Versatile Synthetic Route to Cycloheximide and Analogues That Potently Inhibit Translation Elongation

Article abstract of DOI:10.1002/anie.201901386

Cycloheximide (CHX) is an inhibitor of eukaryotic translation elongation that has played an essential role in the study of protein synthesis. Despite its ubiquity, few studies have been directed towards accessing synthetic CHX derivatives, even though such efforts may lead to protein synthesis inhibitors with improved or alternate properties. Described here is the total synthesis of CHX and analogues, and the establishment of structure–activity relationships (SAR) responsible for translation inhibition. The SAR studies aided the design of more potent compounds, one of which irreversibly blocks ribosomal elongation, preserves polysome profiles, and may be a broadly useful tool for investigating protein synthesis.

Full text of DOI:10.1002/anie.201901386

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Accepted Article
Title: A Versatile Synthetic Route to Cycloheximide and Analogues that
Potently Inhibit Translation Elongation
Authors: Yongho Park, Yumi Koga, Cindy Su, Amanda Waterbury,
Christopher Johnny, and Brian Liau
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901386
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10.1002/anie.201901386
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A Versatile Synthetic Route to Cycloheximide and Analogues that
Potently Inhibit Translation Elongation
Yongho Park, Yumi Koga, Cindy Su, Amanda L. Waterbury, Christopher L. Johnny, and Brian B.
Liau*[a]
Abstract: Cycloheximide (CHX) is an inhibitor of eukaryotic
translation elongation that has played an essential role in the study of
protein synthesis. Despite its ubiquity, few studies have been directed
towards accessing synthetic CHX derivatives, even though such
efforts may lead to protein synthesis inhibitors with improved or
alternate properties. Here, we describe the total synthesis of CHX and
analogues, and establish structure-activity relationships (SAR)
responsible for translation inhibition. The SAR studies aided the
design of more potent compounds, one of which irreversibly blocks
ribosomal elongation, preserves polysome profiles, and may be a
broadly useful tool for investigating protein synthesis.
polysomes is highly desired to enable more robust downstream
experiments to study translation.
Since protein synthesis can be inhibited by stabilizing or
disrupting polysomes, several other natural products have been
evolved to bind the same pocket as 1 with different effects on
polysome stability.[9] For example, chlorolissoclimide (2) stabilizes
polysomes in a similar manner to 1,[17] lactimidomycin (LTM, 3)
only blocks translation at the initiating codon,[8] while
phyllanthoside (PHY, 4) induces dissociation of translating
ribosomes from mRNA.[18] Even though high-resolution structures
of these molecules are now available, how each inhibitor
influences the overall stability of polysomes remains unclear and
presents a challenge in designing analogues with additional
biological function.[19] Motivated by these questions, herein we
report a versatile synthetic route to 1 and potent analogues that
enabled the development of an irreversible elongation inhibitor.
Protein synthesis is a highly coordinated process that
involves ribosomes, mRNA, aminoacyl-tRNAs, and various
cofactors. Due to the essential role of protein synthesis for life,
many organisms for self-defense have evolved to produce
secondary metabolites targeting nearly every step of translation.[1]
The biological activities of these natural products and their
derivatives have been exploited to gain critical insights into tRNA
decoding,[2] peptide bond formation,[3] resistance mechanisms to
antibiotics,[4] and cellular protein synthesis.[5,6] In particular,
cycloheximide (CHX, 1) has been employed routinely for decades
to rapidly and reversibly inhibit elongating ribosomes in order to
study protein synthesis and measure protein half-lives (Figure
1).[7]
Recent biochemical[8] and crystallographic[9] studies
demonstrated that 1 binds to the ribosome exit-site (E-site),
competitively occupying a pocket where the 3' CCA sequences of
deacylated tRNAs reside. By blocking translocation of tRNAs, 1
slows down all actively translating ribosomes on mRNA, leading
to polysome stabilization. The stalled polysomes can then be
visualized in vivo[10] or analyzed to probe post-transcriptional
processes.[11] Moreover, polysome stabilization is essential to
ribosome profiling,[12] which has revealed details regarding
upstream open reading frames,[13] co-translational assembly of
proteins,[14] and elongation rates of translating ribosomes.[15] One
drawback of stabilizing polysomes with 1 is that binding of 1 to
ribosomes is reversible and elongation continues to occur during
the course of the experiment.[16] Even at high concentrations of 1,
it has been estimated that translation elongation still proceeds at
0.1 to 0.3 amino acids per second, resulting in dose- and time-
dependent biases.[16a] Thus, irreversible stabilization of
[a]
Dr. Y. Park, Y. Koga, C. Su, A. L. Waterbury, C. L. Johnny, Prof. B.
