Photocytotoxic Copper(II) Complexes with Schiff-Base Scaffolds
Rong-KaiLin, Chin-I Chiu, Cho-Han Hsu, Ying-Ju Lai, Parthiban Venkatesan, Po-Han Huang,
Ping-Shan Lai,* and Chu-Chieh Lin*
Abstract: Photodynamic therapy (PDT) is apromisingand
minimally invasive method for the treatmentofsuperficial
diseases, and photosensitizers with high phototoxicity indi-
ces (defined as (IC
)) are essential for the de-
velopment of ideal photosensitizing properties for this tech-
nology.Herein,wereport aseries of photocytotoxic cop-
per(II) complexes [Cu(
QYMP = N,N,O-triden-
tate Schiff-base derivatives, dppn = benzo[i]dipyrido[3,2-
a;2’,3’-c]phenazine), the structures of which have been con-
firmed by mass spectrometry and FTIR spectroscopy.X-ray
crystallographyrevealed that the CuN
Ocore of the
)complex (3)has adistorted
against human squamous cell carcinoma(SCC15)and 296
against basal cell carcinoma (BCC) cell lines have been deter-
)(4). Thiscan be at-
tributed to the formation of reactive oxygen species, cell
apoptosis, and caspase-3 activation, indicating high poten-
tial of complex 4 as aphotosensitizer candidateinPDT.
Thus,copper complexes bearing suitable Schiff-base ligands
with adppn co-ligandmay be considered for the design of
efficient metal-based anticancer agentsfor PDT.
Due to the lowerside effects of photodynamic therapy(PDT)
as compared to chemo- and radiotherapies, it has been effec-
tively applied in the development of therapeutic cancertreat-
For this purpose, several photosensitizers, such as
Photofrin, 5-aminolevulinic acid (ALA), Foscan, and Verteporn,
have been clinically approved for the treatment of cancersand
skin diseases with light irradiation.
selectivity and efficacy against cancerinPDT treatments, tran-
sition metal complexes have been considered.
essential transitionmetals,copperisthe third most abundant
crucial transition metal ion in human tissueand plays impor-
tant biological roles in the activesite of cytochrome coxidase
and as acatalyst in oxidation–reduction reactions in many pro-
Furthermore, comparedtoplatinum and ruthenium
complexes,copper complexes have demonstratedgood antitu-
mor activity with fewer side effects.
pyridine-ligand-based complexes have exhibited high reactivity
toward DNA cleavage and cell apoptosis.
In asimilar fashion, metal complexes with Schiff-base scaf-
folds have been effectively applied as antibacterial chemother-
apeutic moieties in medicine.
The chemotherapeutic effect
-containing Schiff-base complexes may be enhanced by
tuningthe electronic properties of the metal centerorthe li-
plexeshave been widely utilized in chemicalnucleases as oxi-
dizing or reducing co-reactants to induce the hydrolysis or oxi-
dativecleavage of DNA.
For instance, asquare-planar Cu
complex chelated by an N,N,O-tridentate Schiff base (with phe-
nolic and pyridyl ring binding sites) has recentlybeen reported
to efficiently catalyzeDNA cleavage withoutthe need for are-
ductant co-factor.The DNA cleavage activity of such com-
plexesoffersarational approach for the development of Cu
complexes with potential as anticancer drugs.
In this work, copper complexes comprising an N,N,O-triden-
tate Schiff-base ligand with abenzo[i]dipyrido[3,2-a;2’,3’-
c]phenazine (dppn) moiety have been studiedfor in vitro pho-
tocytotoxicity in photodynamic therapy and cell apoptosis. The
synthesized copper complexes [Cu(
N,N,O-tridentate Schiff base) (1–6)have been extensivelychar-
acterizedbyspectroscopic and cyclic voltammetric studies.
Furthermore, the crystal structure of complex 3 has been de-
terminedbysingle-crystal X-ray analysis. Notably,the
QYMP)(dppn)] complexes demonstrated DNA cleavage
ability and cell viability,and induced reactive oxygen species
(ROS) generation in cell apoptosis. Ultimately,the photody-
namic properties of the [Cu(
monitored and demonstrated by flow cytometry and confocal
microscopy imaging investigations.
[a] R.-K. Lin, C.-I. Chiu, C.-H. Hsu, Y.-J. Lai, P. Venkatesan, P.-H. Huang, P. -S. Lai,
Department of Chemistry,NationalChung Hsing University
No. 250, Kuo-Kuang Road, Taichung 402(Taiwan)
Supporting information and the ORCID number for the authorofthis article
can be found under https://doi.org/10.1002/chem.201705640.
Chem. Eur.J.2018, 24,4111–4120 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim4111