Synthesis and evaluation of functionalized aminobenzoboroxoles as potential anti-cancer agents

Article abstract of DOI:10.1016/j.jorganchem.2015.06.021

Several aminobenzoboroxole derivatives have been prepared starting from o-boronobenzaldehyde employing reductive amination protocol. The corresponding aminobenzoboroxole derivatives have been further functionalized as N-nitrosoaminobenzoboroxoles as well as N-benzoboroxolylureas. These derivatives have been evaluated for their anti-cancer activity on human pancreatic cancer MIAPaCa-2 and human breast cancer MDA-MB-231 cell lines. 2015 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.jorganchem.2015.06.021

Accepted Manuscript
Synthesis and Evaluation of Functionalized Aminobenzoboroxoles as Potential anti-
Cancer Agents
Pathi Suman, Bhawankumar P. Patel, Agasthya V. Kasibotla, Lucas N. Solano,
Subash C. Jonnalagadda
PII:
S0022-328X(15)30049-8
10.1016/j.jorganchem.2015.06.021
JOM 19126
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 18 April 2015
Revised Date: 11 June 2015
Accepted Date: 15 June 2015
Please cite this article as: P. Suman, B.P. Patel, A.V. Kasibotla, L.N. Solano, S.C. Jonnalagadda,
Synthesis and Evaluation of Functionalized Aminobenzoboroxoles as Potential anti-Cancer Agents,
Journal of Organometallic Chemistry (2015), doi: 10.1016/j.jorganchem.2015.06.021.
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Graphical Abstract
Synthesis and Evaluation of Functionalized
Aminobenzoboroxoles as Potential anti-
Cancer Agents
Leave this area blank for abstract info.
Pathi Suman, Bhawankumar P. Patel, Agasthya V. Kasibotla, Lucas N. Solano, and Subash C. Jonnalagadda*

ACCEPTED MANUSCRIPT
Synthesis and Evaluation of Functionalized Aminobenzoboroxoles as Potential anti-
Cancer Agents
Pathi Suman,a Bhawankumar P. Patel,a Agasthya V. Kasibotla,a Lucas N. Solano,a Subash C.
*
Jonnalagaddaa,b
aDepartment of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, bDepartment of Biomedical and Translational Sciences, Rowan
University, Glassboro, NJ 08028.
Corresponding author. Tel.: +1-856-256-5452; fax: +1-856-256-4478; e-mail: jonnalagadda@rowan.edu
ARTICLE INFO
Article history:
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Revised
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Available online
ABSTRACT
Several aminobenzoboroxole derivatives have been prepared starting from o-boronobenzaldehyde employing reductive amination protocol. The corresponding
aminobenzoboroxole derivatives have been further functionalized as N-nitrosoaminobenzoboroxoles as well as N-benzoboroxolylureas. These derivatives have
been evaluated for their anti-cancer activity on human pancreatic cancer MIAPaCa-2 and human breast cancer MDA-MB-231 cell lines. 2015 Elsevier Ltd. All
rights reserved.
Keywords
Benzoboroxoles; Aminobenzoboroxoles; anti-Cancer Agents;
Reductive Amination; N-Nitrosoaminobenzoboroxoles; N-
Benzoboroxolylureas.
Introduction
Benzoboroxoles (cyclic boronic acids) are highly valuable
compounds because of their use in variety of disciplines such as
organic,
materials,
and
medicinal chemistry
[1-3].
Benzoboroxoles have attracted significant attention because of
their attractive therapeutic and biological profile and have been
reviewed recently [2a-b]. Owing to our interest in boron
chemistry, [4] we have been working on the functionalization of
the oxaborole ring via a plethora of reaction pathways starting
from o-boronobenzaldehyde 1 as our boron precursor (Figure 1)
[5]. For example, reaction of 1 with activated olefins such as
methyl acrylate, acrylonitrile, methyl vinyl ketone, acrolein and
cyclohex-2-enone led to the formation of functionalized
benzoboroxoles 2-3 under Baylis-Hillman [6] conditions (Figure
1, path a, b) [5a-b].
