Endoplasmic reticulum targeting tumour selective photocytotoxic oxovanadium(iv) complexes having vitamin-B6 and acridinyl moieties

Abstract

Oxovanadium(IV) complexes of vitamin-B6 Schiff base, viz., [VO(HL¹/L²/L³)(B)]Cl (1–4), where B is 2,2′-bipyridine (bpy in 1 and 2), 11-(9-acridinyl)dipyrido[3,2-a:2′,3′-c]phenazine (acdppz in 3 and 4), H₂L¹·HCl is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-1-ium chloride (in 1 and 4), HL² is 2-(((2-(1H-imidazol-4-yl)ethyl)imino)methyl)phenol (in 2) and HL³ is 4-(((2-(1H-imidazol-4-yl)ethyl)imino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol (in 3) were synthesized, characterized and their cellular uptake, photo-activated cytotoxicity and intracellular localization were studied. Complexes 1a, as the perchlorate salt of 1, and 2a, as the hexafluorophosphate salt of 2, were structurally characterized. Vitamin-B6 transporting membrane carrier (VTC) mediated entry into tumour cells in preference to the normal ones seems to be responsible for the higher cellular uptake of the complexes into HeLa and MCF-7 cells over MCF-10A cells. Complexes 3 and 4 having acdppz as the photosensitizer exhibit remarkable photocytotoxicity in these cancer cells giving IC₅₀ of <0.9 μM. The complexes remain non-toxic in the dark. The complexes show photo-induced apoptotic cell death via singlet oxygen (¹O₂) generation. Fluorescence microscopy reveals specific localization of complex 4 to endoplasmic reticulum (ER) and generation of ¹O₂ possibly leads to apoptotic cell death by triggering ER stress response (ERSR).