COMMUNICATION
Target-selective degradation of proteins by a light-activated
2-phenylquinoline-estradiol hybrid{
Akane Suzuki, Kana Tsumura, Takeo Tsuzuki, Shuichi Matsumura and Kazunobu Toshima*
Received (in Cambridge, UK) 13th June 2007, Accepted 27th July 2007
First published as an Advance Article on the web 10th August 2007
DOI: 10.1039/b708947c
protein (Fig. 1). It has previously been reported that the
A designed 2-phenylquinoline-estradiol hybrid effectively and
selectively degraded the target transcription factor, human
estrogen receptor-a (hER-a), which has a high affinity with the
estradiol moiety, under long-wavelength UV photo-irradiation,
without additives and under neutral conditions.
2-phenylquinoline scaffold has some similarity to estrogen in
terms of its affinity with hER.4 Furthermore, modulation of hER-
a function is an important factor in a variety of diseases, including
breast cancer and osteoporosis.5
First, we examined the photo-induced protein-degrading activity
of 1 at concentrations of 10, 3.0, 1.0 and 0.1 mM against 1.0 mM of
hER-a in 20% acetonitrile–Tris-HCl buffer (pH 8.0, 50 mM) using
a long-wavelength UV lamp (365 nm, 100 W, 4 mW cm22) for
photo-irradiation. The progress of the photo-degradation reaction
was monitored by sodium dodecyl sulfate polyacrylamide gel
electrophoresis (SDS-PAGE);6 the results are shown in Fig. 2.
Comparison of lanes 3 and 4 with lane 2 shows that neither photo-
irradiation of hER-a in the absence of 1 (lane 3) or treatment of
hER-a with 1 without photo-irradiation (lane 4) resulted in a
change in the SDS-PAGE profile. In contrast, lane 5 shows fading
of the SDS-PAGE band corresponding to hER-a after exposure to
1 with photo-irradiation, which indicates that degradation of hER-
a took place. These results show that 2-phenylquinoline (1) is
capable of degrading a protein, hER-a, upon irradiation with long
wavelength UV light and without further additives, although its
ability is not particularly high. Because degradation of hER-a by 1
did not take place in the absence of light, it was confirmed that UV
light functioned as a trigger to initiate protein degradation by 1. In
addition, since the pattern obtained for hER-a degradation by 1
contained faded and smear bands, it was concluded that
degradation of hER-a by 1 took place in a random fashion.7
In order to improve the protein degrading ability and selectivity
of 2-phenylquinoline (1), we designed and synthesized hybrid
molecule 2, which consists of 2-phenylquinoline and estradiol
(Fig. 1). Estradiol has very strong and selective affinity with hER-
a. The hybrid 2 was synthesized by a modified version of the
procedure reported by Jones et al. in which an enediyne was
employed as a protein cleaver.8 In the chemical synthesis of hybrid
2, which is outlined in Scheme 1, the commercially available
Proteins are key players in many biological events. The develop-
ment of new methods for selective control of specific protein
functions is of considerable importance in the fields of chemistry,
biology, and medicine. In this context, the possibility of developing
an organic photochemical agent that can degrade proteins by
irradiation with a specific wavelength of light under mild
conditions and without any additives (such as metals or reducing
agents) has attracted much attention.1 We reported recently that
anthraquinones can act as protein photocleavers.2 However, there
have as yet been no reports of methods in which a light-activated
agent of this type is used for selective degradation of a target
protein. Here, we report the target-selective degradation of a
protein induced by a light-activated small organic molecule. A
2-phenylquinoline derivative was found to be capable of degrading
proteins under long-wavelength UV photo-irradiation, without
additives and under neutral conditions. Furthermore, the designed
and synthesized 2-phenylquinoline-estradiol hybrid effectively and
selectively degraded the target protein, a transcription factor
known as human estrogen receptor-a (hER-a), which has a high
affinity with the estradiol moiety. To the best of our knowledge,
this is the first successful example of target-selective degradation of
a protein by light switching under neutral conditions. We
anticipate that the present method will be used as a ‘‘smart’’
technology for selective control of specific functions of target
proteins; in addition, it should prove useful for structure–activity
studies of proteins, investigation of structural domains, and design
of novel therapeutic drugs targeting proteins.
In our previous work, certain 2-phenylquinoline derivatives
were found to be efficient agents for DNA photocleavage.3 Based
on these findings, we expected that if a 2-phenylquinoline
derivative could be made to produce a radical or a reactive
oxygen species (ROS) by photo-excitation, this could be used for
degradation not only of DNA, but also of protein molecules. To
investigate this hypothesis, we selected 2-phenylquinoline itself (1)
as a protein photo-degrading agent, and hER-a as the target
Department of Applied Chemistry, Faculty of Science and Technology,
Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522,
Japan. E-mail: toshima@applc.keio.ac.jp; Fax: +81 45-566-1576;
Tel: +81 45-566-1576
{ Electronic supplementary information (ESI) available: Experimental
procedures for chemical synthesis of 2 and degradation reactions of
proteins. See DOI: 10.1039/b708947c
Fig. 1 Chemical structures of 2-phenylquinoline (1) and 2-phenylquino-
line-estradiol hybrid 2.
4260 | Chem. Commun., 2007, 4260–4262
This journal is ß The Royal Society of Chemistry 2007
Suzuki, Akane
