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S Supporting Information
■ INTRODUCTION
The post-translational modification of histones to regulate gene
attractive route to new therapies for various cancers, and
research into new LSD1 inhibitors is an active area of research.
expression via the modeling of nucleosome structure is a central Metal complexes have attracted considerable attention as
theme in epigenetics. 1,2 This “histone code” includes anticancer agents in recent decades.23,24 Although metal
methylation, acetylation, phosphorylation, and ubiquitina- complexes tend not to be readily orally available, they possess
other benefits compared to purely organic molecules, making
tion.3,4 The presence of histone lysine demethylases suggests
them appealing alternatives for therapeutic agent develop-
that histone lysine methylation is a reversible epigenetic
modification.4,5 ment.25,26 Metal complexes can exhibit various shapes depend-
Lysine-specific demethylase 1 (LSD1) catalyzes the deme- ing on the coordination number of the metal complex and the
type of ligands.27 Recent interest has focused on the discovery
thylation of di- and monomethylated Lys4 of histone H3 but
of molecularly targeted metal against specific enzymes or
not trimethylated H3K4.6,7 LSD1 activity is central to the
protein−protein interactions.28−34 In particular, rhodium(III)
development and maintenance of acute myeloid leukemia
complexes have been discovered to inhibit STAT3, β-amyloid
(AML),8,9 as well as prostate carcinoma, colon carcinoma
fibrillation, and JAK2.35−37 Moreover, metal-based epigenetic
cancer, and breast cancer.10,11 Aberrant activity of LSD1 is
modulators have been very recently discovered.25,38 However,
linked with tumor suppressor gene silencing, promoting
there are no metal-based inhibitors of LSD1 reported to date.
tumorigenesis.12,13 Thus, considerable effort has been devoted
We report herein a novel rhodium(III) complex 1 as the first
to developing LSD1 inhibitors for the treatment of cancer,
metal-based inhibitor of LSD1 activity and that shows promise
despite a lack of precise mechanistic insight.14 Several types of
for the treatment of prostate cancer.
■
LSD1 inhibitors have been presented in the literature, including
peptides, natural products and their derivatives, and poly- RESULTS AND DISCUSSION
amines.15−19 Wang and co-workers have reported CBB1007
(6),20 a known potent, reversible, and substrate-competitive Synthesis and Characterization of Metal-Based Com-
LSD1 inhibitor in F9 cells. ORY-1001 (9),21 a potent and plexes. To develop potential metal-based scaffolds as LSD1
selective inhibitor of LSD1, has entered phase I clinical trials for inhibitors, rhodium(III) complexes 1−5 were synthesized
the treatment of AML, while 4-[[4-[[[(1R,2S)-2-phenyl- (Figure 1) bearing structurally diverse C∧N and N∧N ligands.
cyclopropyl]amino]methyl]piperidin-1-yl]methyl]benzoic acid Complex 1 bears the 4-chloro-2-phenylquinoline C∧N ligand,
(GSK2879552),22 an orally available, irreversible inhibitor of
LSD1, has also recently entered phase I trials for AML and Received: January 25, 2017
small-cell lung cancer therapy. Inhibition of LSD1 offers an Published: February 20, 2017
reduced LSD1 activity by nearly 74.7% at the same Figure 3. Top view of complex 1 bound to the LSD1 generated by
concentration.20 Complexes 2, 4, and 5 showed moderate molecular docking. LSD1 (PDB code 2V1D) is depicted in ribbon
inhibitory activity in this assay, while complex 3 was nearly form and is colored purple. Complex 1 is depicted as a space-filling
inactive. A dose−response experiment was then performed to representation showing carbon (yellow), oxygen (red), nitrogen
determine the efficacy of complex 1 against LSD1 demethylase (blue), and chloride (green) atoms. The binding pocket of the
activity. Complex 1 inhibited LSD1 activity in a dose- LSD1 is represented as a translucent green surface.
