An efficient combinatorial synthesis of allocolchicine analogues via a triple cascade reaction and their evaluation as inhibitors of insulin aggregation

Full text of DOI:10.1002/cmdc.201300302

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DOI: 10.1002/cmdc.201300302
An Efficient Combinatorial Synthesis of Allocolchicine
Analogues via a Triple Cascade Reaction and their
Evaluation as Inhibitors of Insulin Aggregation
Subhendu Bhowmik,[a] Shruti Khanna,[b] Kumkum Srivastava,[c] Mohammad Hasanain,[d]
Jayanta Sarkar,[d] Sandeep Verma,*[b] and Sanjay Batra*[a, e]
Colchicine (1), a known antimitotic alkaloid, exerts its biological
action by inhibiting microtubule assemblies via tubulin binding
thus acting as a spindle poison during mitosis.[1] Interestingly,
colchicine (1) also interferes with systemic amyloidosis condi-
tions, and it has been specially used for treatment of amyloido-
sis implicated for familial Mediterranean fever.[2] Formation of
amyloid plaques and fibrils has been established as critically
associated with various neurodegenerative conditions, such as
Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, as
well as type II diabetes.[3] Triggered by aggregation of misfold-
ed proteins, amyloid fibrillation interferes with several bio-
chemical processes.[4] Thus, inhibition of protein aggregation
or disruption of fibrillation might hold the key to understand-
ing the disease pathology and designing small-molecule inhibi-
tors that can interfere with the fibrillation process.[5] Recently,
we successfully demonstrated that colchicine inhibits fiber for-
mation in a synthetic peptide, derived from the prion octare-
peat sequence, with a propensity to undergo aggregation.[6]
Allocolchicine (2) and its analogues, such as compounds 3 and
4, containing a bisbenzocycloheptane [6,7,6] ring system, are
known to be efficient tubulin-interactive agents with less ap-
parent toxicity as compared with colchicine.[7] With this in
mind and as a continuation of our previous investigations, we
designed a set of allocolchicinoids, accessible via a novel syn-
thetic route, to investigate the disaggregation properties of
this class of compounds, and this Communication discloses
our efforts in this direction.
Allocolchicine (2) has been a prominent target in natural
product synthesis, and several distinct synthetic approaches
have been reported in the literature. These synthetic method-
ologies include the transformation of natural colchicines,[8] and
the use of established chemistry, such as Diels–Alder reac-
tions,[9] biaryl oxidative couplings,[10] direct arylations[11] and
Nicholas reactions.[12] Elegant routes to several allocolchicine
variants have also been reported.[13] However, the search for
a general strategies that allow expeditious access to structural
analogues of 2 remains a challenging goal.
Cascade processes, which result in the sequential formation
of multiple new bonds in a single synthetic step, are attractive
options in natural product synthesis.[14] Our own work has in-
vestigated the potential applications of Morita–Baylis–Hillman
(MBH) adducts in the preparation of natural-product-like struc-
tures through cascade strategies.[15] In this context, we envi-
sioned to develop a one-pot cascade approach to allocolchi-
cine analogues using the allylbenzamides prepared from MBH
adducts (Scheme 1). We reasoned that a Suzuki–Miyaura reac-
tion between a 2-formylphenyl boronic acid (IV) and an allyl-
benzamide (III) synthesized from a MBH adduct of a 2-haloben-
zaldehyde in the presence of a base in alkanolic medium
would not only result in the formation of the appropriate
biaryl compound (II) but these conditions might also induce
a successive Michael reaction between the alkoxyl group and
[a] S. Bhowmik, Dr. S. Batra
Medicinal & Process Chemistry Division
CSIR–Central Drug Research Institute
BS 10/1, Sector 10, Jankipuram Extension, Sitapur Rd
Lucknow 226031 (India)
E-mail: batra_san@yahoo.co.uk
[b] S. Khanna, Prof. S. Verma
Department of Chemistry
Indian Institute of Technology Kanpur
Kanpur 208016 (India)
E-mail: sverma@iitk.ac.in
[c] Dr. K. Srivastava
Parasitology Division
CSIR–Central Drug Research Institute
Lucknow 226031 (India)
[d] M. Hasanain, Dr. J. Sarkar
Drug Target Discovery & Development Division
CSIR–Central Drug Research Institute
Lucknow 226031 (India)
[e] Dr. S. Batra
Academy of Scientific & Innovative Research (AcSIR)
