Synthesis and Anticancer Activity of Gold Porphyrin Linked to Malonate Diamine Platinum Complexes.

Isabelle Toubia,Ludivine Larue,Fabrice Odobel,Magali Gary-Bobo,Rabab Aoun,Christophe Nguyen,Lamiaa M A Ali,Marwan Kobeissi,Céline Frochot,Stéphane Diring

doi:10.1021/acs.inorgchem.9b01981

Abstract

Recently, gold(III) porphyrins have gained great interest as anticancer drugs not only for the stability of gold(III) but also for the functionalization of the porphyrin to allow bridging with another metal such as platinum(II). We report here, for the first time, the synthesis of three new bimetal compounds containing a gold(III) porphyrin conjugated to a platinum diamine moiety through malonate bridging to obtain enhanced cytotoxicity from both metals combined with the phototoxicity of the porphyrin. The three complexes differ in the type of diamine ligand around platinum(II): ammonia (NH3), cyclohexanediamine (CyDA), and pyridylmethylamine (Py). The synthesis was carried out using the complexation of activated malonic acid derivatives with aquadiaminoplatinum(II) complexes, and the products were characterized by IR, NMR, mass spectra, and elementary analysis. The cytotoxic activity of the conjugates was screened in both healthy cell lines and cancer cell lines, human fibroblast cells (FS-68) and human breast cancer cells (MCF-7), and was compared to that of the corresponding platinum(II) complexes. The cyclohexyldiamine (CyDA) derivative exhibited the greatest cytotoxic effect among the series. The results showed that Au(III)/Pt(II) conjugates are more potent by 2-5.6-fold than the corresponding platinum complexes. Moreover, the dyad AuP-PtCyDA is 18% more potent and also more selective toward cancer cells than the parent gold porphyrin substituted with malonic acid. On the other hand, the IC50 of the dyad AuP-PtCyDA is 43% lower than that of AuTPP but is more selective toward healthy cells. Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of other reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state. In addition, the increase in cancer cell death obtained after light irradiation is totally absent in healthy cells, demonstrating the specificity of this PDT treatment on cancer cells. Our findings imply that the incorporation of two different cytotoxic metals in the same molecule represents a remarkable cytotoxic effect in comparison to traditional homometallic Pt(II) drugs.

Highlights

Cancer still remains one the major cause of mortality in the world in spite of the many progresses made in medical treatments for several decades
Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of others reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state
We report three new dyads consisting of two appended cytotoxic moieties such as a gold(III) porphyrin and a platinum complex and their biological properties towards cancer cells were investigated in the dark and upon light excitation (PDT effect) and compared to their corresponding individual platinum(II) complexes

Summary

Introduction

Cancer still remains one the major cause of mortality in the world in spite of the many progresses made in medical treatments for several decades. This affinity is not sufficient legitimating that targeting strategies are currently explored to enhance the selectivity towards cancer cells.[13] Overall, the gold porphyrin platinum complex conjugates could have superior anticancer activity than individual compounds To test this idea, we report the preparation and the biological properties of three new dyads composed of gold porphyrin connected to a platinum diamine complex liganded via a malonate anchor (Chart 1). The additional cell mortality generated upon light excitation remains modest, indicating that gold porphyrins have weak, but not null, cytotoxic as compared for other sensitizers, such as free base porphyrins.13a, 27 As mentioned above, the low phototoxicity of gold porphyrins is certainly explained by the very weak singlet oxygen generation quantum yield of these compounds, since porphyrins usually display higher ones.27a, 28. This result highlights the specific effect of PDT on cancer cells and suggests that there could be no photoxicity on healthy cells around the tumor

Conclusion

Findings

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