Copper(ii) curcumin complexes for endoplasmic reticulum targeted photocytotoxicity

Abstract

Three copper(II) complexes viz. [Cu(cur)(L)(ClO₄)] (1–3), where Hcur is curcumin and L is 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, 2), or dipyrido[3,2-a:2′,3′-c]phenazine (dppz, 3) were synthesized, fully characterized by various physicochemical methods and evaluated for their light-assisted chemotherapeutic potential. The complexes [Cu(acac)(L)(ClO₄)] (4–6), where Hacac is acetylacetone and L is phen (in 4), dpq (in 5) and dppz (in 6), were synthesized and used as controls. The solid state structures of complexes 4 and 5 were determined by single crystal X-ray diffraction. The curcumin complexes (1–3) were redox inactive at the copper centre, whereas the acetylacetonato complexes (4–6) displayed a Cu(II)/Cu(I) couple at ∼0.1 V vs. Ag/AgCl reference electrode in DMF. Complexes 1–3 showed an intense curcumin-based band at ∼440 nm in DMF–Tris–HCl buffer (pH = 7.2) (1 : 9 v/v) which masks the copper based d–d band. The complexes bind to human serum albumin (HSA) with moderate efficacy. They also displayed significant binding affinity for calf-thymus (CT) DNA. The lipophilic curcumin complexes show remarkable visible light induced cytotoxicity (IC₅₀ = ∼4 μM) with high phototoxic indices (PI) with low dark toxicity in human cervical carcinoma (HeLa) and human lung carcinoma (A549) cells. The corresponding acetylacetonato controls (4–6) did not show significant cytotoxicity in the dark or light. DCFDA and annexin V-FITC/PI assays using flow cytometry confirm the induction of significant apoptosis in cancer cells via generation of cytotoxic reactive oxygen species upon photoactivation. Confocal microscopic images using complex 3 demonstrate localization of the complexes predominantly in the endoplasmic reticulum of HeLa cells.