Rigid analogues of antimitotic indolobenzazepinones: New insights into tubulin binding via molecular modeling

Article abstract of DOI:10.1021/ml200024y

Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrro

Full text of DOI:10.1021/ml200024y

LETTER
pubs.acs.org/acsmedchemlett
Rigid Analogues of Antimitotic Indolobenzazepinones: New Insights
into Tubulin Binding via Molecular Modeling
Valꢀerie Pons, Stꢀephane Beaumont, Marie Elise Tran Huu Dau, Bogdan I. Iorga, and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
S Supporting Information
b
ABSTRACT:
Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were
prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the
pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen. While both compounds were considerably less
active inhibitors of KB cell growth as compared to 4, inhibition of tubulin polymerization was only moderately reduced. Tubulin
docking studies indicated that the aR and aS atropoisomers of 5 and 6 occupy different binding pockets at the colchicine binding site.
Conversely, both aS-5 and aS-6 occupy the same binding pocket as aSS-4 but do not benefit from the favorable hydrophobic
interactions provided by the C5 alkyl group of 4, thus possibly explaining their lower activities.
KEYWORDS: Indolobenzazepinone, cytotoxicity, tubulin polymerization, atropoisomers, molecular docking
ubulin remains one of the major therapeutic targets for
T
clinically useful anticancer compounds,1 as reflected by the
considerable success of the antimitotic vinca alkaloids (vincristin,
vinblastin, and the synthetic analogue navelbine)2 and taxoid
(taxol and its synthetic analogue taxotere)3 derivatives. The
structural complexity of these families of compounds has spurred
investigations to discover simpler structures having antimitotic
activities. This has led, for example, to the development of
N-acetyl-allocolchinol (NAC, 1),4 a structural analogue of one
of the first described naturally occurring antimitotic agents,
colchicine (2),5 as well as analogues of the combretastins (3)
(see Figure 1).6 However, while some of these compounds or
their analogues are in advanced clinical studies, none have yet
been approved as drugs.
In this regard, we recently described such a family of low
molecular weight and synthetically accessible antimitotic agents,
the C5-alkylated indolobenzazepinones, of which the most active
member was the (S)-5-ethyl derivative 4.7 The latter showed
potent antiproliferative activities in a variety of cancer cell lines
with, for example, an IC50 value of 32 nM in KB cells. Compound
4 also inhibited the polymerization of tubulin with an IC50 of
1.8 μM, comparing favorably with the antimitotic activities of
colchicine (2, IC50 = 2.2 μM) and NAC (1, IC50 = 3.0 μM)
determined under the same test conditions. Compound 4 was,
moreover, shown to be superior to colchicine and NAC in
significantly reducing tumor size in the experimental model of
glioma grafted on the chick chorio-allantoic membrane (CAM).
Figure 1
As part of our ongoing structureꢀactivity relationships develop-
ment for this novel family of antimitotics, we prepared analogues
of 4 in which the relatively flexible 7-membered benzazepinone
ring was rendered more rigid by the presence of a supplementary
ring. The first of these, the indane derivative 5, corresponds to
active compound 4 in which the C5 ethyl group is linked to the
Received: January 31, 2011
Accepted: June 5, 2011
Published: June 05, 2011
r
2011 American Chemical Society
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Scheme 1a
a Reagents and conditions: (a) Ti(Oi-Pr)4, 2 M NH3 solution in EtOH. (b) NaBH4 THF/MeOH. (c) Boc2O, NEt3, THF, 0 °C to room temperature.
(d) NEt3, (pin)BH, Pd(OAc)2, S-Phos, dioxane, 80 °C. (e) Compound 10, CsF, Pd(OAc)2, dppf, dioxane, 80 °C. (f) TFA, CH2Cl2. (g) Na/EtOH,
reflux.
benzo moiety, while in the second rigid target molecule, the same
ethyl group is now connected to the nitrogen atom of the
carboxamide to form the pyrrolidine structure 6.
trifluoroacetic acid in dichloromethane then afforded mono-
methyl derivative 15.
