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

Abstract

Recently, Gold(III) porphyrins have gained great interest as anticancer drugs not only for stability of gold(III), but also for the functionalization of porphyrin to allow bridging with another metal such as platinum(II). We report here, for the first time, the synthesis of three new bi-metal compounds containing gold(III) porphyrin conjugated to a platinum diamine moiety through malonate bridging to obtain enhanced cytotoxicity from both metals combined to the phototoxicity of the porphyrin. The three complexes differ by type of diamine ligands around platinum(II) which are ammonia (NH3), cyclohexane diamine (CyDA) and pyridine methyl amine (Py). The synthesis was carried out using complexation of activated malonic acid derivatives with aqua diamino-platinum(II) complexes and the products were characterized by IR, NMR, mass spectra and by elementary analysis. Cytotoxic activity of the conjugates was screened in both healthy and cancer cell lines, human fibroblast cells (FS-68) and human breast cancer cells (MCF-7), and was compared to the corresponding platinum(II) complexes. The cyclohexyldiamine (CyDA) derivative exhibited the most cytotoxic effect among the series. The results showed that gold(III)/Pt(II)conjugates are more potent by 2 to 5.6-fold than the corresponding platinum complexes. Moreover, the dyad AuP-PtCyDA is 18% more potent and also more selective towards cancer cells than the parent gold porphyrin substituted with malonic acid. On the other hand, the IC50 of dyad AuP-PtCyDA is 43% lower than that of AuTPP, but more selective towards healthy cells. 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. 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 compared to traditional homometallic Pt(II) drugs.

Opportunities for Persistent Luminescent Nanoparticles in Luminescence Imaging of Biological Systems and Photodynamic Therapy

“…Organic dyes such as porphyrins, chlorins, phthalocyanines, and xanthenes are often used in PDT [ 87 , 88 ]. However, this class of compounds is prone to photobleaching, have low light-dark cytotoxicity ratios, and is also known to form aggregates that decrease the singlet oxygen generation efficiency as a function of the elapsed time, and thus decreases the efficiency of the treatment [ 89 ]. Additionally, the need for continuous in situ illumination causes damage to the skin and tissues.…”

Anticancer Gold(III) Compounds With Porphyrin or N-heterocyclic Carbene Ligands

“…The porphyrin ligand can stabilize the gold(III) ion against demetalation and reduction by the biological reductant glutathione (Sun et al, 2010 ). In vitro biological studies have proven the high anticancer potency of gold(III) porphyrin complexes against a wide range of cancer cell lines, such as neuroblastoma, melanoma, ovarian, breast, colorectal, lung, and nasopharyngeal cancers, with IC 50 values at low micromolar or even nanomolar levels (Lammer et al, 2015 ; Toubia et al, 2019 ). Moreover, in vivo studies have demonstrated the promising tumor growth inhibitory ability of gold(III) porphyrins in different mouse models of cancer ( Figures 2A,B,D ) and the induction of apoptosis in tumor xenograft tissues ( Figure 2E ).…”

Synthesis, Biological Activity and Action Mechanism Study of Novel Chalcone Derivatives Containing Malonate

“…Therefore, chalcone has potential research value in the field of new pesticide synthesis. Malonate compounds are important raw materials for the synthesis of many pharmaceutical intermediates and their pharmacologically effective groups also have antibacterial, antiviral, anticancer, anti‐inflammatory and other biological activities.…”