Communications
DOI: 10.1002/anie.201006887
DNA Recognition
Specific Blocking of CREB/DNA Binding by Cyclometalated
Platinum(II) Complexes **
Ping Wang, Chung-Hang Leung, Dik-Lung Ma, Raymond Wai-Yin Sun, Siu-Cheong Yan,
Qing-Shou Chen, and Chi-Ming Che*
DNA is one of the major targets for anticancer drugs, and, as
such, a large proportion of current chemotherapeutic anti-
cancer drugs are DNA-binding agents. Organic molecules
such as anthracyclines bind to the DNA duplex by two
binding modes, namely DNA intercalation and groove bind-
ing.[1] The binding of metal complexes to DNA is well
documented.[2] We propose to employ PtII and AuIII ions to
assemble organic ligands through metal–ligand coordination
into cationic planar structures that have a high level of
functionality; PtII complexes that bear chelating N-donor
ligands have been shown by us and other research groups to
display anticancer activities.[3–8] Cationic planar structures are
known to be bioactive and bind to DNA.[9] However, the
synthesis of organic planar cations that have sophisticated
structures could be a formidable challenge as this goal could
involve multistep synthesis. We have previously developed
cyclometalated PtII complexes that exhibit intercalation[4–7]
and minor-groove-binding[5] properties. The DNA-binding
reactions of the cyclometalated complexes [PtII(C^N^N)L]n+
(where C^N^N = 6-phenyl-2,2’-bipyridyl), which are struc-
turally analogous to [PtII(terpy)Cl]+ (terpy = 2,2’;6’,2’’-terpyr-
idyl), have been studied.[5–8] Given the structural diversity and
the ease with which the [PtII(C^N^N)L]n+ system could be
modified, these PtII complexes could form a class of anti-
cancer agents with tunable biological activities.
critical for normal cellular function. Most therapeutic
approaches to targeting transcription factors indirectly alter
their activity. Research at the chemistry/biology interface has
led to new ways of directly targeting transcription factors,
including blocking the transcription factor/DNA interaction
by DNA-binding agents.[12,13] The metallointercalator [L-1-
RhIII(MGP)2(phi)]5+ (MGP = methylguanidium phenanthro-
line, phi = phenanthrenequinone diimine) and the electro-
static surface binder [CrIII(salen)(H2O)2]+ (salen = N,N’-bis-
(salicylidene)ethylenediamine) are rare examples of metal
complexes that intercalate DNA in the major groove and
inhibit binding of transcription factors AP-1 and Sp1 to their
respective consensus DNA sequences.[14] More recently,
[RuII(phen)2(dppz)]2+ and [PtII(5,6-Me2phen)(S,S-dach)]2+
(phen = 1,10-phenanthroline,
dppz = dipyrido[3,2-a:2’,3’-
c]phenazine, Me2phen = dimethyl-1,10-phenanthroline,
dach = diaminocyclohexane) were found to interfere with
the interaction between the transcription factor PU.1 and
DNA.[15]
The cAMP response element binding protein (CREB) is a
well-characterized transcription factor of the basic leucine
zipper family.[16,17] CREB contacts the DNA major groove of
the consensus sequences referred to as cAMP response
elements (CRE), and thereby activates the transcription of
genes related to growth and survival.[18–21] The activation of
CREB has been demonstrated in a variety of tumor types,
such as acute myeloid/lymphoid leukemia and hepatocellular
carcinoma.[22–24] Herein, we report a class of PtII complexes
that effectively inhibit the DNA-binding activity of tran-
scription factors. Notably, a platinum-based DNA major
groove binder that specifically blocks CREB/DNA binding
has been identified.
Transcription factors are a large class of proteins that bind
to specific DNA sequences, thereby controlling the flow of
genetic information from DNA to mRNA,[10,11] and are thus
[*] P. Wang,[+] Dr. C.-H. Leung,[+] Dr. D.-L. Ma,[$] Dr. R. W.-Y. Sun,
Dr. S.-C. Yan, Dr. Q.-S. Chen, Prof. Dr. C.-M. Che
Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for
Drug Discovery and Synthesis
The cyclometalated PtII complexes 1a–b and 2a–c
(Scheme 1) were synthesized and characterized (see exper-
imental details in the Supporting Information; Figures S1–S6
and Table S1 give photophysical data for complexes 1 and 2
recorded in various solvents). A solution of 1a in CH2Cl2 at
298 K displays a low-energy emission band at lmax = 679 nm
(Figure 1) with vibrational spacing, lifetime, and quantum
yield of 1177 cmÀ1, 26.5 ms, and 0.01, respectively. The energy
of this emission is slightly lower than those of the triplet
intraligand (3IL) excited states of the AuI and PtII pyrenyla-
cetylide complexes (652 and 664 nm, respectively);[25] the
The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
Fax: (+852)2857-1586
E-mail: cmche@hku.hk
[$] Present address: Department of Chemistry, Hong Kong Baptist
University, Kowloon Tong, Hong Kong (P.R. China)
[+] These authors contributed equally to this work.
[**] This work was supported by the Area of Excellence Scheme
established under the University Grants Committee of the Hong
Kong Special Administrative Region, China (AoE/P-10/01), The
University of Hong Kong (University Development Fund), and the
Innovation Technology Fund (ITS/134/09FP) administrated by the
Innovation Technology Commission of the Hong Kong Special
Administrative Region, China. CREB=cAMP response element
binding protein.
3
emission of 1a is assigned to the IL excited state of 1-((4-
isocyano-3,5-diisopropylphenyl)ethynyl)pyrene. As shown in
Figure 1, the emission maximum is slightly red-shifted as the
solvent is changed from MeOH (672 nm) to MeCN (677 nm)
and CH2Cl2 (679 nm), that is, in the presence of solvents with
lower polarities. Complexes 1b and 2a–c exhibit an emission
Supporting information for this article is available on the WWW
2554
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 2554 –2558