expected since these demethylases have a different mechanism μM (Figure S10). Moreover, the toxicity of 1 was significantly
and are not flavin-dependent. reduced in LSD1-knockdown PC3 cells (Figure S10). This
LSD1 belongs to the flavin adenine dinucleotide (FAD)- indicates that complex 1 could be considered as a potential
dependent amine oxidases superfamily, while the monoamine scaffold for the development of antiprostate cancer drugs.
oxidases (MAOs) belong to the same superfamily and share the To evaluate the nature of cell death induced by complex 1,
same enzymatic mechanism of LSD1 demethylase.48 Therefore, we evaluated the levels of proteins related to apoptosis,
the enzyme activity observed activity of complex 1 against including cleaved caspase 3 and cleaved PARP, in the presence
MAO was measured on the same cell treatment as before by of 1. Complex 1 had no effect on the expression level of
monitoring the fluorescence at excitation of 530 nm and apoptosis markers in PC3 cancer cells and LO2 normal cells
emission of 585 nm. In brief, MAO reacts with p-tyramine, a (Figure S11A). In flow cytometry analysis, a minor population
substrate for MAOA and MAOB, resulting in the formation of of complex-1-treated cells were observed in the Q1-LR quarter
H2O2, which is determined by a fluorimetric method. Complex (early apoptosis: FITC annexin V positive and PI negative)
1 exhibited little or no inhibition of MAOA/B in PC3 cells (Figure S11B), indicating that complex 1 below 3 μM, as well
(Figure 6D). Taken together, these results together indicate as 6 at 1 μM, had no effects on early apoptosis in PC3 and LO2
that complex 1 is selective for LSD1 over other related cells. Moreover, the expression of cyclin D1, a protein related to
enzymes, including KDM2b, KDM7, and MAO. G0/G1 cell cycle arrest, was down-regulated after complex 1
Inhibition of GLUT1 Expression in Human Prostate treatment (Figure S11A). Furthermore, complex 1 increased
Carcinoma Cells. Glucose transporter 1 (GLUT1) is a cells in the G0/G1 phase and reduced cell counts in the S phase
uniporter carrier protein that exhibits variable expression in in a dose-dependent manner, indicating that complex 1 could
various tumor types.49 Recent studies have suggested that induce G0/G1 arrest in PC3 and LO2 cell lines (Figure S11C
LSD1 is linked with the increased expression of GLUT1 in and Figure S11D). Taken together, apoptosis and cell cycle
human cancer cells.50 Therefore, the effect of complex 1 on the arrest analysis suggested that complex 1 could induce G0/G1
expression of GLUT1 was further explored. PC3 cells were arrest, but not apoptosis, in PC3 cancer and LO2 normal cell
treated with the indicated concentration of complex 1 for 24 h, lines.
and GLUT1 levels were analyzed by Western blotting. The
results showed that complex 1 could decrease GLUT1
expression and have no effect on the expression of LSD1 and
■ CONCLUSIONS
In summary, we have described a novel rhodium(III) complex
GAPDH in PC3 cells (Figure 7). 1 as the first metal-based inhibitor of LSD1 activity. Complex 1
exhibited superior inhibitory activity against LSD1 in a
fluorescence-based assay and an ELISA assay compared to
the known LSD1 inhibitor, 6. Moreover, complex 1 reduced the
proliferation of human prostate cancer PC3 cells at low
micromolar concentrations. Additionally, complex 1 enhanced
the amplification of LSD1-regulated promoters and decreased
the LSD1-H3K4me2 interaction in PC3 cells. Complex 1 also
selectively inhibited LSD1 activity without inhibiting the
Figure 7. Effect of complex 1 on GLUT1 protein expression in PC3 activity of other related enzymes, KDM2b, KDM7, and
cells. PC3 cells were treated with the indicated concentrations of MAO. Finally, complex 1 inhibited the expression of GLUT1
complex 1 for 24 h, and then GLUT1 levels were analyzed by Western in PC3 cells, presumably due to its ability to inhibit LSD1
blotting. activity. We anticipate that complex 1 could be considered as a
useful scaffold for the further development of more selective
A previous study has reported that GLUT1 expression was and potent epigenetic modulators to treat different types of
reduced in knockdown MAOA cells under hypoxia.51 There- cancer, including prostate cancer.