We were also able to synthesize the
corresponding homologous benzoboroxole esters 4 via the
reaction of Baylis-Hillman bromides with the aldehyde 1 under
Barbier allylation conditions (Figure 1, path c) [5b]. Aldol
addition on the boronoaldehyde 1 led to the formation of ketones
and esters such as 5 and 6 (Figure 1, paths d-e) [5c]. Finally,
Figure 1: Functionalized Benzoboroxoles.
Results and Discussion
reaction of aldehyde
1
with isonitriles furnished the
benzoboroxole amides 7 under Passerini reaction [7] conditions
(Figure 1, path f) [5d] While we have been routinely able to
functionalize the oxaborole unit, much to our dismay, we found
that these molecules did not exhibit any significant biological
activity as anti-bacterial and anti-cancer agents [5]. Accordingly,
we envisioned the preparation of aromatic ring-functionalized
benzoboroxoles while leaving the benzylic carbon unbranched on
the oxaborole ring so as to improve the biological efficacy.
Herein, we provide an account of our synthetic and biological
evaluation results.
We began our efforts with the synthesis of the precursor
aminobenzoboroxole 10. The reaction of commercially available
o-boronobenzaldehyde 1 with sodium borohydride in THF and
water provided benzoboroxole 8 in 87% yield. Nitration of
benzoboroxole with fuming nitric acid resulted in the formation
of 6-nitrobenzoboroxole 9 [8]. Reduction of 9 with Zinc and
hydrochloric acid furnished the aminobenzoboroxole 10 in 78%
yield (Scheme 1). None of these three reactions involved
chromatographic purification and the compounds could be
readily obtained by simple acid-base manipulations.

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Table 1: Preparation of Functionalized Benzoboroxoles via Reductive Amination of Aldehydes with Aminobenzoboroxole.
Yield
No.
RCHO
Product
M.P.
1
12a
12b
12c
82%
123-125oC
2
3
79%
81%
135-137oC
136-138oC
4
5
12d
12e
80%
78%
106-108oC
128-130oC
6
12f
85%
221-223oC
7
8
9
12g
12h
12i
82%
71%
76%
141-143oC
148-150oC
122-124oC
10
11
12j
74%
78%
122-124oC
94-96oC
12k
12
13
12l
73%
77%
65-67oC
12m
136-138oC

ACCEPTED MANUSCRIPT
Scheme 1: Preparation of Aminobenzoboroxole.
Scheme 3: Preparation of Chloroquinoline-Aminobenzoboroxole
Conjugate
After synthesizing 6-aminobenzoboroxole 10, we attempted
the reductive amination of benzaldehyde with 10 (Entry 1, Table
1) in methanol at room temperature, and after stirring for 3 hours,
complete conversion of amine to imine 11 was observed.
Sodium borohydride was then added to the reaction mixture at
room temperature and stirred for 2 hours to effect reduction of
the imine. Our initial efforts of isolating the product proved
difficult and the standard work up with ethyl acetate and water
after evaporation of ethanol did not furnish the product N-
Nitrosoamines and nitrosoureas are of particular interest for
the treatment of various types of cancers and compounds such as
Lomustine and Carmustine are prescribed as alkylating agents in
chemotherapy [10]. To demonstrate the robustness of the
benzoboroxole moiety, some of the representative secondary
amines 12 mentioned above (Table 1), were then subjected to
nitrosation. All of the compounds readily reacted with sodium
nitrite and HCl in acetonitrile/water solvent system and the
corresponding N-nitrosoaminobenzoboroxoles 20a-f precipitated
out of the reaction within 1-2 hours. The products were obtained
in high yields and were characterized by standard analytical
techniques (Scheme 4).
benzylaminobenzoboroxole 12a.
The product was finally
obtained after acidification with dilute HCl to pH 1 and work up
with ethyl acetate, albeit in low yields (~30%). The isolation
step was finally optimized and aminobenzoboroxole 12a was
obtained in 82% yield after careful neutralization of the aqueous
solution to a neutral pH, at which point, the product started
precipitating out of the solution. The solid was then filtered and
dried over vacuum to obtain analytically pure product 12a. We
were then able to extend this protocol for the reaction of 6-
aminobenzoboroxole with a variety of aldehydes substituted with
electron-withdrawing (Entries 2-7, Table 1) as well as electron-
donating (Entries 8-13, Table 1) groups. All of these aldehydes
readily reacted with 10 at room temperature and complete
formation of the imine was observed in all these cases within 3-4
hours. The imines 11b-m were then subjected to NaBH4
reduction to afford the products 12b-m in 72-85% overall yields
(Entries 2-13, Table 1). As expected, imine formation was
observed to be relatively faster with electron withdrawing group
substituted aldehydes and slightly better yields of the product
were observed in these cases (Entries 2-7, Table 1).