Encouraged by the results obtained for 15 (vide infra), we then
proceeded with the synthesis of the rigid pyrrolidine derivative 6
using the strategy shown in Scheme 3. N-Boc chloropropylamine
16 was treated with sodium hydride in THF, and the resulting
sodium salt was reacted with 2-bromobenzyl bromide to provide
17 in 84% yield.10 Cyclization of the latter to the 2-bromophe-
nylpyrrolidine 19 was effected in good yield (78%) by the action
of LDA in THF. Applying the same coupling methodology used
for the preparation of the indane derivative 5, compound 18 was
first transformed into pinacol derivative 19, which was then
coupled to 3-iodoindole derivative 10 under palladium catalysis
to afford 20 in modest yield (28% for both steps). Removal of the
N-Boc group of 20 with TFA followed by sodium ethanolate-
mediated cyclization and N-benzenesulfonamide cleavage pro-
vided the desired pyrrolidino-benzazepine derivative 6.
Rigid analogues 5 and 6, as well as N-methyl derivative 15,
were then evaluated for antiproliferative activities in KB cells
(Table 1).7 Both 5 and 6 were considerably less active than the
nonrigid derivative, compound 4, which possesses an IC50 of 35
nM. Thus, indane derivative 5 inhibited KB cell growth by 63% at
10ꢀ6 M (corresponding to an estimated IC50 of slightly less than
1 μM), while the pyrrolidine analogue 6 was even less cytotoxic,
inhibiting KB cell growth by only 27% at 10ꢀ6 M. Interestingly,
however, while the ability of compounds 5 and 6 to inhibit the
polymerization of tubulin was also diminished (IC50 values of
q5.3 and 4.2 μM, respectively) as compared to compound 4
(IC50 = 1.8 μM), this 2-fold decrease was modest as compared to
the major loss of cytotoxic activity of both rigid molecules. These
apparently paradoxical results may simply reflect poorer cell
penetration by compounds 5 and 6 as compared to the less rigid
analogue 4, a problem that does not come into consideration for
evaluation of antimitotic activity. Gratifyingly, the N-methyl
The synthesis of compound 5 is depicted in Scheme 1. The
bromoindanone 78 was treated with titanium tetra-isopropoxide
and excess ammonia in ethanol to provide the corresponding
imine, which was reduced with sodium borohydride to the amine.
The latter was relatively unstable and was therefore transformed
in situ to the N-Boc derivative 8, which was easily purified by
chromatography. Reaction of compound 8 with pinacol borane
in the presence of catalytic palladium diacetate and S-Phos in
dioxane at 80 °C provided the pinocolindane derivative 9.9
Suzuki coupling of the latter with ethyl 1-benzenesulfonyl-
3-iodoindole-2-carboxylate 107 using the combination palladium
diacetate/dppf as the catalytic system and cesium fluoride as base
provided compound 11 in approximately 50% yield from 8.
Deprotection of the primary amine function of 11 using trifluor-
oacetic acid in dichloromethane gave compound 12. Finally,
treatment of amine 12 with sodium in ethanol led to cyclization
and concomitant deprotection of the indole nitrogen to afford
the desired indane derivative 5.
Our second target molecule, the pyrrolidine derivative 6,
corresponds to an N-alkylated version of compound 4. We have
previously observed that N-methylation of the indole nitrogen as
well as simultaneous methylation of the indole and lactam NH
were detrimental to both the cytotoxic and the antimitotic
activities of 4.7 Therefore, before undertaking the synthesis of
the pyrrolidine derivative 6, it thus seemed appropriate to first
investigate the effect of N-alkylation of only the lactam function
of 4 on activity. Hence, for comparison with 6, we prepared the
N-methyl derivative 15 (Scheme 2). To do so, the indole NH of
compound 4 was first selectively protected by a Boc group to give
13. Methylation of the lactam NH of 13 was then effected with
methyl iodide and sodium hydride in THF. Treatment of 14 with
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LETTER
Scheme 2b
b Reagents and conditions: (a) Boc2O, NEt3, CH2Cl2, 0 °C to room temperature. (b) NaH, CH3I, THF. (c) TFA, CH2Cl2.
