Synthesis, crystal structure and biological activity of β-carboline based selective CDK4-cyclin D1 inhibitors

Article abstract of DOI:10.1039/b613861f

The design, synthesis and biological activity of a series of non-planar dihydro-β-carboline and β-carboline-based derivatives of the toxic anticancer agent fascaplysin is presented. We show these compounds to be selective inhibitors of CDK4 over CDK2 with an IC₅₀ (CDK4-cyclin D1) = 11 mol for the best compound in the series 4d. The crystallographic analysis of some of the compounds synthesised (3b/d and 4a-d) was carried out, in an effort to estimate the structural similarities between the designed inhibitors and the model compound fascaplysin. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613861f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis, crystal structure and biological activity of b-carboline based
selective CDK4-cyclin D1 inhibitors†
Marcos D. Garc´ıa,a A. James Wilson,a Daniel P. G. Emmerson,a Paul R. Jenkins,*a Sachin Mahaleb and
Bhabatosh Chaudhurib
Received 22nd September 2006, Accepted 26th October 2006
First published as an Advance Article on the web 9th November 2006
DOI: 10.1039/b613861f
The design, synthesis and biological activity of a series of non-planar dihydro-b-carboline and
b-carboline-based derivatives of the toxic anticancer agent fascaplysin is presented. We show these
compounds to be selective inhibitors of CDK4 over CDK2 with an IC50 (CDK4-cyclin D1) = 11 lmol
for the best compound in the series 4d. The crystallographic analysis of some of the compounds
synthesised (3b/d and 4a–d) was carried out, in an effort to estimate the structural similarities between
the designed inhibitors and the model compound fascaplysin.
It has been shown, using a computational approach, that one
of the most important features of the predicted binding mode of
fascaplysin 1 in the ATP binding site of a CDK4 homology model
Introduction
The cyclin-dependent kinases (CDKs) are a set of proteins that
is a double hydrogen bonding to Val 96.6,10 It is also noteworthy
that our most active compound so far, the tryptamine based
compound 2 (IC50 = 6 lm), was predicted to be located in the
ATP binding site of the CDK4 homology model in a similar
fashion to fascaplysin 1 but with the double hydrogen-bonding
interaction being with the backbone of His 95/Val 96 and an extra
stabilization arising from a p–p stacking interaction between the
biphenyl moiety of the ligand with the side chains of Phe 93 and
Phe 159 (Scheme 1).6
play a vital role in the regulation of the cell cycle checkpoints,
controlling the transition between the different phases of the
process.1 As a wide variety of diseases (cancer in particular)
are characterised by a deregulation in the cell cycle causing
uncontrolled cell proliferation, the inhibition of CDKs by small
molecules is one of the most active fields in current anti-cancer
research.2
In this context, the specific inhibition of the CDK4-cyclin D1
complex has arisen as an interesting anticancer target.3 CDK4 is
one of the key players in the transition between G1 and S phases
of the cell cycle and is constitutively activated in many human
cancers. Similarly, cyclin D1 is often over expressed, whereas the
CDK4 inhibitor (p16) is deleted in a variety of human tumours.
In recent times our group has been interested in the design, mod-
elling, synthesis and biological evaluation of novel, specific CDK4-
cyclin D1 inhibitors based on the structure of the pentacyclic
quaternary salt fascaplysin 1.4–6 This natural product, originally
isolated from the Fijian sponge Fascaplynosis Bergquist sp,7
inhibits the growth of several microbes including Staphylococcus
aureus, Escherichia coli, Candida albicans and Saccharomyces
cerevisiae, and suppresses the proliferation of mouse leukemia
cells (L-1210) with ED50 = 0.2 lg mL−1. Fascaplysin has been also
reported to specifically inhibit CDK4-cyclin D1 (IC50 = 0.55 lM),
causing G1 arrest of both tumour (U2-OS, HCT-116) and normal
(MRC-5) cells.8 The use of fascaplysin 1 as an anticancer drug is
limited due to its high toxicity; because of its planar structure it can
act as a DNA intercalator.9 The aim of the present study consists
of the design of non-toxic (non-planar) analogues of the natural
product with increased activity as CDK4-cyclin D1 inhibitors.
Scheme
1
Structures of fascaplysin 1 and the tryptamine based
analogue 2.
Taking these facts into account we designed a series of
non-planar b-carboline-based analogues of the natural product
fascaplysin 1 of general type 3 and 4 with different substituents in
the benzenoid ring by removing bond a in the original structure
(Scheme 2) and in some cases converting double bond b into a
single bond. As four of the five rings of fascaplysin 1, and the
relative disposition of the H-bond acceptors/donors needed for
the double interaction with Val 96 (i.e. the carbonyl and the
aDepartment of Chemistry, University of Leicester, Leicester, UK LE1 7RH.
E-mail: kin@le.ac.uk; Fax: +44(0)116 252 3789; Tel: +44(0)116 252 2124
bSchool of Pharmacy, De Montfort University, Leicester, UK LE1 9BH.
E-mail: bchaudhuri@dmu.ac.uk; Fax: +44(0)116 257 7287;
Tel: +44(0)116 250 7280
† Electronic supplementary information (ESI) available: Colour versions
of Fig. 1–3. See DOI: 10.1039/b613861f
Scheme 2 Strategy used to produce the non-planar b-carboline deriva-
tives 3 and 4 from fascaplysin 1.
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indolyl NH group in 3/4), is nearly the same as in fascaplysin
1, by inference, the binding mode and hence the CDK4 inhibition
activity was expected to be retained.
55%). On other occasions, the fully aromatic compounds 4a–e
were obtained in good yields (62–99%) by irradiation in refluxing
toluene of the isolated ketoimines 3a–e.
Moreover, the introduction of different aromatic substituents in
the benzenoid ring into the parent compounds of type 3 and 4,
was also planned in an attempt to explore the presence or not of
stabilizing p–p interactions as for compound 2 leading to increased
activities as CDK4-cyclin D1 specific inhibitors.
Solid state structure
As we wished to maintain the double H-bond to Val 96 as seen in
fascaplysin 1, X-ray structure analysis was carried out for some of
the compounds 3/4 synthesised (3b/d and 4a–d).