Using
aminobenzoboroxole-flutamide hybrid congener 16 was
synthesized as shown in Scheme 2. Briefly, 4-nitro-3-
the
reductive
amination
strategy,
an
trifloromethylaniline 13 was treated with p-formylbenzoic acid
14 in the presence of POCl3 to obtain the aldehyde 15 in 72%
yield. The aldehyde 15 was then subjected to reductive amination
with aminobenzoboroxole 10 under standard conditions in a one-
pot procedure as described above to obtain the hybrid congener
Scheme 4: Preparation of N-Nitrosoaminobenzoboroxoles
Further, N-substituted aminobenzoboroxoles 12a and 12i were
reacted with phenyl, cyclohexyl, and 2-chloroethyl isocyanates in
dioxane to furnish the urea derivatives 21a-f in 79-84% yields
(Scheme 5). The pure products were obtained upon the removal
of solvent and addition of cold water. The products were filtered,
dried, and characterized by IR, NMR, and mass spectrometry. In
the case of cyclohexyl isocyanate and 2-chloroethyl isocyanate,
the products had to be further triturated with hexane under
sonication to remove traces of unreacted starting material or other
16 (Scheme 2).
A chloroquinoline-aminobenzoboroxole
conjugate 19 was also synthesized in a similar manner starting
from acetanilide 17 in two steps using Vilsmeier-Haack
formylation [9] followed by reductive amination (Scheme 3).
byproducts.
Our efforts towards the nitrosation of
chloroethylureas 21e and 21f did not materialize and a complex
mixture of products was observed.
Scheme 2: Preparation of Aminobenzoboroxole-Flutamide
Hybrid

Table 2: %Cell viability of the synthesized compounds on
ACCEPTED MANUSCRIPT
human pancreatic cancer (MIAPaCa-2) and human breast cancer
(MDA-MB-231) cell lines.
MIAPaCa-2
50µM
MDA-MB-231
50µM 12.5µM
12.5µM
76.6
87.2
90.9
86.4
95.3
71.3
80.8
57.2
51.8
72.1
89.1
92.0
88.9
85.8
28.2
83.5
83.0
77.7
70.3
95.7
84.8
49.6
22.4
64.8
45.5
103.9
74.9
100.0
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
16
19
20a
20b
20c
20d
20e
20f
21a
21b
21c
21d
21e
21f
34.5
73.6
63.9
65.8
62.6
80.6
47.0
45.9
37.9
78.4
58.2
49.5
69.0
77.7
28.6
51.5
61.0
62.8
70.5
69.5
59.9
30.0
17.5
39.4
25.1
61.8
60.4
100.0
80.2
91.7
90.0
75.7
68.7
123.6
109.2
82.8
90.0
71.1
73.7
84.0
80.2
75.2
69.2
100.1
77.7
84.1
90.2
97.6
106.5
93.9
88.5
112.0
44.3
120.7
118.7
128.3
121.7
133.7
121.5
115.9
63.0
102.6
90.7
101.7
49.5
44.8
115.3
123.2
107.9
125.6
106.1
146.0
47.0
53.9
127.6
60.8
Scheme 5: Preparation of Aminobenzoboroxole-Based Urea
Derivatives.
After synthesizing the functionalized aminobenzoboroxoles,
these molecules were evaluated for their general cytotoxicity
against breast cancer cell lines (MDA-MB-231) and pancreatic
cancer cell lines (MIAPaCa-2). While most of the compounds
tested were not found to exhibit any significant cytotoxicity at
12.5 and 50 µM concentration, couple of derivatives 19 and 21b
showed activity against MIAPaCa-2 cell lines at 12.5 µM
concentration (Table 2).
80.9
96.3
134.8
95.8
100.0
100.9
63.2
100.0
Control
The IC50 values for the two most active derivatives 19 and 21b
were found to be 11.5 µM and 11.9 µM respectively in human
breast cancer cell lines MDA-MB-231. Similarly, the IC50 values
for these compounds were determined to be 8.3 µM and 2.7 µM
respectively in human pancreatic cancer cell lines MIAPaCa-2
(Figure 2).