2 Rafi Marg, New Delhi 110001 (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300302.
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ments at several sites in the al-
locolchicine structure, making it
useful for a medicinal chemistry
program.
We began our investigations
by exploring the Suzuki–
Miyaura reaction of allylbenz-
amide 5a with 2-formylphenyl
boronic acid 6A in the presence
of tetrakis(triphenylphosphine)-
palladium(0) (Pd(PPh3)4) and
Scheme 1. Retrosynthesis for the preparation of bisbenzocycloheptane ring system (I) from allylbenzamide (III)
and boronic acid (IV) via the biaryl intermediate (II).
the allylic double bond, with subsequent carbocyclization to
afford the bisbenzocycloheptane core (I) in one-pot
(Scheme 1). Such a strategy would be significantly more flexi-
ble than the previously described synthetic approaches to allo-
colchicinoids as it would allow the introduction of diversity ele-
aqueous sodium carbonate in isopropanol (7x) at 808C under
a nitrogen atmosphere. The reaction reached completion in
five hours, giving a product in 95% yield, which was character-
ized to be the anticipated bisbenzocycloheptane derivative
8aAx (Scheme 2). Importantly, while the product was racemic,
Scheme 2. Synthesis of allocolchicine analogues and scope of the strategy. Reagents and conditions: a) 5 (0.5 mmol), 6 (0.6 mmol), Na2CO3 (1.0 mmol),
Pd(PPh3)4 (5 mol%), 7 (3 mL), 808C, 5 h. Isolated yields (%) are reported.
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it was observed to be diasteroisomerically pure. The relative
stereochemistry of the substitutions in the cycloheptane ring
was assigned on the basis of X-ray analysis of the single crystal
of 8aAx. It was observed that the hydroxy group and the ni-
trile groups were oriented syn to each other, while the amide
group was anti (Figure 1).
access to products 8aAy and 8aAz, respectively, in excellent
yields. Finally, in order to obtain the product containing the tri-
methoxy phenyl unit as in allocolchicine, boronic acid 6F was
prepared (see the Supporting Information) and reacted with al-
lylbenzamide 5a in ethanol (7y) to give 8aFy in 68% yield.
A plausible mechanism for the one-pot tandem synthesis of
allocolchicine-like derivatives is outlined in Scheme 3. We pro-
pose that an initially Suzuki coupling between allylbenzamide
(5) and 2-formylaryl boronic acid (6) affords a biaryl intermedi-
ate (A), which in the presence of a base undergoes a Michael
addition of the alkoxyl group onto the double bond to afford
intermediate B. Concomitant carbocyclization of intermediate
B affords product 8.
In order to ascertain the mechanism, in a controlled experi-
ment, 5a was reacted with 6A in the presence of 5 mol% of
Pd(PPh3)4 and aqueous sodium carbonate in dioxane at 808C.
The reaction reached completion in two hours to afford the
anticipated biaryl intermediate (9) in 79% yield as a 1:1 mix-
ture of atropisomers (Scheme 4). Treating biaryl 9 further with
Figure 1. Ortep structure of 8aAx at 35% probability level
Encouraged by this outcome,
the scope of the Suzuki–
Michael–carbocyclization
cas-
cade was investigated with
random combinations of diverse
allylamides (5a–j), substituted
2-formylphenyl boronic acids
(6A–F), and various alkanols
(7x–z), and the results are sum-
marized in Scheme 2. Firstly, dif-
Scheme 3. Plausible mechanism for the triple cascade reaction. The reaction of 5a, 6A and isopropanol (7x) to
form 8aAx is used here as an example.