The conformation of type 4 compounds can be described by
means of the torsion angles s1 (C11–C1–C12–O1) and s2 (C1–
C12–C13–C14) (Fig. 1). Whilst s1 gives a qualitative idea of the
deviation of the carbonyl group from the plane of the heterocyclic
moiety, s2 is connected to the relative disposition of the b-carboline
substructure and the benzenoid ring. For compounds of type 3
an extra degree of conformational freedom arises from the non-
planar (non-aromatic) cyclic imine substructure in the b-carboline
so a third torsion angle s3 (C4–C3–C2–N1) was included. In both
cases, for type-3 and type-4 compounds, these defined torsion
angles are interrelated because of the geometry of the molecules.
Results and discussion
b-Carboline and dihydro b-carboline compounds
In a previous communication,11 the investigation of the spon-
taneous photo-oxidation of the 1-(2-bromo-benzyl)-4,9-dihydro-
3H-b-carboline, led us to the development of a mild, green,
regioselective and practical protocol for the preparation of a
series of dihydro-b-carbolines of type-3 and b-carbolines of
type-4 from tryptamine derivatives 5 by a sequential Bischler–
Napieralski cyclisation followed by induced photo-oxidation of
the non-isolated 1-benzyl-4,9-dihydro-3H-b-carboline derivatives
6 (Scheme 3).
Fig. 1 MERCURY projection (displacement ellipsoids, 50% probability)
of one of the two conformers of 4a in the minimal asymmetric unit of the
crystal, with the arbitrary labelling used in the study.†
As exemplified in Fig. 1 for compound 4a, we found all the
structures 3/4 displaying a strong N2–H · · · O1 intramolecular H-
bond as in the model compound. The geometrical features of this
interaction are shown in Table 1.
Scheme
3 Reagents and conditions: i) RC6H4CH2COCl, CH2Cl2,
This intramolecular hydrogen bond is forced by the molecular
geometry, with the carbonyl group located nearly in the same
plane as the b-carboline moiety (the same situation occurs for
fascaplysin), so the free rotation around the C1–C12 bond
(characterized by the torsion angle s1) in compounds 4 is restricted.
Once this geometry is constrained, the phenyl ring in 4 acquires
a tilted-T shape relative to the planar heterocyclic substructure
characterized by the torsion angle s2. For type-3 molecules the
non-planar configuration of the dihydro-b-carboline substructure
(characterized by s3), causes the carbonyl group to be more out
of the plane of the heterocyclic moiety than for type-4 molecules,
increasing s1 as exemplified in Fig. 2 for compounds 3d and 4d.
Moreover, this nearly planar configuration of the intramolecular
donor/acceptors allows the molecule toform intermolecular cyclic
dimers by a double hydrogen bonding as exemplified in Fig. 3
for 4a. The b-carboline substructures of the two molecules are
arranged in parallel planes separated by a perpendicular distance
di (see Table 1 for geometrical details of the intermolecular
hydrogen bonding).
NaOH(aq). ii) POCl3, toluene, N2, reflux, basic work-up. iii) ht, O2, toluene,
30 ◦C. iv) ht, O2, toluene, reflux.
To circumvent the intrinsic instability of type-6 compounds,
purification after cyclisation of the corresponding acetamide
derivatives 5 was avoided, so the crude reaction product after
basic work-up of the Bischler–Napieralski reaction was irradiated
under the conditions detailed in Scheme 3.
Irradiation of 6a–h in toluene with a 500 Watt halogen lamp
(290–300 nm frequency cut-off) at 30 ◦C led, regioselectively
in most cases, to the dihydro-b-carbolines (3a–d, 3g–h) with
satisfactory yields (44–59%) from the corresponding tryptamine
derivative 5. Irradiation under these conditions of crude 6e led to
decomposition of the starting material to a complex mixture, and
irradiation of 6f yielded a mixture of the dihydro-b-carboline 3f
(31% isolated yield) and the b-carboline 4f (10% isolated yield).
A slight modification of the irradiation method, inducing reflux
of the toluene solution, produced the fully aromatic b-carbolines
4b–d, 4f and 4h with modest to acceptable yields from 5a–h (11–
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Table 1 Geometrical data discussed in the text†
Monomers
Dimers
Structure d(N2 · · · O1)/A ∠N2HO1/◦
s1/◦
2.13
s2/◦
50.05
s3/◦
d(N1 · · · R)/A d(N2 · · · O1)/A ∠N2HO1/◦ di/A
ꢀ
c
˚
˚
˚
˚
4ab
2.744
2.767
2.889
2.808
2.813
2.837
2.935
117.2
115.7
113.4
113.9
114.2
120.5
116.6
—
—
—
—
—
2.603
2.567
3.099
3.262
3.351
2.945
2.944
3.056
2.996
3.013
—
154.9
154.2
144.4
145.6
145.0
—
0.616
0.616
1.095
0.275
0.000
—
11.78 −49.70
−12.54 −63.18
−5.70 −70.49
−4.11 −68.10
4b
4c
4d
3b
3d
19.90
50.34 −45.53 2.939
−24.94 −58.96 −17.30 3.361
3.088
153.8
0.770
a Data measured using the program Mercury. b Two different conformers are presented in the asymmetric unit cell for compound 4a. c Perpendicular
distance between the parallel planes containing the b-carboline (type 4 compounds) or indolyl (type 3) moieties of the molecules involved in the double
hydrogen bonding.
group linked to C14 in the benzenoid ring. These non-covalent
interactions are characterized by a d(N1–R) slightly lower (see
Table 1 for details) than the corresponding sum of the van der
˚
˚
˚
Waals radii of the atoms r (rF 1.47 A, rCl 1.75 A, rBr 1.85 A, rN
13
14
˚
˚
1.55 A and rH 1.09 A). Although these could be considered
as halogen bonding for the compounds 4c/d and 3b/d, and non-
classic hydrogen bonding for the two conformers found in the unit
cell for 4a, these interactions could be artefacts imposed by the
constrained molecular geometry.‡
Fig. 2 MERCURY capped sticks representation of the minimal asym-
metric unit in the crystalline structure for compound 3d (left) and 4d
(right).†
It is also probable that in solution, as in the solid state, these
compounds could present a preferred rigid conformation arising
from the inter/intramolecular H-bonding. For instance, in the 1H-
NMR spectra (CDCl3, 300 MHz) of compounds 6d, 3d and 4d the
dNHindol signal is respectively 8.00, 9.48 and 10.43 ppm; depending
on the environment of the NH group as well as its ability to form
intra and intermolecular hydrogen bondings.
