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Novel achiral titanocene anti-cancer drugs synthesised from bis-N,N-dimethylamino fulvene and lithiated heterocyclic compounds

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Abstract

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 TiCl4 resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC50-values obtained were of 240, and 270 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC50-value of 36 μM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC50 = 5.5 μM) and almost ten times less cytotoxic than cisplatin, which showed an IC50-value of 3.3 μM, when tested on the LLC-PK cell line.

Graphical abstract

Bis-(bis- (N,N-dimethylamino)-2-(N′-methylpyrrolyl)methylcyclopentadienyl) titanium (IV) dichloride, {η5-C5H4-CH[N(CH3)2]2[C5H3NCH3]}2TiCl2 was synthesised starting from 6-bis-(N,N-dimethylamino) fulvene and 2-N-methylpyrrolyl lithium. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells.

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Acknowledgements

The authors thank the Higher Education Authority (HEA), the Centre for Synthesis and Chemical Biology (CSCB), UCD and COST D39 for funding.

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Authors and Affiliations

  1. 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 Pampillón, James Claffey, Megan Hogan & Matthias Tacke

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  1. Clara Pampillón
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  2. James Claffey
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  3. Megan Hogan
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  4. Matthias Tacke
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Correspondence to Matthias Tacke.

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Pampillón, C., Claffey, J., Hogan, M. et al. Novel achiral titanocene anti-cancer drugs synthesised from bis-N,N-dimethylamino fulvene and lithiated heterocyclic compounds. Biometals 21, 197–204 (2008). https://doi.org/10.1007/s10534-007-9108-5

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  • DOI: https://doi.org/10.1007/s10534-007-9108-5

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