Conclusions
In conclusion, we have demonstrated the applicability of
aminobenzoboroxoles towards reductive amination of aldehydes.
Further, the resulting benzoboroxoles have also been transformed
into
N-benzoboroxolylureas
as
well
as
N-
nitrosoaminobenzoboroxoles.
The preliminary biological
evaluation of these molecules has shown some promise and we
have been able to identify few leads for future development as
anti-cancer agents.
Experimental
Procedure for the preparation of 6-aminobenzoboroxole 10: 6-
Nitrobenzoboroxole 9 (400 mg, 2.23 mmol) was stirred in methanol
(15 mL) under sonication until a white turbid solution was obtained.
The solution was cooled to 0°C and conc. HCl (2.5 mL) was added.
After stirring the reaction mixture for 20 min, Zinc powder (1.62 g,
25.0 mmol) was added in three portions at 0-5°C. The reaction
mixture was stirred overnight at room temperature and was filtered
through a celite pad. The filtrate was concentrated in vacuo, and the
crude mixture was stirred in ethyl acetate (20 mL) for 10 min to
dissolve the bright red residue. The resulting solution was
neutralized with 1 M aq. K2CO3 and extracted with ethyl acetate (2 x
10 mL). The combined organic extract was washed with brine (1 x
10 mL), dried over Na2SO4, and concentrated in vacuo to obtain pure
6-aminobenzoboroxole 10 as a pale yellow powder (260 mg, 78%).
The spectral information matched very well with literature data.
Figure 2: In Vitro (IC50) Data for Aminobenzoboroxoles 19 and
21b on human breast cancer MDA-MB-231 and human
pancreatic cancer MIAPaCa-2 cell lines
.

washed with water, and dried under vaccum. The crude solid was
ACCEPTED MANUSCRIPT
triturated with hexane under sonication to obtain the pure urea
derivative 21f (113 mg, 82%) as colourless solid. Anal. Calc. C;
57.71, H; 5.38, N; 7.48. Found C; 57.63, H; 5.50, N; 7.29. M.P: 134-
Representative procedure for the reductive amination of
aldehydes: To a stirred solution of 6-aminobenzoboroxole 10 (200
mg, 1.34 mmol) in 5 mL of methanol was added p-anisaldehyde (163
µL, 1.34 mmol) at room temperature and stirred for 3 hours. Upon
complete consumption of the reactants (TLC), sodium borohydride
(76 mg, 2.01 mmol) was added in portions and stirred for 2 hours.
After completion of the reaction as indicated by TLC, methanol was
removed in vacuo and the residue was dissolved in water (5 mL).
The solution was neutralized to pH 7 with 10% HCl to effect
precipitation. The resulting solid was filtered, washed with water,
1
136 °C; H-NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 7.42 (s,
1H), 7.36 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 1.6, 8.4 Hz, 1H), 7.07 (d,
J = 8.0 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 5.92 (t, J = 5.6 Hz, 1H),
4.93 (s, 2H), 4.71 (s, 2H), 3.68 (s, 3H), 3.53 (t, J = 6.4 Hz, 2H), 3.28-
3.30 (m, 2H); 13C-NMR (100 MHz, DMSO-d6): δ 158.8, 157.4,
152.9, 141.2, 131.4, 130.7(2C), 129.6 (2C), 123.2, 114.3 (2C), 70.5,
55.6, 52.6, 44.1, 42.9; IR (neat): 3244, 2932, 1640, 1594, 1301,
1178, 736 cm-1; ESI-MS: m/z, 388 [M-H+CH3]+.
and
dried
under
vaccum
to
afford
6-N-(p-
methoxybenzyl)aminobenzoboroxole 12i (274 mg, 76%) as pale
cream color solid. Anal. Calc. C; 66.95, H; 5.99, N; 5.20. Found C;
66.85, H; 6.05, N; 5.40. M.P = 122-124°C; 1H-NMR (400 MHz,
DMSO-d6): δ 8.88 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.4
Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.83 (s,
1H), 6.72 (dd, J = 2.4, 8.4 Hz, 1H), 6.11 (t, J = 6.0 Hz, 1H), 4.78 (s,
2H), 4.17 (d, J = 6.0 Hz, 2H), 3.69 (s, 3H); 13C-NMR (100 MHz,
DMSO-d6): δ 158.7, 148.5, 142.1, 132.7, 129.0, 122.1, 117.3, 114.4,
113.0, 70.2, 55.7, 46.8; IR (neat): 3298, 2983, 1526, 1437, 1238,
1172, 769 cm-1; ESI-MS: m/z, 283 [M-H+CH3]+.