Bi/triphenyl compounds
Based on the good biological activity of compound 2, our group
has explored the design, synthesis and biological activity of a wide
range of biphenyl derivatives of 2 demonstrating the existence of
a p-stacking region in the active site of CDK4,17 that could be
analogous to the “Phe 80 pocket” of CDK2.18
In an effort to evaluate the importance of this p-stacking
interaction compared to the double hydrogen bonding presented
for fascaplysin, we planned a further functionalization of the
parent dehydro and dihydro-b-carboline derivatives using the
Suzuki–Miyaura cross-coupling reaction to prepare a library of
bis/triphenyl compounds related to 3 and 4 (Scheme 4).
In a first attempt to use this approach, the para-brominated
dihydro-b-carboline 3h was used as starting material for the cou-
pling reaction. This compound was reacted with phenylboronic
Fig. 3 MERCURY capped sticks representation of the cyclic symmetric
dimer formed by two molecules of 4a (symmetry codes x,y,z and −x + 1,
−y, −z). Intramolecular (N2H1 · · · O1, N2ꢀH2ꢀ · · · O1) and intermolecular
(N2H · · · O1ꢀ, N2ꢀHꢀ · · · O1). Hydrogen bonds shown as dashed blue lines.†
This finding modifies one of Etters rules for hydrogen bond
priorities12 which asserts that: “six-membered-ring intramolecular
hydrogen bonds form in preference to intermolecular hydrogen
bonds”, showing that the two situations can coexist for the same
pair of donor/acceptors.
One interesting consequence of the rigidity of the molecules
studied is the presence in most of the cases of short contacts
between the pyridine-type nitrogen in 3/4 and the ortho-R
‡ The expected priority order for the halogen bond interactions C–X · · · B
is B = S < N < O for the Lewis base and X = Cl < Br < I for the halogen,15
the contact with X = F being rarely reported and quite controversial.16
In our case, with the carbonyl group involved in two hydrogen bonds, the
pyridine-like nitrogen is the only available acceptor for the intramolecular
interaction.
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Table 2 CDK4 activity versus CDK2 activity
CDK4 measured
CDK2 measured
Compound
IC50/lMa
IC50/lMb
Fascaplysin
0.55
500
1
2
6
45
16
1
4
2
521 12
515 11
3a
3b
3c
3d
3g
3h
4a
4b
4c
4d
4f
4g
4h
(7+8a)c
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
812
8
12 1.8
630 15
818 16
1209 15
11
78
34
39
24 2.5
22
14
2
6
2
3
538
913
9
8
974 11
855 10
940 12
2
1
65 3.5
512
7
32
34
61
72
67
77
75
59
30
65
54
42
3
2
4
5
3
4
4
5
1
3
5
2
868 10
538
712
9
7
Scheme 4 Reagents and conditions: i) Pd(PPh3)4(cat), K2CO3(aq), ArB(OH)2,
toluene–EtOH, 90 ◦C.
1216 11
920 20
1135 18
acid in a 1 : 1 mixture of toluene–EtOH at 90 ◦C using Pd(PPh3)4 as
catalyst and aqueous K2CO3 as base. This produced an unresolved
mixture of the desired dihydro-b-carboline 7 and the fully aromatic
b-carboline 8d in a 10 : 1 ratio.
Using the same reaction conditions with the corresponding
ortho/meta/para brominated b-carbolines 4d, 4e and 4h as starting
materials, the synthesis of the target compounds 8a–o was
achieved in a straightforward fashion with high yields (82–99%,
see experimental part for further details).
496
9
384 15
983 17
865 13
367
350
8
8
48 2.5
423 15
971 11
800 15
526 14
437 10
566 12
25
58
77
58 2.5
61 3.5
2
3
4
Biological results
a CDK4-cyclin D1 assay, using GST-RB152 fusion protein as the substrate.
b CDK2-cyclin A assay using histone H1 as the substrate. c Tested as an
unresolved mixture of 7 and 8a in a 10 : 1 ratio.
The CDK4 and CDK2 inhibitory activities of compounds 3a–
d, 3g–h, 4a–d, 4f–h, 7, and 8a–o were measured in terms of IC50
using standard methods6 and the results are shown in Table 2.
As expected, all the compounds are active as CDK4 inhibitors
showing a clear selectivity for this kinase compared to CDK2.
The first series of compounds discussed above, the dihydro-b-
carboline derivatives, shows, in general, better activities compared
to the corresponding fully aromatic compounds. In both series the
introduction of a halogen in the ortho-position of the benzenoid
ring increases the activity, the greater the electronegativity of
the halogen the lesser the effect. Furthermore, taking the ortho-
brominated derivatives 3d and 4d as reference, the activity of these
compounds is decreased if the halogen is located in the meta or
para-positions on the aromatic ring. For these two series the best
in our case, the decreased activities for the coupling products
can be rationalized in terms of a competition between the two
binding modes. Once the molecule is located in the ATP binding
site in a similar fashion as for fascaplysin 1, the bulky introduced
bis/tris aromatic moieties are possibly not oriented properly in the
direction of the p-stacking pocket.
Conclusions
A series of dehydro-b-carboline and b-carboline-based com-
pounds related to the toxic anticancer agent fascaplysin 1 were
synthesised and their biological activities as CDK4-cyclin D1
specific inhibitors measured.
Compounds 3a–d, 3g–h, 4a–d and 4f–h were designed to retain
the double hydrogen bonding to Val 96 and prepared with
acceptable yields by a novel synthetic methodology previously
reported.
hits correspond to the ortho-brominated compounds 3d (IC50
11 lm) and 4d (IC50 = 14 lm).
=
As the crystallographic analysis of compounds of type 3 and
4 has shown, these should exist in a rigid conformation, differing
from fascaplysin only in the relative disposition of the outer phenyl
group (characterised by s2), so a similar binding mode in the ATP
site of the enzyme is expected.
Concerning the bi/triphenyl derivatives, the introduction of
aromatic ring or rings in the initial structure decreases the activity
with respect to the parent brominated compounds, the exception
being 8f (more active than 4h) and 8k (more active than 4g).
