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trans-Platinum Compounds in Cancer Therapy: A Largely Unexplored Strategy for Identifying Novel Antitumor Platinum Drugs

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Metallopharmaceuticals I

Part of the book series: Topics in Biological Inorganic Chemistry ((TBIC,volume 1))

Abstract

In recent years, several exceptions to the rule that the presence of two good leaving groups in cis positions of platinum complexes is a necessary condition for their antitumor activity have been reported. These “exceptions”, which frequently show activity against cis-DDP-resistant cell lines, fall into three classes: 1) platinum(IV) complexes with the general formula trans-[PtC12X2(L)(L’)] (X=hydroxide or carboxylate; L, L’=ammine or amine), 2) trans-[PtC12(L)(L’)] with L and/or L’=pyridine-like ligands, and 3) trans-[PtC12L2] with L=iminoether. Greater inertness in biological media appears to be a common feature of these compounds. Both inter-strand cross-links and single-strand breaks have been proposed as cytotoxic lesions for platinum(IV) species, which might require reduction to platinum(II) prior to their interaction with DNA. Increased cell-membrane permeability, binding affinity for alternating puzine-pyrimidine sites, and enhanced inter-strand cross-linking ability were found for the second class of compounds. Finally, stable monofunctional adducts with duplex DNA, capable of inhibiting DNA and RNA synthesis, appeared to be the cytotoxic lesion for platinum-iminoether complexes. Taken together, these results show that trans-geometry does not impose steric constraints that inhibit antitumor activity and indicate the possibility of identifying novel antitumor platinum drugs in a largely unexplored area.

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Authors and Affiliations

  1. Dipartimento Farmaco-Chimico, Università di Bari, via E. Orabona 4, 70125, Bari, Italy

    Giovanni Natile

  2. Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Bari, piazza G. Cesare, 70126, Bari, Italy

    Mauro Coluccia

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  1. Giovanni Natile
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  2. Mauro Coluccia
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  1. Department of Chemistry, Merkert Center, Boston College, 02167, Chestnut Hill, MA, USA

    Michael J. Clarke

  2. Department of Chemistry, University of Edinburgh, King’s Building, West Mains Road, EH 3JJ, Edinburgh, Scotland, GB

    Peter J. Sadler

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Natile, G., Coluccia, M. (1999). trans-Platinum Compounds in Cancer Therapy: A Largely Unexplored Strategy for Identifying Novel Antitumor Platinum Drugs. In: Clarke, M.J., Sadler, P.J. (eds) Metallopharmaceuticals I. Topics in Biological Inorganic Chemistry, vol 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-03815-4_3

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  • DOI: https://doi.org/10.1007/978-3-662-03815-4_3

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