Synthesis of indole-derived allocolchicine congeners exhibiting pronounced anti-proliferative and apoptosis-inducing properties

Article abstract of DOI:10.1039/c5md00320b

Based on the natural antimitotic agent allocolchicine as a lead structure, a series of novel indole-based allocolchicine congeners was synthesized and assessed in vitro for their cytostatic properties. Several compounds exhibited potent anti-proliferative and apoptosis-inducing activity towards lymphoma cells along with low unspecific cytotoxicity. The observed activity is supposed to result from the inhibition of microtubule assembly, as indicated by the tubulin polymerisation assay.

Full text of DOI:10.1039/c5md00320b

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Synthesis of indole-derived allocolchicine congeners exhibiting
pronounced anti-proliferative and apoptosis-inducing properties†
Received 00th January 20xx,
Accepted 00th January 20xx
Nikolay S. Sitnikov,a,b Alexander V. Sinzov,a Diane Allegro,c Pascale Barbier,c Sebastien Combes,c
Liliane Abodo Onambele, d Aram Prokop,d Hans-Günther Schmalzb and Alexey Yu. Fedorova*
DOI: 10.1039/x0xx00000x
Basing on the natural antimitotic agent allocolchicine as a lead structure, a series of novel indole-based allocolchicine
congeners was synthesized and assessed in vitro for cytostatic properties. Several compounds exhibited potent anti-
proliferative and apoptosis-inducing activity towards lymphoma cells along with low unspecific cytotoxicity. The observed
activity is supposed to result from the inhibition of microtubule assembly, as indicated by the tubulin polymerisation assay.
www.rsc.org/
colchicinoids
3 and 4 showed high levels of proliferation
Introduction
inhibition and apoptosis induction at nanomolar
concentrations against different lymphoma cells, although
their unspecific cytotoxicity was found to be particularly low.28
Herein, we report on the synthesis of pyrrolo-allocolchicinoids
Colchicine (1
),1,2 an alkaloid isolated from plants of the genus
Colchiceae, Merendera and Gloriosa, is a long-known natural
product exhibiting high levels of cytotoxicity towards
proliferating cells. The origin of its biological effect lies in the
ability to inhibit polymerisation of tubulin, the main
constitutive protein of microtubules.3-7 This effect leads to the
disruption of the mitotic spindle formation, arrest of the cell
cycle in G2/M phase and, eventually, to apoptotic cell death.
The intriguing biological properties of colchicine as well as its
unique structural features8 became a motivation for a number
of total syntheses (resulting in one of the most fascinating
endeavours in the history of organic synthesis),8 as well as
several studies concerning structure-activity relationships
(SAR) of colchicine structural analogs.3,9-11 While high systemic
toxicity12,13 (resulting in strong gastrointestinal upset,
neuropathy, bone marrow) has prevented its use in the
of type
5, i.e. the constitutional isomers of 3 and 4, and
present primary results of their biological assessment using a
human lymphoma cell line. In addition, the influence of the
compounds on tubulin polymerisation was determined in vitro.
treatment of cancer, colchicine (1) became a lead structure in
the design of novel tubulin polymerisation inhibitors. Along
with several classes of structurally related compounds (e.g.
combretastatins14-17 and 4-arylcoumarins18), allocolchicine
19
(2
)
and its analogues9-11,20-27 were identified as promising
candidates for further development. Recently, our group
reported on the synthesis and biological evaluation of a series
Figure 1 Structures of colchicine (1), allocolchicine (2), known pyrrolo-
allocolchicinoids (3, 4) and their target constitutional isomers of type 5.
of heterocyclic allocolchicine congeners (for instance
3
and
4;
Figure 1), in which ring C of the parent compound
2 is replaced
by an indole28,29 or a benzofurane30 pharmacophore. Allo-
Results and Discussion
Synthesis
a.Department of Organic Chemistry, Lobachevsky State University of Nizhni
Novgorod, Gagarina av. 23, Nizhni Novgorod 603950 (Russia); afnn@rambler.ru
b.Department für Chemie, Universität zu Köln, Greinstr. 4, 50939, Köln (Germany).
c. Laboratory of Integrative Structural and Chemical Biology, Institut Paoli-
Calmettes, Aix-Marseille Universitꢀ, UM105, F-13009, Marseille (France)
d.Department of Pediatric Hematology/Oncology, Children’s Hospital Köln,
Amsterdamer Str. 59, 50735 Köln (Germany).
† Electronic Supplementary Information (ESI) available: [synthetic procedures and
characterisation data for all new compounds; details of biological experiments].
