Photoactivatable Cell-Selective Dinuclear trans-Diazidoplatinum(IV) Anticancer Prodrugs

Abstract

A series of dinuclear octahedral PtIV complexes trans,trans,trans-[{Pt(N3)2(py)2(OH)(OC(O)CH2CH2C(O)NH)}2R] containing pyridine (py) and bridging dicarboxylate [R = −CH2CH2– (1), trans-1,2-C6H10– (2), p-C6H4– (3), −CH2CH2CH2CH2– (4)] ligands have been synthesized and characterized, including the X-ray crystal structures of complexes 1·2MeOH and 4, the first photoactivatable dinuclear PtIV complexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N3 → Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm2, 1 h), including A2780 human ovarian and esophageal OE19 cells with IC50 values of 8.8–78.3 μM, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4 are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRC5 lung fibroblasts), with IC50 values >100 μM, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear PtIV complexes. Liquid chromatography–mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.

Diazido platinum(iv) complexes for photoactivated anticancer chemotherapy

“…Dinuclear complexes based on 13 also displayed photodecomposition with blue light irradiation. 82 Diazido-Pt(IV) complexes incorporating π-conjugated bidentate diimine ligands trans, cis-[Pt(2,2′-Bpy)(OAc) 2 (N 3 ) 2 ] (14, 2,2′-Bpy = 2,2′-bipyridine) and trans, cis-[Pt(Phen)(OAc) 2 (N 3 ) 2 ] (15, Phen = phenanthroline) exhibited greater absorption at longer wavelengths compared with previously reported diazido-Pt(IV) complexes. 83 Their photodecompositions were observed upon irradiation with both UVA and visible green light.…”

“…10) display similar photocytotoxicity towards cisplatin-resistant ovarian A2780cis and A2780 cells, and interestingly are relatively non-toxic toward normal cells (MRC-5 lung fibroblasts). 82 The TEMPO radical has been conjugated to 13 since nitroxide radicals themselves can possess potent anticancer activity (17, Fig. 10).…”

Axial functionalisation of photoactive diazido platinum(iv) anticancer complexes

“…Notably, the major Pt-GMP adducts generated by 2a are the same as those for 1 and its derivatives, indicating that the axial substituents do not affect the interaction between guanine and the platinum centre upon irradiation. 15,34 Photocytotoxicity and cellular accumulation studies…”

“…The photocytotoxicity of complexes 2a-2c and 3a-3c was determined in A2780 ovarian and A549 lung cancer cells, after 1 h drug incubation, 1 h irradiation (465 nm, 4.8 mW cm −2 ) and 00592, a N NO = 1.43 mT, and a H β = 1.45 mT). 34 24 h recovery ( Table 2). Their dark cytotoxicity was also determined after 2 h incubation and 24 h recovery in A2780 and A549 cancer cells, as well as MRC-5 normal lung fibroblasts for comparison.…”

“…IC 50 values and photocytotoxicity indices (PI) for mono-functionalised complexes 2a-2c and di-functionalised 3a-3c for A2780 ovarian and A549 lung cancer cells, and MRC-5 normal lung fibroblasts (1 h incubation, 1 h irradiation (465 nm), followed by 24 h recovery). Data for unfunctionalised complex 1 are listed for comparison34 Open Access Article. Published on 26 August 2020.…”