Scheme 3c
c Reagents and conditions: (a) Boc2O, NEt3, THF, 0 °C to room temperature. (b) 2-Bromobenzylbromide, NaH, THF, 0 °C to reflux. (c) LDA, THF,
ꢀ78 °C. (d) NEt3, (pin)BH, Pd(OAc)2, S-Phos, dioxane, 80 °C. (e) Compound 10, CsF, Pd(OAc)2, dppf, dioxane, 80 °C. (f) TFA, CH2Cl2. (g) Na/
EtOH, reflux.
but equivalent to that of pyrrolidine derivative 6 (IC50 = 4.2 μM).
Table 1. Antiproliferative Activities of Compounds 4ꢀ6 and
15 in KB Cells
This indicates that a free lactam NH function is not essential for
activity and suggests that the loss of cytotoxic activity in the case of
pyrrolidine derivative 6 is not due to the absence of the lactam NH.
The antiproliferative activities of compounds 5 and 6 were also
evaluated in three other cancer cell lines (HCT116, MCF7, and
HL60), as well as in resistant strains of these same cells (HCT15,
MCF7R, and HL60R). Interestingly, as shown in Table 2, while
both compounds maintain micromolar activities in all cell lines,
they were observed to be generally equally cytotoxic in resistant
and nonresistant cells (HCT and HL60) and, in the case of MCF7
cells, more cytotoxic in the resistant strains. By comparison,
compounds 4 and 15 were equally active in resistant and non-
resistant cell lines except for HL60 where cytotoxic activity was
slightly weaker in the resistant cells.
% inhibition of KB cell growth
compound no.
10 μM
1 μM
ITPc (μM)
4
100
81
100a
63
1.8
5.3
4.2
4.1
5
6
100
100
27
100b
15
a The IC50 of 4 was determined to be 35 nM. b The IC50 of 15 was
determined to be 2 nM. c Inhibition of tubulin polymerization.
derivative of 4, compound 15, was observed to display an anti-
proliferative activity superior to that of 4 itself (IC50 values of 2 vs
34 nM, respectively), while inversely, the antimitotic activity of
15 (IC50 = 4.1 μM) was 2-fold less than that of 4 (IC50 = 1.8 μM)
Joseph and colleagues have recently reported the antiproli-
ferative and antimitotic activities of a series of 5-unsubstituted
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Table 2. Antiproliferative Activities of 5 and 6 as Compared to 4 and 15 in Resistant Cancer Cell Lines
10/1 μM
compound no.
HCT116 (%)a
HCT15 (%)
MCF7 (%)
MCF7R (%)
HL60 (%)
HL60R (%)
4
100/85
80/64
100/94
87/75
92/82
39/46
55/28
96/85
96/84
72/67
75/56
92/75
100/90
90/83
95/78
81/70
80/49
89/70
5
6
81/64
84/78
84/49
15
100/91
100/92
100/85
a Percentage of inhibition of cell growth at 10 and 1 μM concentrations of test compound.
Figure 2. Transition state diagrams for atropoisomeric configuration inversion in the three systems studied.
indolobenzazepinones (i.e., compounds of type 4 devoid of a C5
substituent).11,12 While these activities were generally less robust
than in the case of our C5-alkylated derivatives, the authors were
able to perform docking studies at the colchicine binding site of
tubulin. Interestingly, no hydrogen-bonding interactions of the
nitrogen amide with the protein were observed. The present study
therefore corroborates this conclusion in that major structural
modifications at this center, as in pyrrolidine derivative 6, have
very little impact on the inhibition of tubulin polymerization.
Our own modeling studies did show some notable features
that could explain the diminished antimitotic activities of the two
rigid derivatives 5 and 6 versus more flexible compound 4.
