Design and synthesis of 3,5-disubstituted boron-containing 1,2,4-oxadiazoles as potential combretastatin A-4 (CA-4) analogs

Article abstract of DOI:10.1016/j.tetlet.2012.02.110

We have designed and synthesized a small library of 3,5-disubstituted-1,2, 4-oxadiazole containing combretastatin A-4 (CA-4) analogs. Our objective is to increase the efficacy of the CA-4 as an anti-tubulin and antimitotic agent by substituting the cis-al

Full text of DOI:10.1016/j.tetlet.2012.02.110

Tetrahedron Letters 53 (2012) 3947–3950
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Design and synthesis of 3,5-disubstituted boron-containing 1,2,4-oxadiazoles
as potential combretastatin A-4 (CA-4) analogs
Bhaskar C. Das a, , Xiang-Ying Tang b, Patrick Rogler b, Todd Evans a,
⇑
⇑
a Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
b Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have designed and synthesized a small library of 3,5-disubstituted-1,2,4-oxadiazole containing com-
bretastatin A-4 (CA-4) analogs. Our objective is to increase the efficacy of the CA-4 as an anti-tubulin and
antimitotic agent by substituting the cis-alkene bond with one of its bioisosteres, the 1,2,4-oxadiazole
ring. We also modified the substituents attached to both of the phenyl rings (ring A and B in Fig. 1) of
CA-4 for the purpose of diversifying our analogs based on SAR. These compounds were synthesized via
a coupling reaction between an amidoxime and a carboxylic acid in DMF solvent, with HOBt as a base,
and utilizing EDCI as a coupling reagent. Using this protocol, we synthesized a small library of 10 com-
pounds with moderate to good yields. A detailed biological study is currently undergoing in our labora-
tory to evaluate the activity of these compounds.
Received 5 January 2012
Revised 22 February 2012
Accepted 24 February 2012
Available online 3 March 2012
Keywords:
3,5-Disubstituted 1,2,4-oxadiazole
Combretastatin A-4
Bioisosteres
Vascular disrupting agent
Tubulin
Ó 2012 Elsevier Ltd. All rights reserved.
Boron-containing CA4 compound
Combretastatin A-4 (CA-4) is an antimitotic agent that binds to
the colchicine site on tubulin causing inhibition of tubulin poly-
merization, and in cells microtubule depolymerization and mitotic
block.1 CA-4 exhibits potent cytotoxicity against a broad spectrum
of human cancer lines, including multidrug resistance (MDR) lines,
and also acts as a vascular disrupting agent (VDA).2
The mechanism of action of CA-4 involves reversible, high affin-
ity binding in the colchicine site of tubulin.1b Major limitations of
CA-4 as a therapeutic candidate are its poor aqueous solubility,
bioavailability, short biological half-life, isomerization of the
ethene bond, and exhibition of many deleterious side effects.2g
To improve the therapeutic regimen of CA-4 (Fig. 1,1a), many
analogs have been developed over time that retain the biological
actions of the parent molecule but have improved water solubility
and better pharmacokinetic properties Figure 1.3 In addition to
prodrug 1b, notable analogs undergoing clinical evaluations in-
clude CA-1 (1c), the derivative CA-1P (OXI-4503, 1d4), the amino
acid derivative AC-7739 (2a), and AVE8062 (2b). However, thus
far no compounds have entered into clinical use, and there remains
a need to develop new VDAs to treat solid tumors.
H3C O
A
O
H3C O
R'
H3C
O
A
O
B
H3C
O
H3C
OR
OCH3
B
1
H3C
R
2
OCH3
1a: R = R' = H, CA4 (Combretastatin A4)
1b: R = PO(ONa)2, R' = H, CA4P
2a: R = NH3+Cl-, AC-7739
2b: R = NH-Ser .HCl salt, AVE-8062
1c: R = H, R' = OH, CA1
1d: R = PO(ONa)2, R' = O-PO(ONa)2, Oxi4503
Figure 1. Structures of several known biologically active combretastatin A-4
analogs.
aromatic rings to be at an appropriate distance and to have an opti-
mal dihedral angle to maximize the interactions with tubulin.
