Novel achiral titanocene anti-cancer drugs synthesised from bis-N,N-dimethylamino fulvene and lithiated heterocyclic compounds.
From the carbolithiation of 6-bis-N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4) resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50)-values obtained were of 240, and 270 microM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC(50)-value of 36 microM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC(50) = 5.5 microM) and almost ten times less cytotoxic than cisplatin, which showed an IC(50)-value of 3.3 microM, when tested on the LLC-PK cell line.
Conway Institute of Biomolecular and Biomedical Research, The UCD School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology (CSCB), University College Dublin, Belfield, Dublin 4, Ireland.
Clara
C
Pampillón
James
J
Claffey
Megan
M
Hogan
Matthias
M
Tacke
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; D003517:Cyclopentanes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C406884:titanocene; C017332:fulvene