Specifically, we determined the conformational preferences of
these three compounds using the Monte Carlo random search
method with optimization by the PRCG molecular mechanics
minimization technique using the Macromodel program
(version 5.5)13 with the MM2 force field. Out of a search of
1000 conformers, only one atropoisomer aRR was found for both
the indane and the pyrrolidine analogues 5 and 6, while both aRR
and aSR atropoisomers were obtained for the indolobenzazepi-
none 4. In spite of differences in structural rigidity, all aRR
atropoisomers adopt similar 3D structures (Figure S1 in the
Supporting Information). The 3D structures of the missing
5-aSR and 6-aSR atropoisomers were constructed manually.
Finally, the geometries of these six conformers, as well as
those of the corresponding transition states, were optimized
using the Gaussian 03 program14 at the HF/6-31Gþ(d,p) level
(Figure 2). Subsequent vibrational frequency calculations con-
firmed that these conformations are local minima and maxima,
respectively.
Several conclusions can be drawn from these studies. First, in
all three cases, the transition state energy of the atropoisomer
inversion process allows the establishment, more or less rapidly,
of a thermodynamic equilibrium. The similar energies calculated
for the 4-aRR and 4-aSR atropoisomers are in good agreement
with the diastereomeric mixture observed in solution,15 which is
probably the consequence of atropoisomer interconversion at
room temperature. In contrast, only one diastereoisomer is
observed experimentally for compounds 5 and 6. In both cases,
this can be formally predicted to be the more stable one (aRR),
and its presence can be explained by the complete selectivity of
the seven-membered ring closure reaction and/or by the easy
conversion of aSR diastereoisomers into the aRR ones. Overall,
these modeling studies predict that for compounds 5 and 6, the
only species present in solution are the aRR diastereoisomers
(and, of course, their aSS enantiomers). Thus, while hydrogen-
bonding interactions of tubulin with the lactam function of these
compounds may not be important, conformational considera-
tions may affect binding to tubulin via unfavorable steric
interactions.
Molecular docking studies16 were carried out to identify poten-
tial interactions during indolobenzazepinone 5 and 6 binding to
tubulin. Thus, as mentioned above, all possible stereoisomers of
compounds 5 and 6 (aRR, aSS, aSR, and aRS) were used for
docking on tubulin, in one of the binding sites of DAMA-colchicine
(Figure 3 and Figure S4 in the Supporting Information).17
Previous molecular modeling studies with the C5-substituted
indolobenzazepinone series, that is, of type 4, identified the
existence of two distinct binding subpockets on the tubulin
structure.7,15 These subpockets are partially overlapping (Figure 3b)
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Figure 3. Detail of the tubulin binding site with (a) X-ray conformation of DAMA-colchicine (PDB code: 1SA0); (b) docking conformations of
compounds 4-aRR (orange) and 4-aSS (green); (c) superposition of 6-aSS to the docking conformation of 4-aSR (green) showing a favorable fit for both
molecules in the left-hand subpocket of the tubulin binding site; and (d) superposition of 6-aRR (magenta) to the docking conformation of 4-aRS
(orange) showing potential steric clashes with the protein surface in the right-hand subpocket of the tubulin binding site.17
and occupy approximately the same binding site as DAMA-
colchicine (Figure 3a). The main criterion for ligand selectivity
between the two subpockets is atropoisomerism; ligands with the
aS configuration occupy principally the left subpocket, whereas
those with aR configuration are positioned mainly in the right
subpocket. It is noteworthy that the C5-alkyl substituents of
compounds 4-aRR and 4-aSS occupy the same pocket as the
C ring of colchicine (Figure 3a,b), and the favorable hydrophobic
interactions with this pocket might explain the better biological
activity of these compounds as compared with C5-unsubstituted
derivatives.