For these series of compounds, instead of a synergic effect
between the two interactions (i.e. the fascaplysin-like double
hydrogen bonding and the p-stacking present in compound 2),
Compounds 7 and 8a–o were produced using the well estab-
lished Suzuki–Miyaura coupling methodology in an effort to
increase the activities of the parent compounds by interaction
with a proposed p-stacking pocket (Phe 93–159).
The structural similarity between compounds of type 3/4, and
fascaplysin 1 was estimated by means of the solid state structure
analysis of some of the compounds synthesised (3b/d and 4a–d).
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This analysis showed the compounds have a rigid conformation,
keeping the carbonyl group and the indolyl NH approximately
in the same plane as for fascaplysin 1 caused by a strong
intramolecular hydrogen bonding. As predicted, the compounds
showed a good activity as CDK4-cyclin D1 inhibitors with an IC50
for the best compound of 11 lm.
The second series (compounds 7 and 8a–o), showed in general
a decreased activity compared to the parent compounds. This was
attributed to a competition between the two proposed binding
modes.
were then dried over anhydrous sodium or magnesium sulfate,
filtered and isolated under reduced pressure. The crude products
were then purified by flash column chromatography on silica from
CH2Cl2.
Suzuki coupling of compound 3h. The reaction between the
brominated derivative 3h and phenylboronic acid in the conditions
explained above yielded, after column chromatography (CH2Cl2),
an unresolved mixture of 7 + 8a in a 10 : 1 ratio (isolated overall
yield 67%). The spectroscopic data for the major compound is
described below.
Biphenyl-4-yl(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-methan-
one 7. 67% (Mixture), yellow sticky solid, 1H-NMR (300 MHz,
CDCl3) d 3.05 (2H, t, J 8.8), 4.21 (2H, t, J 8.8), 7.18 (1H, ddd, J
8.0, 7.0, 1.0), 7.33 (1H, ddd, J 8.3, 7.0, 1.2), 7.42–7.52 (4H, m),
7.63–7.66 (3H, m), 7.71 (2H, d, J 8.6), 8.28 (2H, d, J 8.6) and
9.51 (1H, br s) ppm; 13C-NMR (75 MHz, CDCl3) d 19.1 (CH2),
49.3 (CH2), 112.3 (CH), 118.0 (Cq), 119.9 (CH), 120.3 (CH), 124.8
(Cq), 125.1 (CH), 126.6 (Cq), 126.9 (CH), 127.3 (CH), 128.2 (CH),
128.9 (CH), 131.6 (CH), 134.0 (Cq), 136.9 (Cq), 140.0 (Cq), 146.2
(Cq), 155.9 (Cq) and 192.8 (Cq); m/z (ES+) 351 (MH+).
Experimental
General
All reactions were performed under an atmosphere of nitrogen
(unless otherwise stated in the text) and solvent extractions dried
with anhydrous sodium sulfate. NMR spectra were recorded on a
Bruker DPX 300 (1H, 300.13 MHz; 13C, 75.47 MHz) spectrometer.
Chemical shifts were measured relative to chloroform (13C d 77.0)
or dimethylsulfoxide (13C d 39.5) and are expressed in ppm.
Coupling constants J are expressed in Hertz and the measured
values are rounded to one decimal place. Fast atom bombardment
(FAB) mass spectra were recorded on a Kratos Concept 1H using
xenon and m-nitrobenzyl alcohol as the matrix. Electrospray
(ES) mass spectra were recorded on a Micromass Quattro LC
spectrometer. Accurate mass was measured on a Kratos Concept
1H spectrometer using peak matching to a stable reference peak.
Flash column chromatography was carried out using Merck
Kieselgel 60 (230–400 mesh). Melting points were recorded on
a Reichert Kofler thermopan and are uncorrected.
Biphenyl-2-yl-(9H-b-carbolin-1-yl)-methanone 8a. 99% Yield,
◦
yellow solid; mp 194–195 C (from EtOH); Found: C, 82.83; H,
4.70; N 7.84%; C24H16N2O requires: C, 82.74; H, 4.63; N, 8.04%;
mmax/cm−1 3366, 3058, 1635, 1425, 1315, 1210, 1117, 969, 748, 737,
701; 1H-NMR (300 MHz, CDCl3) d 7.06–7.17 (3H, m), 7.30–7.35
(3H, m), 7.48–7.64 (5H, m), 7.72 (1H, dd, J 1.2 and 7.4), 8.00 (1H,
d, J 4.9), 8.11 (1H, d, J 8.0 Hz), 8.42 (1H, d, J 4.9) and 10.28 (1H,
br s, D2O exch, NH) ppm; 13C-NMR (75 MHz, CDCl3) d 112.0
(CH), 115.4 (CH), 118.5 (CH), 120.1 (CH), 120.7 (Cq), 120.8
(CH), 121.8 (CH), 126.8 (CH), 126.9 (CH), 128.1 (CH), 128.9
(CH), 129.2 (CH), 129.5 (CH), 130.2 (CH), 130.6 (CH), 131.4
(Cq), 136.4 (Cq), 136.6 (Cq), 138.5 (CH), 138.6 (Cq), 141.1 (Cq),
142.01 (Cq) and 200.6 (CO) ppm; m/z (ES+) 349 (MH+); m/z
(FAB+) 351 (MH+) (found: MH+, 349.13407; C24H17N2O requires
349.13409).
Crystal structure determinations§
Single crystals of compounds 3b/d and 4a-d suitable for X-
ray diffractometry were obtained by dissolving crystals of the
corresponding pure compound in the minimum quantity of cold
EtOH in an open vial that was then placed in a larger container
with a little H2O in its bottom; the container was closed, and after
a few days in a cool, dark place free from vibrations, afforded
the desired single crystals. These were mounted in inert oil and
transferred to the cold gas stream of the diffractometer.
