Photocytotoxic 3d-metal scorpionates with a 1,8-naphthalimide chromophore showing photoinduced DNA and protein cleavage activity

Abstract

Ternary 3d-metal complexes of formulation [M(T_p^Ph)(py-nap)](ClO₄) (1-3), where M is Co(II) (1), Cu(II) (2), and Zn(II) (3); T_p^Ph is anionic tris(3-phenylpyrazolyl)borate; and py-nap is a pyridyl ligand with a conjugated 1,8-naphthalimide moiety, have been prepared from the reaction of metal perchlorate with KT_p^Ph and py-nap in CH₂Cl₂. The complexes have been characterized from analytical and physicochemical data. The complexes are stable in solution as evidenced from the electrospray ionization mass spectrometry data. The complexes show good binding propensity with calf thymus (CT) DNA, giving binding constant (K_b) values of 10⁵ M^-1 and a molecular "light-switch" effect that results in an enhancement of the emission intensity of the naphthalimide chromophore on binding to CT DNA. The complexes do not show any hydrolytic cleavage of DNA. They show poor chemical nuclease activity in the presence of 3-mercaptopropionic acid or hydrogen peroxide (H₂O₂). The Co(II) and Cu(II) complexes exhibit oxidative pUC19 DNA cleavage activity in UV-A light of 365 nm. The Zn(II) complex shows moderate DNA photocleavage activity at 365 nm. The Cu(II) complex 2 displays photoinduced DNA cleavage activity in red light of 647.1 nm and 676 nm and near-IR light of >750 nm. A mechanistic study in UV-A and visible light suggests the involvement of the hydroxyl radical as the reactive species in the DNA photocleavage reactions. The complexes also show good bovine serum albumin (BSA) protein binding propensity, giving K_BSA values of ~10⁵ M^-1. Complexes 1 and 2 display significant photoinduced BSA cleavage activity in UV-A light. The Co(II) complex 1 shows a significant photocytotoxic effect in HeLa cervical cancer cells on exposure to UV-A light of 365 nm, giving an IC₅₀ value of 32 μM. The IC₅₀ value for the py-nap ligand alone is 41.42 μM in UV-A light. The IC₅₀ value is >200 μM in the dark, indicating poor dark toxicity of 1. The Cu(II) complex 2 exhibits moderate photocytotoxicity and significant dark toxicity, giving IC₅₀ values of 18.6 μM and 29.7 μM in UV-A light and in the dark, respectively.