B. Liau
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
E-mail: liau@chemistry.harvard.edu
Supporting information for this article is given via a link at the end of
the document.
Figure 1. Natural products that bind the ribosome E-site and their effects on
translation.
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The aldol product was then protected to provide TBS ether 10 in
98% yield over two steps. Chemoselective conversion of 10 to a
thioester was achieved using a lithium thiolate,[23] and subsequent
Fukuyama reduction[24] delivered aldehyde 11 in 55% yield over
two steps. Diastereoselective crotylation of 11 was achieved
using (E)-crotylboronic acid pinacol ester to yield homoallylic
alcohol 12 with the correct C10- and C11-stereochemistry. Ring-
closing metathesis of 12 to prepare cyclohexene 13 followed by
directed hydrogenation yielded cyclohexanol 14 as a single
diastereomer. The C10-carbinol was then oxidized to furnish the
corresponding cyclohexanone, and global deprotection of this
intermediate using ceric ammonium nitrate completed the total
synthesis of 1 in 10% and 12 steps from commercial 2-(2,6-
dioxopiperidin-4-yl)acetic acid.
Following the established route, we synthesized several
analogues of 1 with altered C11- and C13-substituents, and
evaluated them in
a cell-based assay using O-propargyl
puromycin (OPP) incorporation (Supporting Information, Figure
S1).[5] Overall, the C11- and C13-methyl substituents were vital to
1’s activity. Inversion of the C11-stereocenter (15), addition of a
second methyl group (16), and removal of the methyl group (17)
all abolished inhibitory activity (Figure 3A). Inversion of the C13-
stereocenter (18) and elongation of C16-methyl to n-butyl (19)
also resulted in highly diminished activity. The activity could be
recovered when the n-butyl chain was positioned
pseudoequatorially (20) instead. These data indicate that CHX
analogues likely need to interact with G4370, G4371, and RPL36a
Phe56 for successful inhibition. It is noteworthy that other E-site
binders (2-4) maintain similar contacts with those residues. For
instance, the corresponding methyl groups in LTM (3) are similarly
positioned (Supporting Information, Figure S2).[9a] Moreover,
C(2)–Cl of chlorolissoclimide (2)[17a] and C11-methyl of PHY (4)[9a]
are also oriented in a similar fashion to the C11-methyl group of
1.
Figure 2. (A) Structural view of the human ribosome E-site bound by 1. Critical
bases in the 28S ribosomal RNA (gray) and RPL36a (yellow) are shown. PDB:
5lks. (B) Retrosynthetic analysis of 1.
Based on these observations, we considered if
incorporation of an additional substituent at the C13-position of 1
could lead to a more potent analogue with a functional group
handle. Toward this goal, we first targeted streptovitacin A (23a)
(Scheme 1). Mukaiyama hydration[25] of 13 afforded the C13-
diastereomeric tertiary alcohols 21a and 21b in 48% and 52%
yield, respectively. Subsequent oxidation to the cyclohexanone
and global deprotection then yielded streptovitacin A (23a, 11%
yield over two steps) and C13-epi-streptovitacin A (23b, 18% yield
over two steps). In the OPP assay, 23a exhibited robust
translation inhibition, thus suggesting the feasibility of derivatizing
the C13-position to generate potent analogues. We then further
leveraged the synthetic versatility of 13 to install a quaternary
center through a radical-mediated olefin cross-coupling reaction
(Scheme 1). Hydrogen atom transfer to 13 and subsequent
reaction with benzyl acrylate installed the side-chain in 2:1
diastereoselectivity.[26] The C13-diastereomers were separated
after Dess–Martin oxidation to give cyclohexanones 25a and 25b
in 21% and 46% yield, respectively, over two steps. Global
deprotection then afforded benzyl esters 26a and 26b.