■
fore, we performed a quantitative PCR experiment to study the
impact of complex 1 on LSD1 or MAOA knockdown cells
EXPERIMENTAL SECTION
(Figure S8A). Knockdown of LSD1 and MAOA resulted in a
decrease of GLUT1 mRNA levels by 40% and 20%, respectively General Synthesis of [Rh2(C∧N)4Cl2] complexes. Cyclometa-
(Figure S8B). However, cells were more resistant to 1 in LSD1 lated dichloro-bridged dimers of the general formula [Rh2(C∧N)4Cl2]
knockdown cells when compared with knockdown cells with were synthesized according to a literature method.52 In brief, RhCl3·
xH2O was heated to 140 °C with 2.1 equiv of cyclometallated C∧N
control or MAOA siRNA (Figure S8C). Taken together, these ligands in 3:1 methoxymethanol and deionized water under a nitrogen
data suggest that 1 suppresses GLUT1 at the transcriptional atmosphere overnight. The reaction was cooled to room temperature,
level in a manner that is, at least in part, LSD1 dependent. and the product was filtered and washed with three portions of
Complex 1 Inhibits Cellular Proliferation and Induces deionized water and then three portions of ether to yield the
Cell Cycle Arrest. The antiproliferative activities of 1 and 6 corresponding dimer.
against 22RV1 cells, human prostate cancer DU145 cells, General Synthesis of [Rh(C∧N)2(N∧N)]PF6 Complexes. These
human breast adenocarcinoma MCF-7 cells, PC3 cells, human complexes were synthesized using a modified literature method.52
epithelial colorectal adenocarcinoma Caco2 cells, human Briefly, a suspension of [Rh2(C∧N)4Cl2] (0.1 mmol) and correspond-
embryonic kidney 293 cells, and human liver LO2 cells were ing N∧N (0.21 mmol) ligands in a mixture of dichloromethane/
methanol (1:1, 6 mL) was refluxed overnight under a nitrogen
assessed by the XTT assay. Cell viability was measured after 72 atmosphere. The resulting solution was allowed to cool to room
h of treatment with complex 1. IC50 values of complex 1 were temperature and was filtered to remove unreacted cyclometallated
greater than 100 μM against PC3 cells, 22RV1 cells, or LO2 dimer. To the filtrate, an aqueous solution of ammonium
cells (Figure S9). By comparison, complex 1 was most potent hexafluorophosphate (excess) was added, and the filtrate was reduced
against human prostate cancer PC3 cells, with an IC50 of 2.83 in volume by rotary evaporation until precipitation of the crude
product occurred. The precipitate was then filtered and washed with (Grants HKBU/12301115, HKBU/204612, and HKBU/
several portions of water (2 × 30 mL) followed by diethyl ether (2 × 201913), the French National Research Agency/Research
30 mL). The solid was dissolved into acetone, and then the product Grants Council Joint Research Scheme (Grant A-HKBU201/
was precipitated by adding diethyl ether and filtered. The purity of all 12, Oligoswitch), National Natural Science Foundation of
complexes was determined by an Agilent 1200 high-performance
liquid chromatography (HPLC) system. The results showed that the
China (Grant 21575121), Guangdong Province Natural
