Cyclopentadienyl‐Based Anticancer Drugs: Improvement of Cytotoxic Activity through Functionalisation of the π Ligand

• Published in: ChemMedChem 2021-06, Vol.16 (11), p.1804-1812
• Main Authors: Absolonová, Monika, Melounková, Lucie, Vinklárek, Jaromír, Honzíček, Jan, Dostál, Libor, Mrózek, Ondřej
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor activity; Antitumor agents; Biological activity; Biological effects; Cancer; Cell Line; Cell Proliferation - drug effects; Chelation; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination compounds; cyclopentadienyl ligand; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; Cytotoxicity; Design modifications; Dose-Response Relationship, Drug; Drug development; Drug Screening Assays, Antitumor; Drugs; fulvene; Humans; Leukemia; Ligands; Molecular Structure; MOLT-4; Molting; Molybdenum; Molybdenum - chemistry; Molybdenum - pharmacology; Side effects; Toxicity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100060

Cytotoxic complexes containing molybdenum are widely studied as a potential substitution for commercially used drugs that often suffer from pronounced side effects and cellular resistance. Compounds of the type [(η5‐Cp′)Mo(CO)2(N,NL)][BF4], where Cp is cyclopentadienyl and N,NL is a bidentate ligand, are well known for their strong anticancer activity. It is a generally accepted paradigm that the nature of the coordinated N,NL ligand has a major impact on the cytotoxicity. In this study, a series of new functionalised Cp complexes of molybdenum was synthesised from derivatised fulvenes as π‐ligand precursors. Indeed, the coordination sphere‘s modulation by various N,N‐chelating ligands afforded species active toward leukemic cell line MOLT‐4 with IC50 values depending on the character of the N,N‐chelator used. However, following study clearly showed that functionalisation of the Cp ring with an amine moiety considerably improved cytotoxicity. These results are of crucial importance for the future design of highly active cytotoxic drugs, as modification of cyclopentadienyl is believed to have a minor effect on biological activity. Cytotoxicity improvement: Series of Mo‐based cytotoxic compounds bearing both an N,N‐chelating ligand and cyclopentadienyl (Cp) substituted by amine group were prepared. Although the derivatisation of Cp has a minor impact on IC50 values, the introduction of amine increased the cytotoxic effect considerably.