Based on the structure of
1 bound to the human
ribosome,[9b] we hypothesized that installation of electrophilic
functionality extending from the cyclohexanone of 1 may allow
covalent interception of nearby lysine residues of RPL36a – a
ribosomal protein that comprises the E-site – and subsequent
irreversible inhibition of translation (Figure 2A). Such a strategy
would require alteration of cyclohexanone of 1 without disrupting
1’s activity, but the relative contribution of the cyclohexanone’s
substituents to 1’s activity remains elusive. The lack of information
could potentially be attributed to the strategy employed in 1’s lone
synthesis,[20] wherein the cyclohexanone moiety was prepared in
the first stage. Since the importance of glutarimide and C(8)-OH
of 1 has already been established,[21] we devised an alternative
route to 1 which would allow for stereodivergent assembly of C11-
and C13-substituents late stage. We envisioned cyclohexene 5
as a key intermediate for incorporating different functionality and
stereochemistry across the alkene. To access 1 from 5, the
desired C13-streeocenter could be installed by directed
hydrogenation. The C11-methyl stereocenter in 6 could be
secured via a diastereoselective crotylation, while the C8- and C9-
stereocenters in 7 could be generated by an Evans’ aldol reaction.
The synthesis commenced with an Evans’ aldol reaction
with N-acyl oxazolidinone 8 and aldehyde 9, each of which was
obtained in three steps from commercial materials (Scheme 1).[22]
In the OPP assay, 26a was approximately an order of
magnitude more potent than 1 (Figure 3B). The cytotoxicity of 26a
was similar to 1, with slightly enhanced selectivity toward certain
cancer cell lines (Supporting Information, Figure S3). Based on
the available structural data,[8a] we speculate that the increased
potency of 26a may be driven by stabilizing interactions involving
the benzyl ester with the E-site in a manner similar to the
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Scheme 1. Total synthesis of cycloheximide (1), streptovitacin A (23a) and irreversible inhibitor (28). Conditions: (a) n-Bu2BOTf, Et2Ni-Pr, CH2Cl2, 0 °C; then 9; (b)
TBSOTf, 2,6-lutidine, CH2Cl2, 98% (2 steps); (c) n-BuLi, C12H25SLi, 0 °C; then 10; (d) Pd/C (10 wt%), Et3SiH, acetone, 55% (2 steps); (e) (E)-crotylboronic acid
pinacol ester, PhMe, 90%; (f) Hoveyda–Grubbs’ catalyst, 2nd generation (2 mol%), 1,2-dichloroethane, 60 °C, 81%; (g) Crabtree’s catalyst (17 mol%), H2 (1 atm),
CH2Cl2, 84%; (h) Dess–Martin periodinane, CH2Cl2, 53% for 22a, 64% for 22b, 21% for 25a (2 steps), 46% for 25b (2 steps); (i) CAN, MeCN/H2O, 42% for 1 (2
steps), 20% for 23a, 28% for 23b, 73% for 26a, 66% for 26b; (j) Co(acac)2 (20 mol%), PhSiH3, O2 (1 atm), THF, 48% for 21a, 52% for 21b; (k) Fe(acac)3 (5 mol%),
PhSiH3, benzyl acrylate, EtOH, 40 °C; (l) Pd/C (20 wt%), H2 (1 atm), EtOH; (m) TSTU, Et3N, CH2Cl2, 41% (2 steps).
Figure 3. (A) Structures of CHX derivatives synthesized in this study. For each compound, IC50 values for translation inhibition are shown in red. Error represent
standard deviation (SD) for n =3. (B) Dose-response curves show relative protein synthesis levels (%max, y axis) after treatment with natural 1, synthetic 1, 26a, or
28 versus vehicle control (0.1% DMSO v/v). Error bars represent standard error (SE) for n = 3.
macrolactone of LTM (3) (Supporting Information, Figure S2 and
S4). Given the increased potency of 26a, installation of
electrophilic functionality was explored to potentially transform
26a into an irreversible inhibitor. Thus, benzyl ester 26a was
converted to N-hydroxysuccinimidyl (NHS)-ester 28 in two steps.