purity of all complexes was over 95% (Figure S12). Science Foundation (Grant 2015A030313816), Hong Kong
Complex 1. Yield: 49%. HPLC purity: >95%. 1H NMR (400 MHz, Baptist University Century Club Sponsorship Scheme 2016,
acetone-d6) δ 8.72 (s, 2H), 8.38 (d, J = 7.9 Hz, 2H), 8.26−8.15 (m, Interdisciplinary Research Matching Scheme (Grant RC-
4H), 7.89 (d, J = 2.6 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.60 (t, J = 8.2 IRMS/15-16/03), the Science and Technology Development
Hz, 2H), 7.31 (t, J = 8.7 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 7.20 (dd, J Fund, Macao SAR (Grant 098/2014/A2), the University of
= 6.3, 2.6 Hz, 2H), 6.94 (t, J = 7.8 Hz, 2H), 6.64 (d, J = 7.6 Hz, 2H), Macau (Grants MYRG2015-00137-ICMS-QRCM,
3.94 (s, 6H); 13C NMR (101 MHz, acetone) δ 169.56, 169.07, 167.16, MYRG2016-00151-ICMS-QRCM, and MRG044/LCH/2015/
156.79, 149.97, 148.32, 146.52, 145.72, 136.13, 132.50, 131.45, 128.88, ICMS), and National Natural Science Foundation of China
128.41, 126.61, 125.96, 124.85, 119.45, 119.43, 114.62, 110.96, 57.03.
(Grant 21628502).
■
MALDI-TOF-HRMS calcd for C42H30Cl2N4O2Rh [M − PF6]+:
795.0801. Found: 794.9014. Anal. (C42H30Cl2F6N4O2PRh + H2O)
C, H, N: calcd 52.57, 3.36, 5.84; found 52.66, 3.23, 5.98. ABBREVIATIONS USED
Complex 2. Yield: 35%. HPLC purity: >95%. 1H NMR (400 MHz, LSD1, lysine-specific histone demethylase 1; AML, acute
acetone-d6) δ 8.64−8.51 (m, 4H), 8.45 (d, J = 5.2 Hz, 2H), 8.40−8.27 myeloid leukemia; H3K4me2, histone H3 dimethyl Lys4;
(m, 4H), 8.10 (t, J = 7.9 Hz, 2H), 7.94 (d, J = 8.1 Hz, 2H), 7.64 (t, J = MAO, monoamine oxidase; MAOA, monoamine oxidase A;
7.6 Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.25 (t, MAOB, monoamine oxidase B; ELISA, enzyme-linked
J = 8.0 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 6.92 (t, J = 7.5 Hz, 2H), 6.61
(d, J = 7.8 Hz, 2H); 13C NMR (101 MHz, acetone) δ 167.35, 155.37,
immunosorbent assay; DMEM, Dulbecco’s modified Eagle
149.10, 147.67, 146.59, 140.82, 140.68, 136.03, 131.46, 131.09, 130.00, medium; FBS, fetal bovine serum; PBS, phosphate buffered
129.10, 128.51, 128.06, 127.76, 125.86, 124.82, 124.52, 119.16. saline; PC3 cell, human prostate carcinoma cell; Caco2 cell,
MALDI-TOF-HRMS calcd for C40H28N4Rh [M − PF6]+: 667.1369. human epithelial colorectal adenocarcinoma cell; LO2 cell,
Found: 667.1373. Anal. (C40H28F6N4PRh + 2H2O) C, H, N: calcd human liver cell; 293 cell, human embryonic kidney cell;
56.62, 3.80, 6.60; found 56.40, 3.52, 6.61. 22RV1 cell, human prostate carcinoma epithelial cell; DU145
Complex 3. HPLC purity: >95% (reported).39 cell, human prostate cancer cell; KDM2b, lysine-specific histone
Complex 4. HPLC purity: >95% (reported).31 demethylase 2b; KDM7, lysine-specific histone demethylase 7;
Complex 5. HPLC purity: >95% (reported).31
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XTT, cell proliferation kit II; H3K26me2, histone H3 dimethyl
Lys26; H3K27me2, histone H3 dimethyl K27
■
ASSOCIATED CONTENT
*
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