ferent allylbenzamides were investigated by intro-
ducing changes in the aryl ring, the electron-with-
drawing group (EWG) and the halogen. With the ex-
ception of 5d, all 2-bromophenyl-substituted allyl-
benzamides (5a–c,e–i) reacted with 2-formylphenyl
boronic acid 6A in isopropanol (7x) to give the an-
ticipated products in excellent yields. In contrast, re-
action with allylbenzamide 5d invariably resulted in
the debrominated allylbenzamide (see the Support-
ing Information). Replacing the nitrile group with
a carboxyethyl as in 5e or varying the aroyl moiety
as in 5 f–i had no effect on the outcome. However,
replacing the bromide with iodide as in allylbenza-
Scheme 4. Synthesis of biaryl intermediate 9 and its transformation to the corresponding
allocolchicine analogue. 8aAx was used as representative compound to study the mech-
anism of formation. Reagents and conditions: a) 5a (0.3 mmol), 6A (0.4 mmol), Na2CO3
(0.6 mmol), Pd(PPh3)4 (5 mol%), dioxane (2 mL), 808C, 2 h; b) 9 (0.1 mmol), Na2CO3
(0.2 mmol), isopropanol (2 mL), 808C, 3 h.
mide 5j did give the desired product (8jAx), albeit in only
moderate yield.
aqueous sodium carbonate in isopropanol (7x) at 808C fur-
nished the expected compound (8aAx) in 91% yield as a pure
diastereomer. This result infers that the Michael-addition-
induced carbocyclization controls the stereochemistry of the
product.
With the effectiveness of the methodology to afford a 6,7,5
tricyclic system confirmed, the versatility of the one-pot proto-
col was further investigated by employing different commer-
cially available 2-formylphenyl boronic acids (6A–E), and en-
couragingly, all reactions afforded the corresponding products
in excellent yields (Scheme 2). The successful formation of
compounds 8aEx and 8aEy containing a 5,7,6 fused tricyclic
core extended the scope of the methodology still further. The
effect of alkanols was investigated by replacing the isopropa-
nol (7x) with ethanol (7y) and methanol (7z). Fortunately, the
reactions were successful in these additional alkanols, giving
With the allocolchicine-like compounds in hand, a structurally
diverse subset including 8aAx, 8aCx, 8aAz, 8eAx, 8eAy and
8hAx was selected to probe their disaggregation potential in
a general assay involving a self-aggregating pentapeptide con-
jugate. Microscopic experiments revealed that co-incubation of
these compounds with the peptide conjugate prevented fibril-
lation, and furthermore, addition of these compounds to
10 days old mature aggregated peptide conjugate samples
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gave rise to disaggregation of the fibers (see the Supporting
Information). All of the synthesized compounds were evaluat-
ed for their cytotoxicity in Vero C1008 cells (monkey kidney fi-
broblasts). Compared with podophyllotoxin, none of the com-
pounds show cytotoxicity. Despite the lack of cytotoxicity,
compounds 8eAx was selected as a representative compound
(due to its superior solubility in aqueous medium) for evalua-
tion of its tubulin polymerization inhibitory activity, and it was
found to have no effect (see the Supporting Information). It is
was previously reported that alteration of the trimethoxy sub-
stitutions in the A ring of allocolchicine (2) leads to loss of
tubulin binding activity.[16]
tion). Maximum inhibition up to 18 hours was seen with 100
and 200 mm solutions of 8hAx. Interestingly, fibrillation was re-
sumed upon longer incubation, as confirmed by the appear-
ance of a peak at 218 nm (see the Supporting Information).
