Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues

Article abstract of DOI:10.1016/j.bmcl.2013.06.004

A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and evaluated for their antitubulin and antiproliferative activity. We wanted to test whether intramolecular hydrogen-bonding used as a conformational locking element in these analogues would improve their activity. The correlation of crystal structures with the antitubulin and antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated conformational control of the A ring is deleterious to the bioactivity. In contrast, although there was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we found that increased substitution on the B ring had a positive effect on antitubulin and antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e, having hydrogen-bonding donor groups at the ortho and meta-positions on the 4-methoxy phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having IC₅₀ value in micromolar concentrations.

Full text of DOI:10.1016/j.bmcl.2013.06.004

Accepted Manuscript
Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-
tethered combretastatin analogues
Ganesh S. Jedhe, Debasish Paul, Rajesh G. Gonnade, Manas K. Santra, Ernest
Hamel, Tam Luong Nguyen, Gangadhar J. Sanjayan
PII:
S0960-894X(13)00711-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.06.004
BMCL 20566
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
5 February 2013
21 May 2013
1 June 2013
Please cite this article as: Jedhe, G.S., Paul, D., Gonnade, R.G., Santra, M.K., Hamel, E., Nguyen, T.L., Sanjayan,
G.J., Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin
analogues, Bioorganic & Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/10.1016/j.bmcl.2013.06.004
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Correlation of hydrogen-bonding propensity
and anticancer profile of tetrazole-tethered
combretastatin analogues.
Ganesh S. Jedhe,a Debasish Paul,b Rajesh G. Gonnade,c Manas K. Santra,b Ernest Hamel,*d Tam Luong
Nguyen,*e and Gangadhar J. Sanjayan.*a
2

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-
tethered combretastatin analogues.
Ganesh S. Jedhe,a Debasish Paul,b Rajesh G. Gonnade,c Manas K. Santra,b Ernest Hamel,*d Tam Luong
Nguyen,*e and Gangadhar J. Sanjayan.*a
aDivision of Organic Chemistry, cCenter for Materials Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
b National Centre for Cell science, University of Pune Campus, Ganeshkhind, Pune 411007, Maharashtra, India.
dScreening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for
Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
eTarget Structure-Based Drug Discovery Group, SAIC-Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United
States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended
hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and
evaluated for their antitubulin and antiproliferative activity. We wanted to test whether
intramolecular hydrogen-bonding used as a conformational locking element in these analogues
would improve their activity. The correlation of crystal structures with the antitubulin and
antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated
conformational control of the A ring is deleterious to the bioactivity. In contrast, although there
was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we
found that increased substitution on the B ring had a positive effect on antitubulin and
antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e,
having hydrogen-bonding donor groups at the ortho and meta-positions on the 4-methoxy
phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having
IC50 value in micromolar concentrations.
Keywords:
Combretastatin
Tetrazole
Crystal
Colchicine
Tubulin
2009 Elsevier Ltd. All rights reserved.
Combretastatins (CAs) A-11 1 and A-42 2 (Chart 1) are natural
products isolated from the African bush willow Combretum
caffrum and are well known antimitotic agents causing vascular
disruption.3 CAs bind to the colchicine site of αβ-tubulin.4
Combretastatin A-1 phosphate (OXi4503; CA1P) and
combretastatin A-4 phosphate (Fosbretabulin; CA4P) are well-
known vascular disrupting agents currently in human clinical
trials for the treatment of cancer.5-7 CA1P demonstrated higher
vascular disrupting and antitumor activity when compared with
CA4P.8 The increase in efficacy of CA1P as a vascular disrupting
agent is attributed to the presence of an additional hydroxyl
substituent, which may result in the formation of a highly
aromatic rings 3 (Chart 1), such as thiophene,15 furan,15
pyrazole,16 imidazole,16,17 thiazole,16 isoxazole,18,19 1,2,3-
thiadiazole,20 isomeric triazoles,15,16,21-23 and tetrazole,16,24,25 have
been evaluated to arrest the conformation in the cisoid form and
for effects on cytotoxicity and on the tubulin target. So far, the
restriction in conformation achieved has been essentially quasi-
cisoid. It should be noted that in the absence of a conformational
restriction, both the A and B rings of CA can rotate about the sp2
bond that connects them.
reactive
ortho-quinone-like
moiety through
oxidative
metabolism.9,10
SAR studies of CAs analogues have suggested that there are
three crucial structural components essential for activity, i.e., the
trimethoxy group on the A ring, cisoid configuration at the
olefinic double bond and the methoxy group at the para-position
on the B-ring.11-13 The cis double bond in CAs can be converted
into the more stable trans configuration in vivo. This would result
in a drastic loss of activity14 and, therefore, several hetero-
Chart 1. Structures of CA-1 1, CA-4 2 and their known heteroaromatic
analogs 3.
In the present work, we attempted to arrest the cis-
conformation effectively by introducing hydrogen-bond donor
groups, such as a hydroxyl moiety, at ortho-positions on the A
1