Biphenyl-3-yl-(9H-b-carbolin-1-yl)-methanone 8b. 93% Yield,
◦
yellow solid; mp 151–152 C (from EtOH); Found: C, 82.83; H,
4.56; N 7.99%; C24H16N2O requires: C, 82.74; H, 4.63; N, 8.04%;
1
mmax/cm−1 3436, 3057, 1614, 1425, 1316, 1203, 748, 722, 693; H-
NMR (300 MHz, CDCl3) d 7.34–7.41 (2H, m), 7.48 (2H, t, J 7.4),
7.59–7.70 (5H, m), 7.85 (1H, dt, J 1.4 and 7.8), 8.18–8.21 (2H, m),
8.29 (1H, dt, J 7.7 and 1.3), 8.52 (1H, t, J 1.7), 8.62 (1H, d, J 4.9)
and 10.46 (1H, br s, D2O exch, NH) ppm; 13C-NMR (75 MHz,
CDCl3) d 110.9 (CH), 117.5 (CH), 119.7 (CH), 119.7 (Cq), 120.7
(CH), 126.2 (CH), 126.5 (CH), 127.3 (CH), 127.8 (CH), 128.2
(CH), 128.4 (CH), 128.7 (CH), 129.1 (CH), 129.9 (Cq), 129.9
(CH), 130.6 (Cq), 135.1 (Cq), 136.2 (Cq), 137.0 (CH), 139.5 (Cq),
140.0 (2 × Cq) and 194.5 (CO) ppm; m/z (ES+) 349 (MH+); m/z
(FAB+) 351 (MH+) (found: MH+, 349.13404; C24H17N2O requires
349.13409).
General method for the Suzuki coupling reaction
To a stirred solution of the corresponding brominated intermedi-
ate (3h, 4d/e/h, 1 mmol) in toluene (10 mL), under nitrogen, was
added K2CO3 (1 mmol, 2M aqueous solution) and Pd(PPh3)4 (5
mol%, 0.05 mmol). The solution was stirred for 20 minutes at room
temperature before the addition of a solution of the appropriately
substituted phenylboronic acid (1.2 mmol) in EtOH (10 mL), the
◦
reaction mixture was then heated to 90 C for 24 h and allowed
to cool to room temperature before the addition of H2O2 (30%,
1 mL). The reaction mixture was then stirred for a further hour,
and extracted into CHCl3, washed with saturated brine solution
(2 × 25 mL) and H2O (2 × 25 mL), aqueous washings being re-
extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
Biphenyl-4-yl-(9H-b-carbolin-1-yl)-methanone 8c. 99% Yield,
◦
yellow solid; mp 183–184 C (from EtOH); Found: C, 82.63; H,
4.59; N 7.91%; C24H16N2O requires: C, 82.74; H, 4.63; N, 8.04%;
mmax/cm−1 3377, 3055, 1641, 1425, 1318, 1205, 742, 728, 709, 688;
1H-NMR (300 MHz, CDCl3) d 7.33–7.43 (2H, m), 7.49 (2H, t,
J 7.3), 7.62–7.64 (2H, m), 7.66–7.60 (2H, m), 7.76 (2H, dt, J 1.8
§ CCDC reference numbers 621742–621747. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b613861f
4482 | Org. Biomol. Chem., 2006, 4, 4478–4484
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The Royal Society of Chemistry 2006
©

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1
and 8.4), 8.18–8.21 (2H, m), 8.43 (2H, dt, J 1.7 and 8.4), 8.63
(1H, d, 4.9 Hz) and 10.48 (1H, br s, D2O exch, NH) ppm; 13C-
NMR (75 MHz, CDCl3) d 112.0 (CH), 118.5 (CH), 120.7 (CH),
120.8 (Cq), 121.8 (CH), 126.7 (CH), 127.3 (CH), 128.0 (CH), 128.9
(CH), 129.2 (CH), 131.6 (Cq), 131.8 (CH), 136.3 (Cq), 136.4 (Cq),
137.3 (Cq), 138.0 (CH), 140.3 (Cq), 141.0 (Cq), 145.0 (Cq) and
194.8 (CO) ppm; m/z (ES+) 349 (MH+); m/z (FAB+) 351 (MH+)
(found: MH+, 349.13416; C24H17N2O requires 349.13409).
1209, 1117, 970, 859, 750, 734; H-NMR (300 MHz, CDCl3) d
6.84 (2H, t, J 8.6), 7.27–7.36 (3H, m), 7.48–7.62 (5H, m), 7.71
(1H, d, J 7.2), 8.03 (1H, d, J 4.9), 8.13 (1H, d, J 8.0), 8.41 (1H,
d, J 4.9) and 10.28 (1H, br s, D2O exch, NH) ppm; 13C-NMR
2
(75 MHz, DMSO) d 113.0 (CH), 114.7 (CH, d, JCF 21.5), 119.0
(CH), 119.9 (Cq), 120.2 (CH), 121.8 (CH), 126.7 (CH), 128.9
(CH), 129.1 (CH), 129.6 (CH), 130.0 (CH), 130.2 (CH, d, JCF
8.1), 130.8 (Cq), 135.1 (Cq), 136.2 (Cq), 137.0 (Cq), 137.4 (CH),
139.3 (Cq), 139.6 (Cq), 141.8 (Cq), 161.2 (Cq, d, 1JCF 243.6) and
198.8 (CO) ppm; m/z (ES+) 367 (MH+); m/z (FAB+) 367 (MH+)
(found: MH+, 367.12476; C24H15FN2O requires 367.12468).
3
(9H-b-Carbolin-1-yl)-(4ꢀ-methyl-biphenyl-2-yl)-methanone 8d.
99% Yield, yellow solid; mp 185–186 ◦C (from EtOH); Found:
C, 82.95; H, 4.98; N 7.65%; C25H18N2O requires: C, 82.85; H,
5.01; N, 7.73%; mmax/cm−1 3407, 3045, 1641, 1463, 1315, 1207,
1114, 972, 766, 750, 728, 711; 1H-NMR (300 MHz, CDCl3) d 2.20
(3H, s), 6.96 (2H, d, J 7.9), 7.20 (2H, d, J 8.0), 7.34 (1H, t, J
7.3), 7.45–7.63 (5H, m), 7.69 (1H, dd, J 1.0 and 7.6), 8.05 (1H,
d, J 4.9), 8.13 (1H, d, J 7.8), 8.45 (1H, d, J 4.9) and 10.31 (1H,
br s, D2O exch, NH) ppm; 13C-NMR (75 MHz, CDCl3) d 21.01
(CH3), 111.9 (CH), 118.5 (CH), 120.7 (CH), 120.7 (Cq), 121.7
(CH), 126.4 (CH), 128.7 (CH), 128.9 (CH), 129.2 (CH), 129.5
(CH), 130.2 (CH), 130.4 (CH), 131.4 (Cq), 131.6 (Cq), 136.3 (Cq),
136.6 (2 × Cq), 138.1 (Cq), 138.4 (CH), 141.0 (Cq), 141.9 (Cq) and
200.6 (CO) ppm; m/z (ES+) 363 (MH+); m/z (FAB+) 363 (MH+)
(found: MH+, 363.14973; C25H18N2O requires 363.14975).