However, the cis-configuration is prone to isomerization, which re-
duces the potency and bioavailability. By comparing the minimal
energy conformations for both colchicine and combretastatin, it
has been demonstrated that it is possible to overcome the problem
of the isomerization of the active cis double bond to the inactive
trans -configuration, by introducing five-membered heterocycles
in place of the olefin group without substantial loss of potency.6
Therefore, to improve the efficacy and potency of combretasta-
tin a number of heterocyclic compounds as new possible bioisoster-
es of the double bond of the combretastatins have been prepared.5,3
As heterocyclic compounds are concerned, it was reported that
substituted oxadiazoles including 3,4-disubstituted-1,2,5-oxadiaz-
ole (Combretafurazan),7 and 2,5-disubstituted-1,3,4-oxadiazole4c
Based on structure–activity relationship studies, it was reported
that the cis-configuration of the double bond and the 3,4,5-trimeth-
oxy group on ring A is essential for the biological activity of CA-4.5
The key structural factor for the cytotoxic activity is the presence
of the double bond (in cis-configuration) which forces the two
⇑
Corresponding author. Tel.: +1 212 746 3290; fax: +1 212 746 0201.
E-mail address: bcd2004@med.cornell.edu (B.C. Das).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.110

3948
B. C. Das et al. / Tetrahedron Letters 53 (2012) 3947–3950
are more potent than combretastatin itself. However, 1,2,4-oxadi-
azole substituted CA-4 has not yet been explored. Herein, we report
for the first time, to the best of our knowledge, the synthesis of bor-
on-containing 3,5-disubstituted 1,2,4-oxadiazole derivates as po-
tential new CA-4 analogs. The oxadiazole moiety should provide
an optimal conformational geometry for interaction with the col-
chicine binding site of tubulin, while increasing the number of het-
eroatoms in the core structure. The net effect is an increase in the
polarity of the molecule, which would also enhance water
solubility.
group positions in ring B. We introduced oxadiazole group in the
place of ethene group with three objectives, (a) this will protect
cis–trans isomerization, (b) oxadiazole moiety would provide an
optimal conformational geometry for interaction with colchicines
binding site, and (c) by increasing the number of heteroatoms in
the core structure of the molecule would increase the polarity
and enhance water solubility.
To synthesize compound 5, we first synthesized amidoxime
derivatives 4a–d (Scheme 1).
The different substituted amidoximes were synthesized by
refluxing an ethanolic solution of substituted phenyl nitriles and
hydroxylamine hydrochloride using NaOH as base.13 The oxadiaz-
ole-containing CA-4 analog was synthesized by an amide coupling
strategy14 using amidoxime 4a and acid 3 (commercially available
from Aldrich), which were readily available though simple trans-
formations, as the substrates. Thus, the corresponding acid 3 was
treated with 1.2 equiv of CDI (carbonyldiimidazole) in DMF for
30 min at room temperature. Then the amidoxime 4a was added
and the resulting reaction mixture was heated under reflux for
about 12 h (or until the acid was consumed completely as moni-
tored by TLC) (Scheme 1).15 Compound 5 was obtained as a yellow
solid (mp 181–183 °C, 58% yield), after purification by silica-gel
chromatography (Hexanes/EtOAc, 3:1). Using the same reaction
protocol and different amidoximes 4b, 4c, and 4d we synthesized
the compounds 6, 7, and 8 in moderate to good yields (Fig. 3).15
In compound 8, we replaced both the methoxy and hydroxyl
groups in ring B by an acetylene derivative with an objective to
derivatize different functional groups and thereby increase water
solubility and binding potency to colchicines sites. To synthesize
our target compound 9, we first tried to synthesize amidoxime