and B rings that might form stable six-membered hydrogen-
bonds with acceptor atoms at the 2 or 4 or both 2 and 4 position
of the central hetero-aromatic ring.
Scheme 2. Reagents and conditions: (a) MeI, K2CO3, acetone,
6 h reflux; (b) BnBr, K2CO3, DMF, 6 h; (c) NaOH, THF,
H2O, 12 h; (d) Ac2O, AcOH, HNO3, 30 min, 0 C to rt.
β-Resorcylic acid 7a (Scheme 2) was dimethylated to give
phenol 7b,34 followed by benzyloxy protection to furnish ester
7c. Methyl ester 7c was hydrolyzed to give the acid 8a. Phenol
7b was nitrated to afford nitro phenol 7d in 25% yield,35 then
phenol 7d was benzyloxy-protected to afford ester 7e. Ester 7e
was hydrolyzed to furnish the free acid 8d.
Chart 2. Rationale for the design of conformationally restricted CA
analogues (present work).
We have designed, synthesized and evaluated a series of 1,5-
disubstituted tetrazole analogues with extended hydrogen-bond
donors at the ortho-positions as potentially cis-restricted CA
analogues. It is well-known in the case of triazole-based
combretastatin analogues that when ring A is connected to a
triazole nitrogen, the resultant analogue would show better
antitubulin activity than analogues having a nitrogen connected
to the B ring.21 We therefore initially designed analogues with a
tetrazole nitrogen connected to the A ring rather than the B ring.
However, we found that a hydroxyl group at the ortho position of
the B ring also enhanced activity. We therefore also introduced a
hydroxyl or an amino group at the meta position of the B ring.
Amides 10a-f (Scheme 3) were synthesized from respective
carboxylic acids 8a-d and anilines by the acid chloride method.
Amides 10a-f were converted to imidoyl chloride by a modified
literature protocol29 and then reacted with sodium azide to form
respective benzyloxy protected tetrazoles 11a-e. Tetrazoles 11a-e
were subjected to hydrogenolysis to afford the target compounds
5a-e. The known analog 5f (Chart 2) was also synthesized
following the reported protocol25 for crystallographic studies.
There are several modifications known with 2,3-dihydroxy
26-28
groups on the B-ring as analogues of CA1,23,
but our
modification of having 2-hydroxy and 3-amino groups on the B
ring (5e, Chart 2) has not been previously reported.
We followed the reported imidoyl chloride procedure for the
construction of the tetrazoles.29 2,3,4-trimethoxy-benzaldehyde
6a was demethylated to afford 6b,30 which was further
dibenzylated by using BnBr in DMF to furnish di-benzyloxy-
aldehyde 6c (Scheme 1). The aldehyde 6c was oxidized to the
acid 8c by following a literature procedure.31 In another set of
experiments, 2,3,4-trimethoxy-benzaldehyde 6a was nitrated to
give nitro-benzaldehyde 6d.32 Aldehyde 6d was then converted to
phenol 6e by the Dakin reaction.33 Phenol 6e was O-benzylated
by standard conditions to give benzyloxy derivative 6f, which
was then reduced to its corresponding amine with stannous
chloride to afford aniline 9a.
Scheme 3. Reagents and conditions: (a) (COCl)2, cat. DMF,
DCM. 2 h; (b) Et3N, DCM, 6 h; (c) (COCl)2, pyridine, DCM,
4 h; (d) NaN3, DMF, 12 h, 60 C; (e) 10% Pd/C, H2, 60 psi,
MeOH, 8 h.
The crystal structure of 5a (Fig. 1) clearly shows that rings A
and B are not co-planar. Instead of the expected 6-membered
hydrogen-bonding between the phenolic OH on the
trimethoxyphenyl A ring and a second nitrogen in the tetrazole
ring, there was a 5-membered hydrogen bond formed within ring
A. In the crystals of 5a and 5c, conformational restriction was
observed by formation of a 6-membered hydrogen bond between
the phenolic OH of the para-methoxyphenyl ring and the fourth
nitrogen in the tetrazole ring as shown in the figure 1. The crystal
structures of 5a, 5c and 5f showed that the aromatic rings having
a trimethoxyphenyl structure and a para-methoxy structure were
out of plane with each other. Crystallographic data for the
structures 5a, 5b and 5c have been deposited at the Cambridge
Scheme 1. Reagents and conditions: (a) BCl3, DCM, 24 h; (b)
BnBr, K2CO3, DMF, 6 h; (c) NaH2PO4, NaClO2, 30% H2O2, 6
h; (d) HNO3, AcOH, 1 h; (e) mCPBA, DCM 6 h; (f) NaOH,
H2O, 4 h; (g) SnCl2:2H2O, AcOEt, 60 C. 8 h.
2

