Diazido Mixed‐Amine Platinum(IV) Anticancer Complexes Activatable by Visible‐Light Form Novel DNA Adducts

Abstract

Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable PtIV prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans-[Pt(N3)2(OH)2(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans-[Pt(N3)2(OH)2(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on H bonding and crystal packing, as shown by polymorphs 1 p and 1 q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis). Analysis of binding to calf-thymus (CT), plasmids, oligonucleotide DNA and individual nucleotides reveals that photoactivated 1 and 2 form both mono- and bifunctional DNA lesions, with preference for G and C, similar to transplatin, but with significantly larger unwinding angles and a higher percentage of interstrand cross-links, with evidence for DNA strand cross-linking further supported by a comet assay. DNA lesions of 1 and 2 on a 50 bp duplex were not recognised by HMGB1 protein, in contrast to cisplatin-type lesions. The photo-induced platination reactions of DNA by 1 and 2 show similarities with the products of the dark reactions of the PtII compounds trans-[PtCl2(MA)(Py)] (5) and trans-[PtCl2(MA)(Tz)] (6). Following photoactivation, complex 2 reacted most rapidly with CT DNA, followed by 1, whereas the dark reactions of 5 and 6 with DNA were comparatively slow. Complexes 1 and 2 can therefore give rapid potent photocytotoxicity and novel DNA lesions in cancer cells, with no activity in the absence of irradiation.

Reduction Process of Tetraplatin in the Presence of Deoxyguanosine Monophosphate (dGMP): A Computational DFT Study

“…As imilar topic was also explored by Vicha et al [22] In contrastt op revious authors, they used the relativistic approach, that is, the two-component zeroth-order regular approximation (SO-ZORA) with the PBE0/TZP/COSMO computational level for successful determination of the NMR shielding constants.A nother interesting paper was recently published by Wilson et al [23] where, by combining experimental and computational tools, the oxidation of platinum(II) complexesw ith iodobenzene dichloride in DMF was studied, yieldingt he respectivep latinum(IV) analogues.T ime-dependent (TD)-DFT/ LANL2DZ/COSMO approachw as employed for the determination of the singlet excited states of both sets of Pt II and Pt IV complexes.T he calculations confirmed that the quenching of an excitation state (originally based on the LUMO in the Pt II complex) arises from the presence of metal-based dorbitals energetically positioned between the HOMO and the LUMO of the fluorophore ligand. Similar supporting calculations on diazido-platinum(IV) complexes were performed by Zhao et al [24] where thirty-two singlet and eightt riplet excited states with the corresponding oscillator strengths wered etermined by using aT D-DFT(PBE1PBE/LanL2DZ/CPCM) model. Based on am etal-ligand charge-transfer (LMCT) process of the azido ligand they confirmt he dissociative charactero ft he low-lying exited states.Q uantum chemistry parameters (for example, dipole moments, solvatione nergies, electrostatic potential, and partial charges) wereu sed in quantitative structure-activity relationship (QSAR)i nvestigations forn ovel cytotoxic Pt IV complexes by Varbanov et al…”

De Novo Generation of Singlet Oxygen and Ammine Ligands by Photoactivation of a Platinum Anticancer Complex

“…[3] A particularly potent photocytotoxic anticancer complex is trans,trans,trans-[Pt(N 3 ) 2 (OH) 2 (MA)(Py)] (1, MA = methylamine, Py = pyridine). [4] Herein we report the unprecedented oxidation of 5'-GMP by 1 upon irradiation with UVA and the identification of some unexpected reaction pathways involving singlet oxygen ( 1 O 2 ) and nitrene (Pt-N) intermediates. The source of the 1 O 2 was also investigated.…”

Visible‐Light‐Induced Annihilation of Tumor Cells with Platinum–Porphyrin Conjugates

“…Oxaliplatin was able to overcome some of the resistance associated with cisplatin. [8,9] Tetraplatinated porphyrins have long been used as supramolecular guests that interact with cationic, anionic, or neutral micelles [10] and have been studied as mimics of natural peroxidase. Hence, there is a growing need for new and effective drugs.…”