This resumption of insulin fiber formation could be ascribed to
a shift in the equilibrium of the fibrillation process.[17b]
A ThT florescence assay, typically used to observe amyloid fi-
brillation, was employed to further monitor the inhibition pro-
cess. Upon interaction with amyloid fibers, ThT, a nonflorescent
dye, exhibits an enhanced emission at 482 nm.[21] Incubation of
insulin with ThT alone (20 mm) afforded a fluorescence maxima
at ~485 nm after two hours, suggesting the amyloidogenic
nature of the aggregated fibers. Next, fresh solutions of BI
were co-incubated with five different concentrations of 8hAx
along with ThT (pH 1.6) at 658C. Compound 8hAx exerted an
inhibitory effect as evident by a loss of fluorescence intensity.
Notably, a concentration as low as 50 nm was able to inhibit in-
sulin fibrillation up to three hours (Figure 3). This is a remark-
Encouraged by the preliminary result concerning the poten-
tial of these compounds to inhibit fibrillation of a synthetic
peptide, we were prompted to investigate their ability to inter-
fere with protein aggregation taking bovine insulin (BI) as
a model. Insulin, a zinc-containing peptide hormone, is an es-
sential component of glucose metabolism, and it self-aggre-
gates to form amyloidogenic fibers.[17] These fibers are formed
through a series of sequential events that include monomer
nucleation, elongation, and maturation. These stages require
an intricate interplay of both hydrophobic and electrostatic in-
teractions, along with the requirement of cross b-structures.[18]
External factors such as temperature, pH, ionic strength, and
solvent effects, are known to accelerate the process of fiber
formation.[19]
As a preliminary screen, 8hAx was selected for the insulin
aggregation inhibition studies using circular dichroism (CD),
thioflavin T (ThT) florescence, and atomic force microscopy
(AFM). The inhibitory effect of 8hAx was first monitored by
far-ultraviolet (UV) CD spectroscopy. As a control, a fresh solu-
tion of BI was prepared in hydrochloric acid (pH 1.6) at 658C.
CD bands characteristic of the native a-helix conformation
were noted at 209 and 220 nm (Figure 2).[5e,20] However, after
one hour of incubation, a new CD band at 218 nm correspond-
ing to a b-sheet was observed, indicating involvement of a con-
formational change during insulin fibrillation. BI was then co-
incubated with 8hAx at three different concentrations (50 and
100 mm: Figure 2; and 200 mm: see the Supporting Informa-
Figure 3. Results of a ThT fluorescence assay of bovine insulin (BI) and its in-
hibition by 8hAx at varying concentrations in HCl (pH 1.6) at 658C recorded
at different time intervals.
able observation as further optimization of pharmacophores
present in the allocolchinoid skeleton might afford better and
more potent inhibitors of insulin amyloidogenesis.
The native state of the insulin polypeptide can become com-
promised under particular solution conditions, characterized
by a conformational switch from a predominantly helical struc-
ture to a cross b-structure, which is a hallmark of amyloidogen-
ic fibrillar aggregates.[22] It is also recognized that insulin fibers
impede long-term storage of hormone and may lead to forma-
tion of insulin fibers at the site of hormone injection.[17c] Thus,
it was of interest to visualize aggregated fibers and possible
changes in their morphology upon interaction with 8hAx.
Using AFM, mature bovine insulin fibers were characterized as
having a diameter of 20 nm after incubation in HCl solution
(pH 1.6) at 658C for 18 hours (Figure 4a). Notably, time-depen-
dent microscopy of insulin solution, co-incubated with 8hAx
Figure 2. Far-UV circular dichroism (CD) spectra of bovine insulin (BI) and its
inhibition by 8hAx at 50 mm and 100 mm in HCl (pH 1.6) at 658C recorded at
different time intervals.
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Figure 4. AFM micrographs of a) bovine insulin after 18 h; inset shows magnified view of the braided fibrillar structure. Time dependent co-incubation with
8hAx (100 mm) after b) 6 h and c) 18 h.
