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

Abstract

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.

Cyclopentadienyl Molybdenum(II) Compounds Bearing Ether and Thioether Functions in the Side Chain: Synthesis, Characterization, and Cytotoxic/Cytostatic Studies

“…[16] The improved activity has been documented for the molybdenum compounds with amine and thiophene functions in the side chain of the Cp/Ind ligand. [23,24,25] Such observation implies a strong impact of the outer coordination sphere modification on activity of the molybdenum complexes.…”

“…However, scrutinizing a wider range of compounds bearing modified Cp/Ind ring has shown unusually high cytotoxicity against MOLT‐4 and HL‐60 leukemia cells for particular complexes of 2,2’‐bipyridine (bpy) [23] even though parent cyclopentadienyl species [(η 5 ‐Cp)Mo(CO) 2 (bpy)][BF 4 ] is almost inactive [16] . The improved activity has been documented for the molybdenum compounds with amine and thiophene functions in the side chain of the Cp/Ind ligand [23,24,25] . Such observation implies a strong impact of the outer coordination sphere modification on activity of the molybdenum complexes.…”

Crystal structure of bis[(η5-tert-butylcyclopentadienyl)tricarbonylmolybdenum(I)](Mo—Mo)

“…Cyclopentadienyl (Cp) complexes can be employed as versatile precursors for the synthesis of new functional materials, including heterocycles, catalysts, organic conductors or pharmaceuticals (Absolonova ´et al, 2021;Kharitonov et al, 2022). Not only the exchange of the central metal atoms to which the Cp ligands are bound, but also the decoration of Cp ligands with functional groups can be used as a synthetic strategy to develop new catalysts (Loginov et al, 2019).…”