(9H-b-Carbolin-1-yl)-(4ꢀ-fluoro-biphenyl-3-yl)-methanone 8h.
97% Yield, yellow solid; mp 188–189 ◦C (from EtOH); Found:
C, 78.59; H, 4.04; N 7.51%; C24H15FN2O requires: C, 78.68; H,
4.13; N, 7.65%; mmax/cm−1 3437, 3053, 1615, 1593, 1425, 1317,
1
1204, 1162, 979, 840, 751, 736; H-NMR (300 MHz, CDCl3) d
7.16 (2H, t, J 8.7), 7.37 (1H, quintet, J 4.0), 7.58–7.66 (5H, m),
7.78 (1H, dt, J 1.4 and 7.7), 8.18–8.21 (2H, m), 8.30 (1H, dt, J
1.3 and 7.7), 8.47 (1H, t, J 1.6), 8.3 (1H, d, 4.9) and 10.46 (1H,
br s, D2O exch, NH) ppm; 13C-NMR (75 MHz, CDCl3) d 113.0
2
(CH), 115.8 (CH, d, JCF 21.4), 118.9 (CH), 120.0 (Cq), 120.2
(CH), 121.8 (CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 130.0
(CH), 129.6 (CH), 130.2 (CH), 131.1 (Cq), 135.9 (Cq), 136.0 (Cq),
136.1 (Cq), 137.2 (CH), 138.3 (Cq), 138.7 (Cq), 141.7 (Cq), 162.0
(9H-b-Carbolin-1-yl)-(4ꢀ-methyl-biphenyl-3-yl)-methanone 8e.
94% Yield, yellow solid; mp 159–160 ◦C (from EtOH); Found:
C, 82.75; H, 5.11; N 7.63%; C25H18N2O requires: C, 82.85; H,
5.01; N, 7.73%; mmax/cm−1 3437, 3060, 1615, 1425, 1316, 1249,
1204, 978, 785, 750, 734, 723; 1H-NMR (300 MHz, CDCl3) d 2.41
(3H, s), 7.27 (2H, d, J 8.0), 7.36 (1H, quintet, J 4.0), 7.57–7.64
(5H, m), 7.81 (1H, dt, J 1.7 and 7.7), 8.18–8.21 (2H, m), 8.28
(1H, dt, J 1.3 and 7.7), 8.50 (1H, t, J 1.6), 8.62 (1H, d, J 4.9)
and 10.46 (1H, br s, D2O exch, NH) ppm; 13C-NMR (75 MHz,
CDCl3) d 21.2 (CH3), 112.0 (CH), 118.6 (CH), 120.8 (CH), 120.9
(Cq), 121.8 (CH), 127.1 (CH), 128.4 (CH), 129.3 (CH), 129.6 (CH),
130.0 (CH), 130.9 (CH), 131.70 (Cq), 136.3 (Cq), 137.3 (Cq), 137.4
(2xCq), 137.8 (Cq), 138.1 (Cq), 138.2 (CH), 141.0 (Cq) and 195.7
(CO) ppm; m/z (ES+) 363 (MH+); m/z (FAB+) 363 (MH+) (found:
MH+, 363.14976; C25H18N2O requires 363.14975).
(Cq, d, JCF 244.6) and 193.9 (CO) ppm; m/z (ES+) 367 (MH+);
1
m/z (FAB+) 367 (MH+) (found: MH+, 367.12462; C24H15FN2O
requires 367.12468).
(9H-b-Carbolin-1-yl)-(4ꢀ-fluoro-biphenyl-4-yl)-methanone
8i.
95% Yield, yellow solid; mp 221–222 ◦C (from EtOH); Found:
C, 78.53; H, 4.05; N 7.54%; C24H15FN2O requires: C, 78.68; H,
4.13; N, 7.65%; mmax/cm−1 3431, 3041, 1601, 1426, 1317, 1215,
1
1164, 970, 837, 794, 736, 714; H-NMR (300 MHz, CDCl3) d
7.17 (2H, t, J 8.7), 7.36 (1H, quintet, J 4.0), 7.62–7.66 (4H,
m), 7.71 (1H, d, J 8.4), 8.18–8.20 (2H, m), 8.42 (2H, d, J 8.4)
and 10.48 (1H, br s, D2O exch, NH) ppm; 13C-NMR (75 MHz,
CDCl3) d 113.0 (CH), 115.8 (CH, d, 2JCF 21.5), 118.8 (CH), 120.0
(Cq), 120.2 (CH), 121.8 (CH), 126.1 (CH), 128.1 (CH), 128.9
(CH), 131.0 (Cq), 131.5 (CH), 135.6 (Cq), 135.7 (Cq), 135.8 (Cq),
136.2 (Cq), 136.3 (Cq), 137.1 (CH), 141.7 (Cq), 142.6 (Cq), 162.3
(9H-b-Carbolin-1-yl)-(4ꢀ-methyl-biphenyl-4-yl)-methanone 8f.
97% Yield, yellow solid; mp 209–210 ◦C (from EtOH); Found: C,
82.77; H, 4.96; N 7.61%; C25H18N2O requires: C, 82.85; H, 5.01;
N, 7.73%; mmax/cm−1 3398, 3056, 1640, 1424, 1317, 1214, 1204,
970, 793, 737, 727, 707; 1H-NMR (300 MHz, CDCl3) d 2.42 (3H,
s), 7.31 (2H, d, J 8.0 Hz), 7.36 (1H, quintet, J 4.0), 7.57–7.63 (4H,
m), 7.74 (2H, dt, J 1.7 and 8.4), 8.17–8.20 (2H, m), 8.28 (2H, dt,
J 1.3 and 7.7 Hz), 8.64 (1H, d, J 4.9 Hz) and 10.48 (1H, br s,
D2O exch, NH) ppm; 13C-NMR (75MHz, CDCl3) d 21.2 (CH3),
112.0 (CH), 118.5 (CH), 120.7 (CH), 120.8 (Cq), 121.8 (CH),
126.5 (CH), 127.18 (CH), 129.3 (CH), 129.6 (CH), 131.7 (Cq),
131.8 (CH), 136.0 (Cq), 136.5 (Cq), 137.3 (Cq), 137.4 (Cq), 138.0
(Cq), 138.1 (CH), 141.0 (Cq), 141.0 (Cq) and 194.9 (CO) ppm;
m/z (ES+) 363 (MH+); m/z (FAB+) 363 (MH+) (found: MH+,
363.14979; C25H18N2O requires 363.14975).