See DOI: 10.1039/x0xx00000x
Multiple strategies to access the tricyclic fused ring system of
allocolchicine (
2) and its analogues have been developed to
date.31-43 For the construction of the carbocyclic skeleton of
5
we followed the strategy depicted in Scheme 1, which relies on
intramolecular Friedel-Crafts acylation and Pd-catalysed cross-
coupling as the C-C bond forming steps.
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Alcohol rac-5a further served as the substrate for the synthesis
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§
of allocolchicinoids with various functionaliDtiOesI: 1a0t.1C0(379)/C(5sMchDe0m03e230)B.
Thus, oxidation of rac-5a with N-methylmorpholine-N-oxide in the
presence of catalytic Pr4NRuO4 (Ley oxidation)49 gave ketone 5b in
90% yield. Quantitative conversion of rac-5a to the corresponding
acetate rac-5c was achieved via transesterification with ethyl
acetate. The reaction of rac-5a with Zn(N3)2×2Py under Mitsunobu
conditions50 resulted in the formation of azide rac-5d (91% yield)
which was subsequently reduced with lithium aluminum hydride to
the amine rac-5e (93% yield). Finally, acylation of rac-5e with acetic
anhydride in pyridine provided acetamide rac-5f in 94% yield.
Scheme 1 Retrosynthetic analysis of pyrrolo-allocolchicinoids of type 5
First, the halogen-selective Suzuki-Miyaura reaction
between methyl (iodoaryl)propionate 730 and indolylboronate
8
generated biaryl
ester yielded acid
methylpropenyl)dimethylamine
9
, which upon basic hydrolysis of the methyl
. Treatment of with (1-chloro-2-
10
(Ghosez reagent)44,45
6
6
(
)
resulted in the formation of acyl chloride 11 which was used in
situ in the intramolecular Friedel-Crafts acylation. Under the
previously reported30 cyclisation conditions (ZnCl2, 0.02M 11 in
DCM) the tetracycle 12 was formed as a single regioisomer,
however, in only 17% yield (as a consequence of the acid-
catalysed oligomerisation of the starting material). Application
of Et2AlCl or EtAlCl2 as proton-scavenging Lewis acids46 also
gave only low yields of 12 due to competing nucleophilic
addition of Al-alkyl reagent to acid chloride 11. However,
treatment of 11 with an excess of bulky diisobutylaluminum
chloride resulted in efficient seven membered ring closure
and, in addition, an in situ reduction of the carbonyl group47,48
(via β-hydride transfer). This way, the tetracyclic alcohol rac-
13 was obtained in 68% yield over three steps in a one-pot
procedure.‡ After the cyclization, the bromine in rac-13 was
removed via halogen-lithium exchange/protonation to give
Scheme
3 Synthesis of pyrrolo-allocolchicinoids 5a-f with various
functionalities at C(7). Reagents and conditions: (a) N-methylmorpholine-N-
oxide, Pr4NRuO4 (0.05 equiv.), molecular sieves 4 Å, CH2Cl2/MeCN, r.t., 1 h;
(b) EtOLi, EtOAc, 40 oC, 50 torr, 30 min; (c) Zn(N3)2×2Py, PPh3, diisopropyl
azodicarboxylate, toluene, r.t., 5 h; (d) LiAlH4, THF, r.t., 24 h; (e) Ac2O,
pyridine, CH2Cl2, 0 oC, 10 min.
Biological assessment
rac-5a in 96% yield (32% overall from 7).
The cytostatic activity of the target pyrrolo-allo-
colchicinoids 5a-f against BJAB (Burkitt-type lymphoma) cells
was evaluated using colchicine (1) as a standard (Table 1). All
compounds exhibited a clear dose-dependent effect on cell
proliferation and apoptosis (see ESI for detailed information).
As a general tendency, compounds bearing an oxygen-based
functionality at C(7) possessed higher cytostatic activity and
lower unspecific cytotoxicity as compared to the
corresponding analogues with a C(7)-N bond. Acetate rac-5c
was identified as a particularly potent antimitotic agent, as it
caused virtually complete inhibition of cell proliferation at low
nanomolar concentrations (Figure 2), while no necrosis was
detected (in a lactate dehydrogenase (LDH) release assay after
1 h) at concentrations of up to 5 μM. Noteworthy, the novel
pyrrolo-allocolchicinoids 5a-f possess biological activity in the
same concentration range as the previously reported isomeric
series
3 and 4 (Figure 1). This indicates that the mode of the
Scheme
2 Construction of the carbocyclic scaffold of the target
pyrrole ring fusion to the allocolchicine scaffold does not
excert a profound influence on the cytostatic properties.
allocolchicinoids. Reagents and conditions: (a) Pd(OAc)2 (0.05 equiv.), PPh3
o
(0.1 equiv.), Cs2CO3, toluene, reflux, 24 h; (b) LiOH aq., THF/MeOH, 40 C, 1
h; (c) CH2Cl2, 0 C, 12 h; (d) (i-Bu)2AlCl (2 equiv.), CH2Cl2, 0 oC to r.t., 30 min;
o
e) t-BuLi, THF, -78 oC, 30 min, then MeOH.