12 (Scheme 2). Unfortunately, we failed to synthesize 12 despite
using different bases [like NaOH/EtOH, K2CO3/DMSO, Et3N/EtOH,
and (iPr)2NH/EtOH)] and reaction conditions (Scheme 2).16
The failure of amidoxime 12 (Scheme 2) preparation forced us
to develop an alternative route for accomplishing the synthesis
of the target compound 9. Thus, a Suzuki coupling reaction was
employed using bromide compound 715 and B2Pin2 (bis-pinocola-
todiboron) as the substrates to give the boronic ester containing
compound 9 in 45% yield as a white solid (Scheme 3).15
Oxadiazoles are not only used as bioisosteres of ethene bonds
but also as pharmacophore groups, known to possess a broad spec-
trum of biological activities,8 including anticancer activity.9
A
number of oxadiazole derivatives, depending upon the substitu-
ents and positions of heteroatoms, namely 1,2,4- and 1,3,4-oxadi-
azoles, are known to have anticancer effects.10
Considering the potential importance of CA-4 and oxadiazole
derivatives, we were interested in synthesizing a small library of
new CA-4 derivatives to increase cytotoxicity and anti-tubulin
activity. This is in the context of an ongoing chemical biology pro-
ject, studying the role of key developmental signaling pathways
during embryogenesis. Our goal is the development of new thera-
peutic and diagnostic agents for targeting these signaling path-
ways to modulate disease progression.11
To increase the cytotoxicity and anti-tubulin activity of CA-4,
we envisioned developing a set of boron-containing, 3,5-disubsti-
tuted, 1,2,4-oxadiazole derivatives as potential new analogs of
CA-4, based on a hypothesis that (a) introduction of a constrained
1,2,4-oxadiazole ring system will protect cis–trans isomerization of
the ethene group and improve water solubility, and (b) introduc-
tion of boronic acid as an acceptor-type functional group into the
aromatic ring B in CA-4 may enhance biological activity, because
it is expected that the boron atoms introduced into biologically ac-
tive molecular frameworks may interact with a target protein not
only through hydrogen bonds but also through covalent bonds,
and this interaction would impact biological function.12 Further-
more, CA-4P (a water-soluble prodrug of CA-4) is dephosphoryl-
ated in vivo to generate CA-4, and has a short plasma half-life.
We anticipate that hydrolysis might not occur with our boronic
acid and ester compounds, because the aryl carbon boron bond is
not known to be prone to hydrolysis, and thus would increase plas-
ma half-life.12h With these objectives in mind, we sought to syn-
thesize the boron-containing 3,5-disubstituted-1,2,4-oxadiazole
containing CA-4 analogs, substituting different functional groups
in rings A and B of CA-4.
It has been shown that the cis-configuration of the double bond
and the 3,4,5-trimethoxy group on ring A are the basic require-
ments for CA-4 cytotoxicity and anti-tubulin activity. However,
Gaukroger et al. questioned the importance of the trimethoxy-
phenyl group for the anti-tubulin activity.17 Based on these obser-
vations, Pettit’s group developed fluorcombstatins, where the
methoxy group at the meta position in ring A of CA-4 was replaced
with a fluorine group. In this case, the compounds showed antitub-
ulin activity comparable to that of CA-4.18 Based on these observa-
tions, we attempted to generate a small library of CA-4 analogs by
To synthesize these compounds, we first attempted to synthe-
size the model compound 5 (Fig. 2), keeping the trimethoxy-substi-
tuted A ring intact and substituting an ethene group with the
oxadiazole moiety, and interchanging the methoxy and hydroxyl
N
O
Cl
N
14
OH
OCH3
Cl
N
O
N
O
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
N
9
N
5
A
B
O
B
O
OH
OCH3
OCH3
OCH3
OCH3
OH
OCH3
Combretastatin A4
N
O
Cl
N
O
B
O
18
Cl
Figure 2. Structures of 3,5-substituted-1,2,4-oxadiazole derivatives.