(Cq, d, JCF 245.3) and 193.0 (CO) ppm; m/z (ES+) 367 (MH+);
1
m/z (FAB+) 367 (MH+) (found: MH+, 367.12471; C24H15FN2O
requires 367.12468).
(4ꢀ-tert-Butyl-biphenyl-2-yl)-(9H-b-carbolin-1-yl)-methanone 8j.
96% Yield, yellow solid; mp 176–177 ◦C (from EtOH); Found: C,
83.02; H, 5.86; N 6.83%; C28H24N2O requires: C, 83.14; H, 5.98; N,
6.93%; mmax/cm−1 3421, 2921, 1651, 1429, 1315, 1245, 1206, 969,
835, 762, 752, 737, 725; 1H-NMR (300 MHz, CDCl3) d 1.12 (9H,
s), 7.11 (2H, d, J 8.4 Hz), 7.22 (2H, d, J 8.4 Hz), 7.32 (1H, t, J
6.5 Hz), 7.46–7.63 (5H, m), 7.71 (1H, dd, J 0.8 and 7.4 Hz), 7.98
(1H, d, J 5.0 Hz), 8.12 (1H, d, J 7.9 Hz), 8.40 (1H, d, J 5.0 Hz) and
10.23 (1H, br s, D2O exch, NH) ppm; 13C-NMR (75 MHz, CDCl3)
d 31.1 (CH3), 31.3 (Cq), 112.0 (CH), 118.3 (CH), 120.7 (CH),
120.7 (Cq), 121.8 (CH), 125.0 (CH), 126.5 (CH), 128.5 (CH), 129.2
(CH), 129.4 (CH), 130.2 (CH), 130.6 (CH), 131.3 (Cq), 136.5 (Cq),
136.7 (Cq), 138.0 (Cq), 138.4 (CH), 138.7 (Cq), 141.1 (Cq), 142.0
(Cq), 149.7 (Cq) and 194.9 (CO) ppm; m/z (ES+) 405 (MH+); m/z
(9H-b-Carbolin-1-yl)-(4ꢀ-fluoro-biphenyl-2-yl)-methanone 8g.
97% Yield, yellow solid; mp 245–246 ◦C (from EtOH); Found:
C, 78.52; H, 4.07; N 7.58%; C24H15FN2O requires: C, 78.68; H,
4.13; N, 7.65%; mmax/cm−1 3390, 3059, 1634, 1624, 1426, 1316,
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(FAB+) 405 (MH+) (found: MH+,405.19661; C28H24N2O requires
405.19670).
(CH), 127.6 (CH), 127.7 (CH), 128.5 (CH), 128.8 (CH), 129.3
(CH), 129.7 (CH), 130.3 (CH), 130.9 (CH), 131.7 (Cq), 136.3
(Cq), 137.2 (Cq), 137.4 (Cq), 138.2 (CH), 139.5 (Cq), 140.4 (Cq),
140.5 (Cq), 140.6 (Cq), 140.5 (Cq), 141.1 (Cq) and 195.6 (CO)
ppm; m/z (ES+) 425 (MH+); m/z (FAB+) 425 (MH+) (found:
MH+, 425.16536; C30H20N2O requires 425.16540).
(4ꢀ-tert-Butyl-biphenyl-3-yl)-(9H-b-carbolin-1-yl)-methanone 8k.
99% Yield, yellow solid; mp 173–174 ◦C (from EtOH); Found: C,
83.06; H, 5.89; N 6.83%; C28H24N2O requires: C, 83.14; H, 5.98;
N, 6.93%; mmax/cm−1 3423, 2962, 1621, 1427, 1317, 1248, 1207,
979, 841, 791, 754, 728; 1H-NMR (300 MHz, CDCl3) d 1.38 (9H,
s), 7.36 (1H, quintet, J 4.0 Hz), 7.50 (2H, d, J 8.4 Hz), 7.60–7.64
(5H, m), 7.83 (1H, d, J 7.8 Hz), 8.18–8.21 (2H, m), 8.28 (1H, d, J
7.7 Hz), 8.52 (1H, br t), 8.63 (1H, d, J 4.9 Hz) and 10.47 (1H, br s,
D2O exch, NH) ppm; 13C-NMR (75 MHz, CDCl3) d 31.3 (CH3),
34.5 (Cq), 112.0 (CH), 118.5 (CH), 120.7 (CH), 120.8 (Cq), 121.8
(CH), 125.8 (CH), 126.9 (CH), 128.3 (CH), 129.2 (CH), 129.7
(CH), 129.9 (CH), 130.9 (CH), 131.6 (Cq), 136.3 (Cq), 137.3 (Cq),
137.7 (Cq), 138.0 (Cq), 138.1 (CH), 140.9 (Cq), 141.0 (Cq), 150.6
(Cq) and 195.6 (CO) ppm; m/z (ES+) 405 (MH+); m/z (FAB+) 405
(MH+) (found: MH+, 405.19660; C28H24N2O requires 405.19670).
(9H-b-Carbolin-1-yl)-[1,1ꢀ;4ꢀ,1ꢀꢀ]terphenyl-4-yl-methanone 8o.
82% Yield, yellow solid; mp 255–256 ◦C (from EtOH); mmax/cm−1
3387, 3053, 3034, 1640, 1426, 1316, 1247, 1206, 1117, 970, 758,
735; 1H-NMR (300 MHz, CDCl3) d 7.34–7.40 (2H, m), 7.48 (2H,
t, J 7.6), 7.63–7.84 (10H, m), 8.19–8.21 (2H, m), 8.44 (2H, d, J
8.2), 8.66 (1H, d, J 4.9) and 10.48 (1H, br s, D2O exch, NH) ppm;
13C-NMR (75 MHz, DMSO) d 113.5 (CH), 116.2 (CH), 119.4
(CH), 120.6 (CH), 120.7 (Cq), 122.3 (CH), 126.4 (CH), 127.8
(CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 129.2 (CH), 129.5
(Cq), 131.6 (CH), 136.3 (Cq), 136.8 (Cq), 136.9 (Cq), 137.7 (CH),
138.6 (Cq), 139.9 (Cq), 140.5 (Cq), 142.2 (Cq), 143.6 (Cq) and
193.6 (CO) ppm; m/z (ES+) 425 (MH+); m/z (FAB+) 425 (MH+)
(found: MH+, 425.16538; C30H20N2O requires 425.16540).