Comparable activities were obtained for 28 and 1 in the OPP
assay (Figure 3).
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1. Additionally, competition experiments between 28 and 1
strongly suggest that 1, in a dose-dependent manner, prevents
28 from binding the same site as 1 (Figure 4C). Moreover, one
minute of incubation time was sufficient to induce irreversible
inhibition by 28 at 100 μM (Supporting Information, Figure S5).
Altogether, our data support the notion that NHS-ester 28
effectively irreversibly inhibits protein synthesis and targets the
same ribosome E-site as 1.
Mechanistically, translation inhibition could be driven by
either stabilization or dissociation of polysomes (e.g. PHY, 4). To
distinguish between the two possibilities, polysome profiles were
obtained after treatment of 293T cells with vehicle, 1, or 28.
Similar levels of polysomes were observed in samples treated
with 1 and 28, demonstrating 28’s ability to globally inhibit
translation elongation unlike LTM (3) or PHY (4). It is noteworthy
that a single treatment with 28 at 100 μM prior to lysis was
sufficient to preserve the integrity of polysome. Currently, typical
polysome profiling experiments require a high concentration of 1
in all buffers after cell lysis due to the reversibility of 1.[27]
To understand how irreversible inhibition by 28 might be
mediated, we conducted immunoprecipitation (IP) mass
spectrometry (MS) experiments on RPL36a. Mass shifts
corresponding to acylation of Lys22 by 28 were observed in both
trypsin and chymotrypsin digests (Figure 4E and Supporting
Information, Figure S6); no other adducts of 28 were detected.
Since Lys22 is located outside of the putative binding pocket of
28, it remains to be established how the modification of Lys22 is
mechanistically relevant to 28’s binding to the E-site and its effect
on protein synthesis.[28]
In conclusion, NHS-ester 28 acts as an effectively
irreversible inhibitor of protein synthesis by maintaining polysome
stability. We anticipate that 28 may serve as an important tool
compound to study translation, especially in applications of
ribosome profiling where 1 is suspected of displaying bias due to
reversibility.[16] Future studies using these CHX analogues to
investigate structure-function relationships in the ribosome E-site
and interrogate protein synthesis will be reported in due course.
Figure 4. (A) Dose-response curves show relative protein synthesis levels for
CHX and 28 treatments after being retained or washed out from the media for
30 min. Error bars represent SE for n = 3. (B) Relative protein synthesis levels
(%max, y axis) as measured by OPP incorporation after compounds (100 μM)
are retained or washed out for 30 min. Error bars represent SE for n = 3. (C)
Relative protein synthesis levels after co-treatment with CHX and 28 at various
doses. Cells were preincubated with CHX for 5 min before 28 was added. Error
bars represent SE for n = 3. (D) Polysome profiles obtained from 293T cells
treated with vehicle (0.1% DMSO v/v), CHX (100 μM), or 28 (100 μM) for 90
min. (E) HPLC-MS/MS analyses of the lysine 22-modified peptide resulting from
trypsin digestion (* indicates modification by 28 (100 μM, 90 min), while #
indicates alkylation of cysteine resulting from iodoacetamide treatment).
Observed mass-to-charge (m/z) values of y and b ions are shown, with charge
states in brackets. Ions in bold: |error| < 500 ppm; ions in gray: 500 ppm < |error|
< 1000 ppm. (F) Structural view of the human ribosome. E-site tRNA (yellow),
P-site tRNA (blue), mRNA (orange), Lys22 (red) of RPL36a (green), CHX (pink)
are shown. PDB: 5lks aligned to 5lzt. (G) Zoomed-in view of the E-site.
Experimental Section
Experimental details are reported in the Supporting Information.