B. C. Das et al. / Tetrahedron Letters 53 (2012) 3947–3950
3949
N
O
O
N
O
N
NH2
N
N
16
O
H3CO
H3CO
H3CO
H3CO
Cl
HO
CDI, DMF, rt, 30 min
then reflux
55% - 76%
N
OH
B2Pin2, Pd(PPh3)2Cl2
N
Cl
B
A
A
B
O
R2
B
O
18
R2
AcOK, DMSO, 80
12 h
°C
Br
R1
OCH3
OCH3
Cl
R1
Cl
3
4a:R1= OCH3, R2 = OH
4b: R1= H, R2 = OCH3
4c: R1= H, R2 = Br
5: R1= OCH3, R2 = OH
6: R1= H, R2 = OCH3
7: R1= H, R2 = Br
Scheme 5. Synthesis of compound 18.
4d: R1= H, R2 =
H
8: R1= H, R2 =
H
To synthesize compound 18, we used Suzuki coupling reaction
conditions, as described above for compound 9 (Scheme 5).15
In conclusion, we have successfully synthesized a small library
of 3,5-disubstituted boron-containing, 1,2,4-oxadiazole derivative
compounds. In five compounds of this library (5–9), we substituted
ring B of CA-4 (trimethoxy and hydroxyl groups) with different
functional groups, including boronic ester. In five additional com-
pounds (14–18), we substituted both ring A and ring B. In ring A,
the three methoxy groups were replaced with dichloro groups
and in ring B the trimethoxy and hydroxyl groups were replaced
with different functional groups. In all 10 compounds the cis-al-
kene bond of CA4 was substituted with one of its bioisosteres,
1,2,4-oxadiazole ring. This is the first report, to our knowledge, of
boron-containing 3,5-disubstituted 1,2,4-oxadiazole-containing
CA-4 analogs. A detailed biological study is currently undergoing
in our laboratory to evaluate the activity of these compounds.
Scheme 1. Synthesis of compounds 5–8.
N
N
O
N
N
O
N
N
O
H3CO
H3CO
H3CO
H3CO
H3CO
3H3CO
OH
OCH3
OCH
6
5
Br
7
OCH3
OCH3
OCH3
N
O
N
N
N
9
O
H3CO
H3CO
H3CO
H3CO
O
B
O
8
OCH3
OCH3
Figure 3. Structure of compounds 5–9.
O
N OH
NH2
Bases, EtOH
rt
O
B
.
B
CN
+
H2NOH HCl
O
O
11
12
10
Acknowledgments
Scheme 2. Attempt at synthesis of compound 12.
The author BCD is thankful to WCMC for startup funding. BCD is
supported by Grants from the NIH (AA020630 and AI093220). TE is
supported by a Grant from the NIH (HL56182).
N
N
9
O
N
O
H3CO
H3CO
B2Pin2, Pd(PPh3)2Cl2
H3CO
H3CO
N
O
B
AcOK, DMSO, 80
12 h
°C
Br
7
O
OCH3
OCH3
Supplementary data
Scheme 3. Synthesis of compound 9.
Supplementary data (copies of 1H, 13C NMR and Mass spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2012.02.110.
N
O
O
NH2
Cl
Cl
HO
CDI, DMF, rt, 30 min
then reflux
55% - 76%
N
OH
N
B
A
A
References and notes
B
R2
R2
B
R1
Cl
Cl
13
R1
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4a:R1= OCH3, R2 = OH
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4c: R1= H, R2 = Br
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4d: R1= H,
17: R1= H, R2 =
H
H
Scheme 4. Synthesis of compounds 14–17.
substituting the trimethoxy group in ring A with more hydropho-
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N
N
O
N
N
15
O
N
N
O
Cl
Cl
Cl
OH
OCH3
OCH3
Cl
14
Br
16
Cl
Cl
Cl
N
O
N
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Cl
Cl
N
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O
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18
O
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Figure 4. Structure of compounds 14–18.

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Compound 6. A yellow solid. Yield: 63%, mp 148–150 °C. 1H NMR (CDCl3,
300°MHz, TMS) d 3.91 (s, 3H, CH3), 3.97 (s, 3H, CH3), 4.01 (s, 6H, 2CH3), 7.04 (d,
J = 8.7 Hz, 2H, Ar), 7.47 (s, 2H, Ar), 8.14 (d, J = 8.7 Hz, 2H, Ar); 13C NMR (CDCl3,
75 MHz, TMS) d 55.4, 56.4, 61.0, 105.4, 114.2, 119.4, 129.1, 142.0, 153.6, 161.9,
168.8, 175.3.
