‐cymene)Ru(maleonitriledithiolate)] does not interact with the biomolecules that poison a number of organometallic compounds. This half‐sandwich complex has remarkable antiproliferative properties, and is cytotoxic to cisplatin‐sensitive and ‐resistant cell lines tested in vitro. Furthermore, some in vivo activity is exhibited in mice.