Acknowledgements
Y.K. acknowledges funding from a Funai Fellowship. We thank
Mr. Alex Peterson and Dr. Karen Ocwieja for experimental
assistance. We thank J.J. Chen, L. Gehrke, J. Kim, and S. Shao
for thoughtful discussion.
Keywords: cycloheximide • proteins • inhibitors • irreversible •
To determine if 28 irreversibly inhibits protein synthesis,
OPP-translation assays were conducted after inhibitor washout
(Figure 4). Consistent with the literature, reversible inhibition was
observed with 1[7b] and irreversible with 4.[18] Treatment with 28
resulted in irreversible inhibition, which was not due to hydrolysis
of 28 or non-specific effects of an NHS-ester (Figure 4A and 4B).
By contrast, inhibition induced by benzyl ester 26a could be
rescued by inhibitor washout, albeit to a reduced extent; this
partial effect may reflect the increased potency of 26a relative to
polysome
[1]
[2]
For a recent review on protein synthesis and translation inhibitors, see:
S. Arenz, D. N. Wilson, Mol. Cell. 2016, 61, 3–14.
(a) J. Davies, W. Gilbert, L. Gorini, Proc. Natl. Acad. Sci. U.S.A. 1964,
51, 883–890; (b) J. Davies, P. Anderson, B. D. Davis, Science 1965, 149,
1096–1098; (c) K. B. Grodmadski, M.V. Rodnina, Nat. Struct. Mol. Biol.
2004, 11, 316–322.
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[3]
(a) A. Sievers, M. Beringer, M. V. Rodnina, R. Wolfenden, Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 7897–7901; (b) S. T. Martin, K. S. Huang,
S. A. Strobel, T. A. Steitz, Nature 2005, 438, 520–524; (c) R. M.
Voorhees, A. Weixlbaumer, D. Loakes, A. C. Kelley, V. Ramakrishnan,
Nat. Struct. Mol. Biol. 2009, 16, 528–533.
[4]
[5]
[6]
[7]
For a recent review on ribosome-related antibiotic resistance, see: D. N.
Wilson, Nat. Rev. Microbiol. 2014, 12, 35–48.
J. Liu, Y. Xu, D. Stoleru, A. Salic, Proc. Natl. Acad. Sci. U.S.A. 2012, 109,
413–418.
R. A. J. Signer, J. A. Magee, A. Salic, S. J. Morrison, Nature 2014, 509,
49–54.
(a) H. L. Ennis, M. Lubin, Science 1964, 146, 1474 – 1476; (b) B. S.
Baliga, A. W. Pronczuk, H. N. Munro, J. Biol. Chem. 1969, 244, 4480–
4489.
[8]
[9]
T. Schneider-Poetsch, J. Ju, D. E. Eyler, Y. Dang, S. Bhat, W. C. Merrick,
R. Green, B. Shen, J. O. Liu, Nat. Chem. Biol. 2010, 6, 209–217.
(a) N. Garreau de Loubresse, I. Prokhorova, W. Holtkamp, M. V. Rodnina,
G. Yusupova, M. Yusupov, Nature 2014, 513, 517–522; (b) A. G.
Myasnikov, S. K. Natchiar, M. Nebout, I. Hazemann, V. Imbert, H. Khatter,
J.-F. Peyron, B. P. Klaholz, Nat. Commun. 2016, 7, 12856.
[10] C. Wang, B. Han, R. Zhou, X. Zhuang, Cell 2016, 165, 990–1001.
[11] H. Chassé, S. Boulben, V. Costache, P. Cormier, J. Morales, Nucleic
Acid Res 2017, 45, e15 and references therein.
[12] For a recent review on ribosome profiling, see: N. T. Ingolia, Cell 2016,
165, 22–33.
[13] A. Sendoel, J. G. Dunn, E. H. Rodriguez, S. Naik, N. C. Gomez, B.
Hurwitz, J. Levorse, B. D. Dill, D. Schramek, H. Molina, J. S. Weissman,
E. Fuchs, Nature 2017, 541, 494–499.
[14] A. Shiber, K. Döring, U. Friedrich, K. Klann, D. Merker, M. Zedan, F.
Tippmann, G. Kramer, B. Bukau, Nature 2018, 561, 268–272.