Compound 7.
A
red solid. Yield: 62%, mp 155–157 °C. 1H NMR (CDCl3,
300°MHz, TMS) d 3.97 (s, 3H, CH3), 4.00 (s, 6H, 2CH3), 7.46 (s, 2H, Ar), 7.67
(d, J = 8.4°Hz, 2H, Ar), 8.07 (d, J = 8.4°Hz, 2H, Ar); 13C NMR (CDCl3, 75°MHz,
TMS) d 56.4, 61.0, 105.4, 118.6, 125.8, 125.9, 129.0, 132.1, 142.2, 153.6, 168.3,
175.9.
Compound 8. A white solid. Yield: 56%, mp 141–143°°C. 1H NMR (CDCl3,
300°MHz, TMS) d 3.23 (s, 1H, CH), 3.97 (s, 3H, CH3), 4.01 (s, 6H, 2CH3), 7.47 (s,
2H, Ar), 7.65 (d, J = 8.4°Hz, 2H, Ar), 8.17 (d, J = 8.4°Hz, 2H, Ar); 13C NMR (CDCl3,
75 MHz, TMS) d 56.4, 61.1, 79.3, 83.0, 105.4, 119.1, 125.0, 127.1, 127.4, 132.6,
142.1, 153.7, 168.4, 175.7.
Compound 9. A white solid. Yield: 45%, mp 161–163°°C. 1H NMR (CDCl3,
300 MHz, TMS) d 1.39 (s, 12H, 4CH3), 3.97 (s, 3H, CH3), 4.01 (s, 6H, 2CH3), 7.48
(s, 2H, Ar), 7.96 (d, J = 8.4 Hz, 2H, Ar), 8.18 (d, J = 8.4 Hz, 2H, Ar); 13C NMR
(CDCl3, 75 MHz, TMS) d 56.4, 61.0, 84.1, 105.4, 119.3, 126.6, 129.2, 135.1, 142.0,
153.6, 169.0, 175.6.
Compound 14. A yellow solid. Yield: 56%, mp 169–171°°C. 1H NMR (DMSO,
300 MHz) d 3.88 (s, 3H, CH3), 6.97 (d, J = 8.1 Hz, 1H, Ar), 7.57 (s, 1H, Ar), 7.59 (d,
J = 1.8 Hz, 1H, Ar), 8.03 (dd, J1,2 = 1.8 Hz, 1H, Ar), 8.16 (d, J = 1.8 Hz, 1H, Ar), 9.84
(s, 1H, OH); 13C NMR (DMSO, 75 MHz) d 56.6, 111.3, 116.8, 117.4, 121.8, 127.3,
127.5, 133.4, 136.2, 149.1, 151.2, 169.3, 173.6.
13. Vallin, K. S. A.; Posaric, W. D.; Hamersak, Z.; Svensson, M. A.; Minidis, A. B. E. J.
org. chem. 2009, 74, 9328–9336.
Compound 15. A yellow solid. Yield:76%, mp 142–144°°C. 1H NMR (CDCl3,
300 MHz, TMS) d 3.88 (s, 3H, CH3), 7.02 (d, J = 8.7 Hz, 2H, Ar), 7.58 (dd,
J1,2 = 1.8 Hz, 1H, Ar), 8.08–8.11 (m, 4H, Ar); 13C NMR (CDCl3, 75 MHz, TMS) d
55.4, 114.3, 118.8, 126.4, 126.9, 129.1, 132.5, 136.0, 162.2, 168.9, 173.0.
14. Liang, G.-B.; Feng, D. D. Tetrahedron Lett. 1996, 37, 6627–6630.
15. General procedure for synthesis of amidoximes: nitrile compound (10.0 mmol),
hydroxylamine hydrochloride (11.0 mmol, 754.0 mg), NaOH (11.0 mmol,
440.0 mg) and EtOH (20.0 mL) were added to a 50.0 mL RBF. The resulting
mixture was stirred reflux overnight. After the reaction complete (Monitored
by TLC), ethanol was removed under vacuum and the residue was purified by a
silica-gel chromatography to give a white solid amidoxime product.