Cell Viability Assay: Human pancreatic cancer MIAPaCa-2 cells
were purchased from ATCC and were maintained in D-MEM
supplemented with 10% FBS, 2.5% horse serum, and 1% Penicillin
Streptomycin in a humidified atmosphere of 5% CO2 at 37°C.
Human breast cancer MDA-MB-231 cells were purchased from
ATCC and were maintained in D-MEM supplemented with 10%
FBS and 1% Penicillin Streptomycin in a humidified atmosphere of
5% CO2 at 37°C. Cells were seeded in 96 well plates at a density of
5 x 104 cells/mL, incubated for 18-24 hours, then exposed to
benzoboroxoles 1-21 at 50µM and 12.5µM concentrations in
duplicate for 72 hours. DMSO was added as a negative control. To
determine the cell viability, MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-
diphenyltetrazolium bromide) was dissolved in PBS solution
(5mg/mL) and 10µL was added to each well and incubated. After 4
hours, 100µL of SDS (sodium dodecyl sulfate) solution (1g in 10 mL
of 0.01 N HCl) was added to solubilize formazan precipitate and
incubated for an additional 4 hours. The absorbance of each well was
then measured using a microplate reader at 570 nm. The absorbance
of control wells was defined as 100% viability and all of the tested
compounds were expressed as percentage relative to the control.
Procedure for the preparation of aldehyde 15: POCl3 (136 µL,
1.46 mmol) was added to a solution of 4-formylbenzoic acid 14 (200
mg, 1.33 mmol) and 4-nitro-3-(trifluoromethyl)aniline 13 (247 mg,
1.20 mmol) in pyridine (5 mL) at -10°C dropwise and the reaction
was stirred 1 hour at the same temperature. Upon completion (TLC),
the reaction was quenched with cold water and extracted with ethyl
acetate (2 x 10 mL). The combined organic extracts were washed
with sat. aq. NaHCO3 solution (1 x 10 mL), brine (1 x 10 mL), and
dried over anhydrous Na2SO4. The ethyl acetate was concentrated in
vacuo and the crude product was purified by silica gel column
chromatography (ethyl acetate/hexane, 2:8) to yield aldehyde 15
(292 mg, 72%) as pale yellow solid. M.P: 185-187°C; 1H-NMR (400
MHz, DMSO-d6): δ 11.12 (s, 1H), 10.10 (s, 1H), 8.43 (s, 1H), 8.31
(d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.4 Hz,
2H), 8.05 (d, J = 8.4 Hz, 2H); 13C-NMR (100 MHz, DMSO-d6): δ
193.5, 166.2, 155.0, 144.3, 142.5, 139.2, 139.1, 130.3, 130.2, 129.3,
128.2, 124.1, 119.2; IR (neat): 3483, 3370, 2956, 1720, 1680, 1524,
1331, 1139, 1042, 749 cm -1; ESI-MS: m/z, 339 [M+H]+.
Acknowledgements
We sincerely thank Avante Pharmaceuticals and Channel
Therapeutics for their financial support. We also thank the
Departments of Chemistry and Biochemistry and of Biomedical
and Translational Sciences, Rowan University.
Representative procedure for the preparation of N-
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20a-f:
6-N-(p-methoxybenzyl)
aminobenzoboroxole 12i (100 mg, 0.37 mmol) was dissolved in a
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was cooled to 0°C. HCl (155µL, 12M solution, 1.86 mmol) was
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ACCEPTED MANUSCRIPT
Highlights
1. We have prepared functionalized benzoboroxoles via reductive amination protocol.
2. We have also prepared N-nitrosoaminobenzoboroxoles and benzoboroxolylureas.
3. These benzoboroxoles have been further evaluated as potential anti-cancer agents.