Crystallographic Data Centre with the deposition numbers CCDC
910097 (5a), CCDC 910098 (5c), CCDC 910099 (5f).
Table 1.
IC50a values (expressed in M) of compounds 2, 5a-f.
Compound
HeLa
A549
MCF-7
H1299
5a
5b
5c
5d
5e
5f
2
45 ± 4
50 ± 0.8
46 ± 1.2
49 ± 2.1
40 ± 1.8
7.9 ± 0.8
8.8 ± 0.7
4.0 ± 0.4
n.d.b
92 ± 0.3
>100
72 ± 1.4
2.4 ± 0.09
0.95 ± 0.001
0.9 ± 0.0016
0.0026 ± 0.0b
0.004±0.0012
6.4 ± 0.43
6.7 ± 0.29
0.52 ± 0.0009
0.222 ± 0.059b
0.28±0.05
8.2 ± 0.09
6.6 ± 0.04
2.9 ± 0.07
0.0385 ± 0.0058b
0.098±0.003
0.0062±0.002
aIC50 = compound concentration required to inhibit tumor cell proliferation by 50%. Data are expressed as the mean ± SE from the dose-
response curves of at least three experiments. bValues taken from the literature for comparison.25 n.d. indicates not determined.
ortho-hydroxyl group in the ring B shown in the crystal structure
to hydrogen bond to N-4 of the tetrazole ring, was moderately
less active than 5d and 5e in both tubulin assays. Based on
historical data, in fact, 5c had activity indistinguishable from 5f,
so that the ortho-hydroxyl moiety neither enhanced nor reduced
activity in this class of agent. Activity was, however, increased
by adding a meta-substituent in the B ring, between the other two
substituents, with the amino group of 5e increasing antitubulin
activity somewhat more than the hydroxyl group of 5d.
Table 2.
Inhibition of Tubulin Polymerization and Colchicine Binding
by Compounds 5a-f.
Tubulin assemblya
Colchicine bindingb
%inhibition ± SD
Compound
IC50 ± SD(M)
5a
5b
5c
5d
5e
5f
2
> 20
> 20
Figure 1: Crystal structures of 5a, 5c and 5f with polar hydrogens showing
hydrogen bonds.
2.7 ± 0.2
2.5 ± 0.1
2.2 ± 0.1
2.5 ± 0.3c
1.1 ± 0.1
52 ± 0.6
62 ± 0.4
69 ± 0.3
54 ± 0.3c
99 ± 0.06
The 1,5 disubstituted tetrazole analogues of Combretastatin
5a-e were evaluated for their inhibition of the growth of four
different human cancer cell lines i.e, human cervix carcinoma
(HeLa), human non-small-cell lung carcinoma (A549 and
H1299), and breast adenocarcinoma (MCF-7). A comparison was
made with the data obtained earlier for compound 5f25 (Table 1).
Compounds 5a and 5b, which has an ortho-hydroxyl group in the
A-ring, were least active against the cancer cell lines tested with
IC50 > 45 M. Compound 5c bearing ortho-hydroxyl group in the
B-ring was shown to enhance antiproliferative activity, in
comparison with 5a and 5b. Although activity further enhanced
with increased substitution in the B-ring, as in compounds 5d and
5e, lesser antiproliferative activity was observed when compared
to 5f25 in the common cell lines tested i.e, HeLa, A549 and MCF-
7.
aInhibition of tubulin polymerization (tubulin was at 10 M).
bInhibition of [3H]colchicine binding (tubulin, colchicine, and
tested compounds were at 1, 5, and 5 M, respectively).cValues
taken from the literature for comparison.25
Using the 1SA0 crystal structure of -tubulin as a template,36
compounds 5c-f were docked into the colchicine binding site to
provide a molecular basis for understanding their activity, and,
concomitantly, to explain the lesser activity of compounds 5a and
5b. In the docking studies, compound 5e nicely overlaps with all
structural features of colchicine in the binding site (Fig. 2A).
Similarly, the trimethoxyphenyl moieties of compounds 5c, 5d
and 5f occupied similar conformational space as the
trimethoxyphenyl motif of colchicine, which is perhaps the
structural basis for the observed bio-activity of these compounds.
The new tetrazole compounds 5a-e were also examined for
potential inhibition of tubulin assembly, inhibition of
[3H]colchicine binding to tubulin. A comparison was made with
the data obtained earlier for compound 5f25 (Table 2).
Compounds 5a and 5b, both of which had an ortho-hydroxyl
group in the A ring, were inactive as inhibitors of tubulin
polymerization. Compound 5c, analogous to 5f except for an
3