Docking of compounds 5 and 6 in the colchicine binding
site of tubulin followed the same trend, the compounds with
aS configuration occupying mainly the left subpocket (Figure S2
in the Supporting Information) and those with aR configuration
being positioned principally in the right subpocket (Figure S3 in
the Supporting Information). In the first case, the docking
conformations are very similar with the reference compound
4-aSR (Figure 3c and Figure S2aꢀd in the Supporting In-
formation), and their superimposition does not show steric
clashes with the protein surface (Figure S2eꢀh in the Supporting
Information). This means that the binding of aS isomers of
compounds 5 and 6 in the colchicine binding site of tubulin is
favored but without the benefit of hydrophobic interactions
observed for C5-alkyl indolobenzazepinones. This is in good
agreement with the similar biological activities determined for the
compounds 5 and 6 (IC50 = 4.2ꢀ5.3 μM, Table 1) and for the
C5-unsubstituted indolobenzazepinone (IC50 = 5.3 μM).11,12
In the second case, the docking conformations are positioned
quite differently as compared with the reference compound
4-aRS (Figure S3aꢀd in the Supporting Information), and their
superimposition shows that the difference is due to important
steric clashes between ligands and the protein surface, especially
for 6-aRR and 6-aRS (Figure 3d and Figure S3eꢀh in the
Supporting Information). Thus, it can be predicted that the
binding of the aR isomers of compounds 5 and 6 in the colchicine
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LETTER
site of tubulin is less favorable and that the biological activity
of these compounds is most likely due to the binding of the
aS isomers.
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In tandem, the quantum chemistry calculations results, which
indicate that the isomers aRR/aSS represent the only species
present in solution, and the docking results, which provide
evidence that binding of the aS isomers is favored, are strong
indicators that 5-aSS and 6-aSS are the stereoisomers respon-
sible for the biological activity of the compounds 5 and 6.
A similar atropoisomer binding preference for biphenyl analo-
gues of colchicine inhibitors has also been reported.18 The
presented results should be very useful for the future, rational
design of novel atropo- and enantioselective inhibitors of tubulin
polymerization.
’ ASSOCIATED CONTENT
(13) http://www.schrodinger.com/.
S
Supporting Information. Description of the tubulin
b
(14) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.;
Pople, J. A. Gaussian 03, revision E.01; Gaussian, Inc.: Wallingford,
CT, 2003.
docking studies with compounds 4ꢀ6, theoretical data, synthesis
and characterization of compounds 5, 6, 8, 11, 15ꢀ18, and 20,
and the cell proliferation inhibition assay. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 33-1-69824594. Fax: 33-1-69077247. E-mail: robert.dodd@
icsn.cnrs-gif.fr.
Funding Sources
We thank the ICSN for fellowships (V.P. and S.B.).
’ ACKNOWLEDGMENT
(15) Unpublished results.
We thank Geneviꢁeve Aubert and Dr. Thierry Cresteil of the
ICSN for the inhibition assays and Dr. Philippe Dauban for
helpful discussions.
(16) Docking studies were carried out using the GOLD 4.0 software
(Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor,
R. D. Improved protein-ligand docking using GOLD. Proteins 2003,
52, 609–623. ) with the GoldScore scoring function and 100% search
efficiency, all other parameters being used with default values. The
binding site was defined as a 15 Å radius sphere around the SG atom of
Cys241 from the chain D of the structure 1SA0 (Ravelli, R. B.; Gigant,
B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Insight
into tubulin regulation from a complex with colchicine and a stathmin-
like domain. Nature 2004, 428, 198–202). The 3D structures of ligands
were constructed with CORINA 3.44 (Molecular Networks GmbH).
(17) Images were created with the Chimera software (Pettersen,
E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.;
Meng, E. C.; Ferrin, T. E. UCSF Chimera—A visualization system for
exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605ꢀ
1612) and the PovRay module (http://www.povray.org/).
(18) Herrbach, A.; Marinetti, A.; Baudoin, O.; Guꢀenard, D.;
Guꢀeritte, F. Asymmetric synthesis of an axially chiral antimitotic biaryl
via an atropo-enantioselective Suzuki cross-coupling. J. Org. Chem. 2003,
68, 4897–4905.
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