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Table 1 Anti-proliferative and apoptosis-inducing activity of pyrrolo-
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DOI: 10.1039/C5MD00320B
allocolchicinoids 5a-f (in comparison with colchicine (
1
)) against BJAB
Burkitt-type lymphoma cells
Proliferation
inhibition at
AC50 [%]
a
b
IC50
AC50
Necrosis at
AC50 [%]c
[μM]
[μM]
colchicine (1)
5a (X = OH)d
5b (X = O)
0.02
0.001
0.03
0.001
0.05
0.05
>100
5
n.d.
52
98
89
30
90
-
n.d.
7
0.01-0.05
0.01-0.05
50
4
5c (X = OAc)
5d (X = N3)
0
1
5e (X = NH2)
5f (X = NHAc)
0.5-1
29
-
>100
>100
Each experiment was performed in a triplicate; n.d. = not determined.
a
IC50: concentration of the compound causing 50% cell growth
b
inhibition after 24 h, as determined by CASY cell counting. AC50:
concentration of the compound causing 50% cell apoptosis after 72 h,
c
as determined by a DNA-fragmentation assay. Necrosis level caused
by the compound at AC50 concentration after 1 h, measured by the
d
LDH-release assay. X corresponds to the functional group at C(7) (Fig
1).
Figure 3 Effect of pyrrolo-allocolchicinoids rac-5c, rac-3 (X = OH) and rac-4 (X
= OH) on the polymerisation of tubulin. A: Turbidimetry curves of tubulin
assembly in the presence of different concentrations of rac-5c. B:
Comparative polymerisation inhibition efficiency of rac-5c and previously
reported allocolchicinoids rac-3 (X = OH), rac-4 (X = OH); R = ligand to
tubulin molar ratio.
Conclusions
Figure
2 Concentration-dependent inhibition of BJAB lymphoma cell
A synthetic route to a new structural type of pyrrolo-
allocolchicinoids was developed. The cytostatic properties of
target compounds 5a-f bearing different functional groups
were evaluated employing Burkitt-like lymphoma cells (BJAB).
Allocolchicinoids 5a-c exhibited potent anti-proliferative and
apoptosis-inducing activity with IC50 and AC50 values in the low
nanomolar concentration range along with low unspecific
cytotoxicity (according to LDH-release measurements). The in
vitro tubulin polymerisation assay revealed that compound 5a
proliferation by 5c as determined by CASY cell counting after 24 h.
To probe whether the cytostatic activity of the pyrrolo-
allocolchicinoids might be a consequence of tubulin binding,
acetate rac-5c as well as rac-3 (X = OH) and rac-4 (X = OH) (as the
most active of the previously reported compounds) were tested in a
fluorescence-based tubulin polymerisation assay (Figure 3). The
depicted turbidimetry curves reflect the effect of all three
compounds on the microtubule assembly from purified tubulin. A
clear inhibition was noted, as the rate of assembly as well as the
final amount of microtubules were clearly lower in the presence of
allocolchicinoids than in the control experiment. The extent of
inhibition increased steadily with the mole ratio of the total ligand
to total tubulin in the solution (R). All three compounds
demonstrated sub-stoichiometric mode of action.51 Half-inhibition
as well as the previously reported structural isomers rac-
3 (X =
OH) and rac- (X = OH) inhibit the assembly of tubulin into
4
microtubules. This indicates that, similarly to colchicine, the
anti-proliferative and pro-apoptotic effect of pyrrolo-
allocolchicinoids most probably results from the disruption of
the mitotic spindle formation and subsequent cell-cycle arrest.
of tubulin polymerisation was achieved at
a molar ratio
(compound/tubulin) of 0.125 for rac-5c, 0.264 for of rac-3 (X=OH)
and 0.228 for rac-4 (X = OH) (the corresponding value for colchicine
(1) is 0.375,52 for combretastatin A-4 – 0.09 (own data)). Thus, the
high cytostatic activity of pyrrolo-allocolchicinoids 3-5 appears to be
a direct consequence of efficient tubulin binding.
Acknowledgements
We gratefully acknowledge the Russian Foundation for Basic
Research (project 14-03-91342), the Deutsche Forschungs-
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The synthesis and biological assessment of indole-based allocolchicine congeners with potent anti-
proliferative and apoptosis-inducing activity towards lymphoma cells is reported.