Abstract
We report a detailed study of a promising photoactivatable metal-based anticancer prodrug candidate, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (C1; py = pyridine), using vibrational spectroscopic techniques. Attenuated total reflection Fourier transform infrared (ATR-FTIR), Raman, and synchrotron radiation far-IR (SR-FIR) spectroscopies were applied to obtain highly resolved ligand and Pt-ligand vibrations for C1 and its precursors (trans-[Pt(N3)2(py)2] (C2) and trans-[PtCl2(py)2] (C3)). Distinct IR- and Raman-active vibrational modes were assigned with the aid of density functional theory calculations, and trends in the frequency shifts as a function of changing Pt coordination environment were determined and detailed for the first time. The data provide the ligand and Pt-ligand (azide, hydroxide, pyridine) vibrational signatures for C1 in the mid- and far-IR region, which will provide a basis for the better understanding of the interaction of C1 with biomolecules.
Highlights
Cancer chemotherapy is landmarked by the indisputable clinical success of cisplatin,[1−3] with ca. 50% of all the cancer patients receiving a platinum compound.[4]
photodynamic therapy (PDT) relies on the presence of oxygen at the targeted treatment site, which is a major drawback, as many malignant and most aggressive tumors are hypoxic by nature.[20]
Diazido anticancer prodrug candidate for photoactivated chemotherapy (PACT), which can be locally activated in cancer cells under UV-A and visible light irradiation while being stable in the dark under biological conditions.[10,14,29−31] Upon photoactivation, C1 undergoes changes in the metal coordination environment, giving rise to Pt(II), nitrene, and radical photoproducts, as well as cleaved ligands, which act in concert to elicit the observed multitargeted biological activity;[10] irradiation of C1 results in stalling of RNA polymerase II and an ∼16-fold increase in DNA “platination” compared to cisplatin.[32]
Summary
Cancer chemotherapy is landmarked by the indisputable clinical success of cisplatin,[1−3] with ca. 50% of all the cancer patients receiving a platinum compound.[4]. PDT relies on the presence of oxygen at the targeted treatment site, which is a major drawback, as many malignant and most aggressive tumors are hypoxic by nature.[20] By contrast, local activation of metalbased prodrugs by light, referred to as inorganic photoactivated chemotherapy (PACT), offers the possibility of oxygenindependent treatment, where reactive (metal-based) species are formed upon irradiation.−. Diazido anticancer prodrug candidate for PACT, which can be locally activated in cancer cells under UV-A and visible light irradiation while being stable in the dark under biological conditions.[10,14,29−31] Upon photoactivation, C1 undergoes changes in the metal coordination environment, giving rise to Pt(II), nitrene, and radical photoproducts, as well as cleaved ligands, which act in concert to elicit the observed multitargeted biological activity;[10] irradiation of C1 results in stalling of RNA polymerase II and an ∼16-fold increase in DNA “platination” compared to cisplatin.[32]
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