trimethoxyphenyl ring was not achieved. Instead, a five-
membered hydrogen-bond with the vicinal para-methoxy on the
A ring occurred. Further, introduction of this hydroxyl group into
the trimethoxyphenyl ring A resulted in the loss of antitubulin
activity in both 5a and 5b. Introduction of polar groups, such as
hydroxyl and amino groups, into the B ring were tolerated. We
achieved the desired intramolecular hydrogen bond with the
tetrazole ring with the ortho-hydroxyl of 5c, but there was no
enhancement of antitubulin activity, although, antiproliferative
activity has been reduced relative to compound 5f, lacking
hydrogen bond, as demonstrated using crystallographic data. We
were able to enhance the antitubulin as well as antiproliferative
activity of 5c by incorporating either a hydroxyl (5d) or,
especially, an amino (5e) moiety at the meta position of ring B,
between the ortho-hydroxyl and the para-methoxyl moieties.
Acknowledgments
GSJ is thankful to CSIR, New Delhi, for a research
fellowship. GJS thanks CSIR-Biodiversity programme (BSC-
0120) for funding this project. This project has been funded in
part with federal funds from the National Cancer Institute,
National Institutes of Health, under contract N01-CO-12400. The
content of this publication does not necessarily reflect the views
or policies of the Department of Health and Human Services nor
does the mention of trade names, commercial products, or
organizations imply endorsement by the U.S. government. This
research was supported in part by the Developmental
Therapeutics Program in the Division of Cancer Treatment and
Diagnosis of the National Cancer Institute.
Figure 2: Predicted binding model from Schrodinger: (A) Binding model of
compound 5e overlaid with that of colchicine in the binding site on -tubulin,
which is shown in cyan ribbon with binding site amino acids rendered in cyan
stick. The ligands are rendered in stick with oxygen, nitrogen, and hydrogen
atoms colored red, blue, and white, respectively, and the carbon atoms are
colored yellow and pink for compound 5e and for colchicine, respectively.
(B) Corey-Pauling-Koltun (CPK) rendering of compound 5e docked in -
tubulin showing the tight molecular packing of the trimethoxy aromatic ring.
(C) Superimposition of the crystal structure of compound 5a (grey carbon
atoms) with potential binding modes (green and cyan carbon atoms) of
compound 5a in the colchicine site. Red dashes indicate probable steric clash.
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Supplementary Material
Experimental procedures, 1H NMR, 13C NMR and DEPT-135,
LCMS spectra, HPLC analysis, and crystal data (CIF format) of
compounds.
5