General procedure for synthesis of oxadiazole compounds: Acid (0.5 mmol) and
CDI (Carbonyl diimidazole) (97.3 mg, 0.6 mmol) were dissolved in 3.0 mL of
DMF and stirred at room temperature. After 30 min, amidoxime (0.6 mmol)
was added and the reaction mixture was heated under reflux for about 24 h
(Monitored by TLC). Then the mixture was poured into water (20.0 mL),
extracted with ethyl acetate (3 Â 15.0 mL), and the combined organic
extractions were dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by silica-gel chromatography (hexanes/
ethylacetate) to give the oxadiazole product.
Compound 16.
A
red solid. Yield: 67%, mp 168–170°°C. 1H NMR (CDCl3,
300 MHz, TMS) d 7.63 (br s, 1H, Ar), 7.68 (d, J = 8.7 Hz, 2H, Ar), 8.05 (d,
J = 8.7 Hz, 2H, Ar), 8.12 (d, J = 1.8 Hz, 2H, Ar); 13C NMR (CDCl3, 75 MHz, TMS) d
125.4, 126.2, 126.4, 126.6, 129.0, 132.3, 132.7, 136.2, 168.5, 173.6.
Compound 17. A white solid. Yield: 59%, mp 153–155°°C. 1H NMR (CDCl3,
300 MHz, TMS) d 3.25 (s, 1H, CH), 7.63–7.67 (m, 3H, Ar), 8.12–8.16 (m, 4H, Ar);
13C NMR (CDCl3, 75 MHz, TMS) d 79.5, 82.9, 125.3, 126.4, 126.6, 126.7, 127.4,
132.6, 132.7, 136.1, 168.6, 173.5.
Compound 18. A white solid. Yield: 48%, mp 175–177°°C. 1H NMR (CDCl3,
300 MHz, TMS) d 1.40 (s, 12H, 4CH3), 7.62 (dd, J1,2 = 2.4 Hz, 1H, Ar), 7.98 (d,
J = 8.4 Hz, 2H, Ar), 8.14 (d, J = 2.4 Hz, 2H, Ar), 8.18 (d, J = 8.4 Hz, 2H, Ar); 13C
NMR (CDCl3, 75 MHz, TMS) d 25.3, 84.6, 126.8, 127.1, 127.2, 129.1, 133.0,
135.7, 136.5, 169.6, 173.8.
16. Kianmehr, E.; Yahyaee, M.; Tabatabai, K. Tetrahedron Lett. 2007, 48, 2713–2715.
17. Gaukroger, K.; Hadfield, J. A.; Lawrence, N. J.; Nolan, S.; McGown, A. T. Org.
Biomol. Chem. 2003, 1, 3033–3037.
18. Pettit, G. R.; Minardi, M. D.; Rosenberg, H. J.; Hamel, E.; Bibby, M. C., et al J. Nat.
Prod. 2005, 68, 1450–1458.
Compound 5. A yellow solid. Yield: 58%, mp 181–183 °C. 1H NMR (CDCl3,
300 MHz, TMS) d 3.97 (s, 3H, CH3), 4.01 (s, 6H, 2CH3), 4.04 (s, 3H, CH3), 5.94 (s,
1H, OH), 7.06 (d, J = 8.4 Hz, 1H, Ar), 7.47 (s, 2H, Ar), 7.67 (d, J = 1.5 Hz, 1H, Ar),
7.78 (dd, J1 = 8.4 Hz, J2 = 1.5 Hz, 1H, Ar); 13C NMR (CDCl3, 75 MHz, TMS) d 56.2,
56.4, 61.1, 105.4, 109.5, 114.7, 119.0, 119.5, 121.7, 142.1, 146.7, 148.4, 153.6,
168.8, 175.3.