(4ꢀ-tert-Butyl-biphenyl-4-yl)-(9H-b-carbolin-1-yl)-methanone 8l.
99% Yield, yellow solid; mp 245–246 ◦C (from EtOH); Found: C,
83.21; H, 5.88; N 6.82%; C28H24N2O requires: C, 83.14; H, 5.98;
N, 6.93%; mmax/cm−1 3420, 2964, 1649, 1604, 1424, 1309, 1242,
Acknowledgements
1
1203, 1182, 1118, 964, 827, 796, 747, 732; H-NMR (300 MHz,
This work was supported by Cancer Research UK. The authors
are highly grateful to Drs I. Alkorta and J. Elguero for their
useful discussions on the structure of the compounds investigated.
We also would like to thank K. Singh for the X-ray measure-
ments. M. D. Garc´ıa thanks the Xunta de Galicia for financial
support.
CDCl3) d 1.38 (9H, s), 7.36 (1H, quintet, J 4.0 Hz), 7.52 (2H, d,
J 7.5 Hz), 7.62–7.65 (4H, m), 7.77 (2H, d, J 8.3 Hz), 8.18–8.21
(2H, m), 8.28 (1H, d, J 7.7 Hz), 8.43 (2H, d, J 8.3 Hz), 8.64 (1H,
d, J 4.9 Hz) and 10.48 (1H, br s, D2O exch, NH) ppm; 13C-NMR
(75 MHz, CDCl3) d 31.4 (CH3), 34.6 (Cq), 112.0 (CH), 118.5 (CH),
120.8 (CH), 120.9 (Cq), 121.8 (CH), 125.9 (CH), 126.6 (CH), 127.0
(CH), 129.3 (CH), 131.7 (Cq), 131.9 (CH), 136.0 (Cq), 136.5 (Cq),
137.3 (Cq), 137.4 (Cq), 138.1 (CH), 141.0 (Cq), 145.0 (Cq), 151.2
(Cq) and 194.9 (CO) ppm; m/z (ES+) 405 (MH+); m/z (FAB+) 405
(MH+) (found: MH+, 405.19663; C28H24N2O requires 405.19670).
References
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Marechal and M. J. Sutcliffe, Org. Biomol. Chem., 2006, 4, 787.
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9, 917–921.
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Kontopidis, C. Meades, M. Mezna, M. Thomas, G. Wood, D. P. Lane
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(9H-b-Carbolin-1-yl)-[1,1ꢀ;4ꢀ,1ꢀꢀ]terphenyl-2-yl-methanone 8m.
98% Yield, yellow solid; mp 216–217 ◦C (from EtOH); Found:
C, 84.93; H, 4.56; N 6.55%; C30H20N2O requires: C, 84.88; H,
4.75; N, 6.60%; mmax/cm−1 3324, 3027, 1644, 1425, 1313, 1205,
966, 755, 721; 1H-NMR (300 MHz, CDCl3) d 7.22–7.42 (10H, m),
7.48–7.64 (5H, m), 7.73 (1H, dd, J 0.7 and 7.5), 7.98 (1H, d, J 4.9),
8.07 (1H, d, J 7.9), 8.42 (1H, d, J 4.9) and 10.32 (1H, br s, D2O
exch, NH) ppm; 13C-NMR (75 MHz, CDCl3) d 112.0 (CH), 118.5
(CH), 120.7 (Cq), 120.8 (CH), 121.8 (CH), 126.8 (CH), 126.9
(CH), 127.1 (CH), 128.6 (CH), 129.2 (CH), 129.6 (CH), 130.2
(CH), 130.6 (CH), 131.4 (Cq), 136.3 (Cq), 136.6 (Cq), 138.5 (CH),
138.5 (Cq), 139.6 (Cq), 140.1 (Cq), 140.5 (Cq), 141.1 (Cq), 141.5
(Cq) and 200.4 (CO) ppm; m/z (ES+) 425 (MH+); m/z (FAB+) 425
(MH+) (found: MH+, 425.16543; C30H20N2O requires 425.16540).
11 M. D. Garc´ıa, A. J. Wilson, D. P. G. Emmerson and P. R. Jenkins,
Chem. Commun., 2006, 2586.
(9H-b-Carbolin-1-yl)-[1,1ꢀ;4ꢀ,1ꢀꢀ]terphenyl-3-yl-methanone 8n.
97% Yield, yellow solid; mp 216–217 ◦C (from EtOH); Found: C,
84.80; H, 4.80; N 6.58%; C30H20N2O requires: C, 84.88; H, 4.75;
N, 6.60%; mmax/cm−1 3424, 3034, 1619, 1425, 1315, 1203, 977,
12 M. C. Etter, Acc. Chem. Res., 1990, 23, 120.
13 A. Bondi, J. Phys. Chem., 1964, 68, 441.
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15 J. P. M. Lommerse, A. J. Stone, R. Taylor and F. H. Allen, J. Am. Chem.
Soc., 1996, 118, 3108.
1
757, 733, 717; H-NMR (300 MHz, CDCl3) d 7.37 (2H, quintet,
J 3.8), 7.47 (2H, t, J 7.5), 7.61–7.67 (5H, m), 7.73 (4H, q, J 8.3
and 17.5), 7.89 (1H, d, J 7.8), 8.19–8.22 (2H, m), 8.30 (1H, d, J
7.7), 8.57 (1H, br t), 8.65 (1H, d, J 4.9) and 10.48 (1H, br s, D2O
exch, NH) ppm; 13C-NMR (75 MHz, CDCl3) d 112.0 (CH), 118.6
(CH), 120.8 (Cq), 120.8 (CH), 121.8 (CH), 127.1 (CH), 127.4
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4484 | Org. Biomol. Chem., 2006, 4, 4478–4484
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