[15] D. E. Weinberg, P. Shah, S. W. Eichhorn, J. A. Hussmann, J. B. Plotkin,
D. P. Bartel, Cell Reports 2016, 14, 1787–1799.
[16] (a) J. A. Hussmann, S. Patchett, A. Johnson, S. Sawyer, W. H. Press,
PLOS Genetics 2015, 11, e1005732; (b) M. V. Gerashchenko, V. N.
Gladyshev, Nucleic Acid Res. 2014, 42, e134.
[17] (a) Z. A. Könst, A. R. Szklarski, S. Pellegrino, S. E. Michalak, M. Meyer,
C. Zanette, R. Cencic, S. Nam, V. K. Voora, D. A. Horne, J. Pelletier, D.
L. Mobley, G. Yusupova, M. Yusupov, C. D. Vanderwaal, Nat. Chem.
2017, 9, 1140–1149; (b) F. Robert, H. Q. Gao, M. Donia, W. C. Merrick,
M. T. Hamann, J. Pelletier, RNA 2006, 12, 717–725.
[18] J. Chan, S. N. Khan, I. Harvey, W. Merrick, J. Pelletier, RNA 2004, 10,
528–543.
[19] O. Robles, D. Romo, Nat. Prod. Rep. 2014, 31, 318–334.
[20] F. Johnson, N. A. Starkovsky, A. C. Paton, A. A. Carlson,
J. Am. Chem. Soc. 1966, 88, 149–159.
[21] (a) M. R. Siegel, H. D. Sisler, F. Johnson, Biochem. Pharmacol. 1966,
15, 1213–1223; (b) H. Ennis, Biochem. Pharmacol. 1968, 17, 1197–
1206; (c) S. Kudo, T. Oritani, K. Yamashita, Agric. Biol. Chem. 1984, 48,
2315–2319;
(d)
S.
Kudo,
T.
Oritani,
K.
Yamashita,
Agric. Biol. Chem. 1984, 48, 2739–2743; (e) C. Christner, R. Wyrwa, S.
Marsch, G. Küllertz, R. Thiericke, S. Grabley, D. Schumann, G.
Fischer, J. Med. Chem. 1999, 42, 3615–3622; (f) F. Edlich, M. Weiwad,
D. Wildemann, F. Jarczowski, S. Kilka, M.-C. Moutty, G. Jahreis, C.
Lücke, W. Schmidt, F. Striggow, G. Fischer, J. Biol. Chem. 2006, 281,
14961–14970.
[22] See the Supporting Information for details.
[23] R. E. Damon, G. M. Coppola, Tetrahedron Lett. 1990, 31, 2849–2852.
[24] T. Fukuyama, S. C. Lin, L. Li, J. Am. Chem. Soc. 1990, 112, 7050–7051.
[25] S. Isayama, T. Mukaiyama, Chem. Lett. 1989, 18, 1071–1074.
[26] J. C. Lo, D. Kim, C.-M. Pan, J. T. Edwards, Y. Yabe, J. Gui, T. Qin, S.
Gutierrez, J. Giacoboni, M. W. Smith, P. L. Holland, P. S. Baran, J. Am.
Chem. Soc. 2017, 139, 2484–2503.
[27] N. J. McGlincy, N. T. Ingolia, Methods 2017, 126, 112–129.
[28] We cannot currently rule out a possibility that the labeling is due to the
intrinsic nucleophilicity of the lysine. Lys22 is not identified as “hyper-
reactive” in global profiling on lysine reactivity. See: S. M. Hacker, K. M.
Backus, M. R. Lazear, S. Forli, B. E. Correira, B. F. Cravatt, Nat. Chem.
2017, 9, 1181–1190.
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Y. Park, Y. Koga, C. Su, A. L.
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A Versatile Synthetic Route to
Cycloheximide and Analogues that
Potently Inhibit Translation
Elongation
An irreversible
inhibitor of protein synthesis based on the cytotoxic natural product cycloheximide
is presented. The inhibitor preserves polysome profiles even after the compound is
washed out.
This article is protected by copyright. All rights reserved.