Platinum-based chemotherapy has been a mainstay of oncology for a number of decades. Currently, three platinum(II) complexes, cisplatin, oxaliplatin, and carboplatin, are approved by the FDA. These drugs show very potent antiproliferative activity but are characterized by dose-limiting side effects. An attractive means of modulating the reactivity, and hence presumably their off-target toxicity, of platinum complexes is to use a platinum(IV) species. Typically, Pt(IV) complexes are kinetically less reactive than their platinum(II) analogues. Pt(IV) complexes may be viewed as prodrugs because it is belived that they need to be reduced to Pt(II) to be active. This activation by reduction occurs intracellularly, where the concentration of reducing agents is generally higher. It’s would be interesting to take advantage of the relative inertness of some Pt(IV) complexes and activate them by reduction preferentially in the cancer cells. In this presentation we describe a new approach to achieving the reductive activation of Pt(IV) species. It is based on the use of texaphyrins. In previous work,[1] we showed that motexafin gadolinium (MGd), a particular texaphyrin derivative,[2], not only accumulates preferentially in cancer tissues but also acts as a redox mediator producing reactive oxygen species under aerobic conditions in the presence of biological reducing agents such as sodium ascorbate. We have now discovered[3] that in presence of a platinum(IV) complex, MGd catalyzes the reduction of the metal ion, leading to the formation of the active Pt(II) form. Since MGd tends to accumulate more in cancer tissue, this activation is expected to be selective in vivo. This targeting can be increased via the creation of so-called conjugates, wherein the texaphyrin is linked directly to the Pt(IV) center.[4] [1] D. Magda, N. Gerasimchuk, P. Lecane, R. A. Miller, J. E. Biaglow and J. L. Sessler, Chem. Commun. 2002, 2730. [2] J. L. Sessler, T. D. Mody, G. W. Hemmi, V. Lynch, Inorg. Chem. 1993, 32, 3175. [3] G. Thiabaud, J. L. Arambula, Z. H. Siddik, J. L. Sessler U.S. Provisional Patent Application, 2015, “Methods Of Treating Cancers Comprising Administering A Texaphryin Compound and A Metal Chemotherapeutic Complex”. [4] G. Thiabaud, J. L. Arambula, Z. H. Siddik, J. L. Sessler, Chem. Eur. J., 2014, 20, 8942.

Combination of texaphyrin and platinum(IV) prodrugs as a potential new anticancer therapy

251st National Meeting (2016)

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