(100 mm), also showed effective inhibition of fibril formation
(Figure 4b,c). Hence, from the results of inhibition of BI aggre-
gation, it can be inferred that 8hAx could serve as a potential
peptide/protein aggregation inhibitor possibly by interfering
with the early steps of insulin nucleation. The precise mecha-
nism of this interference remains to be elucidated.
formation at 50 nm in ThT amyloidogenic fluorescence studies
suggesting potential of these derivatives as inhibitors of insulin
amyloid formation. These results show that allocolchicinoids
warrant further exploration as inhibitors of peptide/protein
amyloidogenesis, and it is proposed that further structural re-
finement will be able improve the activity of this class of com-
pounds.
In conclusion, we have developed a one-pot diastereoselec-
tive preparation of allocolchicine analogues from allylbenza-
mides derived from MBH adducts. This protocol, which pro-
gresses via an unusual triple cascade reaction comprising of
a Suzuki coupling, a Michael addition, and a carbocyclization,
is highly versatile, working over a broad range of substrates,
and affords structurally diverse allocolchinoids, which may
become important when creating drug-like libraries of this
class of compound. The preliminary results with 8hAx, one of
the synthesized derivatives, reveal effective inhibition of fiber
Experimental Section
An example procedure for the synthesis of compounds 8 is given
below. Full experimental protocols and characterization data for all
other compounds 8 are given in the Supporting Information, along
with details of the biological assays used to evaluate these com-
pounds.
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753.
N-(6-Cyano-7-hydroxy-6-(isopropoxymethyl)-6,7-dihydro-5H-
dibenzo[a,c][7]annulen-5-yl)benzamide (8aAx): A suspension of
5a (0.20 g, 0.59 mmol), 2-formylphenylboronic acid 6A (0.10 g,
0.65 mmol), 2m aq Na2CO3 (0.13 g, 1.18 mmol) in 2-propanol
(3 mL) was degassed with N2 for 15 min and maintained under an
N2 atmosphere. Pd(PPh3)4 (0.034 g, 0.03 mmol) was added to the
suspension, and the reaction mixture was transferred to an oil bath
and heated with stirring at 808C until all starting materials were
consumed (monitored by TLC). Excess 2-propanol was removed in
vacuo, and the crude aqueous mixture was extracted with EtOAc
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ed aq NaCl, dried over anhyd Na2SO4, filtered and concentrated in
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purification using silica gel (EtOAc/hexane, 1:4) afforded 8aAx as
a white solid (0.24 g, 95%): Rf =0.21 (hexane/EtOAc, 70:30); mp>
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2508C; H NMR (300 MHz, CDCl3): d=1.34 (d, 3H, J=6.0 Hz), 1.41
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(m, 4H), 7.76–7.84 (m, 3H), 9.00 ppm (d, 1H, J=6.3 Hz); 13C NMR
(75 MHz, CDCl3 +[D6]DMSO): d=21.6, 22.1, 55.7, 57.1, 68.5, 69.2,
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Two of the authors S.B. and S.K. acknowledge the financial sup-
port from Council of Scientific and Industrial Research (CSIR),
New Delhi (India). This work was carried out under a grant to
S.B. from the Department of Science and Technology (DST), New
Delhi (India). S.V. is supported by a Department of Atomic
Energy–Science Research Council (DAE–SRC) Outstanding Investi-
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data. This article is CDRI comm. no. 8518.
Keywords: alkaloids
· antiaggregation agents · cascade
reactions · natural products · one-pot syntheses
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Published online on && &&, 0000
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 6
&
6
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ÞÞ
These are not the final page numbers!

COMMUNICATIONS
A controlled cascade: A divergent,
diastereoselective and efficient one-pot
synthesis of allocolchicinoids via a cas-
cade Suzuki–Michael addition–Carbo-
cyclization sequence is described. The
utility of the compounds as possible
inhibitors of insulin aggregation is also
presented.
S. Bhowmik, S. Khanna, K. Srivastava,
M. Hasanain, J. Sarkar, S. Verma,*
S. Batra*
&& – &&
An Efficient Combinatorial Synthesis
of Allocolchicine Analogues via
a Triple Cascade Reaction and their
Evaluation as Inhibitors of Insulin
Aggregation
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 6
&
7
&
ÞÞ
These are not the final page numbers!