Preparation of apoptotic inducers, 2,2-diphenyl-1,3,2-oxazaborolidin-5- ones, under alkaline conditions

Article abstract of DOI:10.1055/s-2007-973886

An efficient and high-yielding procedure has been developed for the synthesis of a set of fifteen 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones, through the reaction of the corresponding examino acid with diphenyl borinic acid under alkaline conditions (pH 7.5

Full text of DOI:10.1055/s-2007-973886

LETTER
921
Preparation of Apoptotic Inducers, 2,2-Diphenyl-1,3,2-oxazaborolidin-5-ones,
Under Alkaline Conditions
P
reparation of 2,2
e
-diphenyl-
n
1,3,2-oxazab
j
orolidi
a
n-5-ones mín Velasco-Bejarano,*a,b José Trujillo-Ferrara,a René Mirandab
a
Departamento de Bioquímica Médica, Escuela Superior de Medicina-IPN, México D.F., 11340, México
b
Departamento de Ciencias Químicas, Facultad de Estudios Superiores Cuautitlán-UNAM, Estado de México, 54740, México
Fax +52(55)56232056; E-mail: qfbbevebe@gmail.com
Received 13 July 2006
mixture of water, 2-propanol and acetic acid. Another
method using an acidic medium was reported by Farfán et
al.12 and Trujillo et al.13Chremos et al.14 described a facile
method of both preparing and liberating the ethanolamine
Abstract: An efficient and high-yielding procedure has been devel-
oped for the synthesis of a set of fifteen 2,2-diphenyl-1,3,2-ox-
azaborolidin-5-ones, through the reaction of the corresponding a-
amino acid with diphenyl borinic acid under alkaline conditions (pH
7.5–8). It is of note that these compounds showed potent cytotoxic ester of diphenylborinic acid. As a continuation of our ef-
forts in this area,13 we addressed our attention to the effect
activity on K-562 and HCT-15 cell lines.
of alkaline conditions in the production of a set of fifteen
2,2-diphenyl-1,3,2-oxazaborolidin-5-ones (3a–o). Thus,
the aim of this work is to report a new and convenient pro-
tocol under mild alkaline conditions16 for the production
of target molecules (Scheme 1). In addition, the cytotoxic
activity of 3a–o was evaluated against two tumor cell
lines, HCT-15 (human colon cancer) and K-562 (human
leukemia) using the sulforhodamine B assay.17
Key words: a-amino acids, diphenyloxazaborolidinones, boron
complexes, apoptosis, diphenylborinic acid
Much interest is currently focused on the synthesis of bo-
ron-containing compounds due to their biological impor-
tance. In particular, certain molecules containing boron–
nitrogen bonds have shown interesting biological activity,
including insecticidal, fungicidal, herbicidal,1 antibacteri-
al,2,3 inhibitor thrombin-induced Ca2+,4 and apoptotic ac-
tivity.5 Belonging to this class of nitrogen–boron-
coordinated compounds is a group that deserves particular
attention, 2,2-dialkyl or 2,2-diphenyl-1,3,2-oxazaboroli-
din-5-ones (Figure 1), which are generally obtained by the
reaction of a-amino acids with alkyl boranes, aryl boranes
or alkylborinates under acidic conditions. For example,
Lang et al.6 prepared several of these compounds, using
glycine and L-methionine with tri-n-propylborane or tri-
arylboranes in refluxing o-xylene under nitrogen. Another
protocol was described by Skoog,7 employing a diaryl
alkyl borinate with glycine, alanine, leucine or amino-
ethanol, thus obtaining the corresponding borinates. In
addition, Shih-Hua et al.8 reported the synthesis of various
diarylborinates by treating several amino acids with n-
butyldiarylborane. Nefkens et al.9 produced a series of
diethyl or diphenyl oxazaborolidinones from glycine,
phenylalanine, tryptophan, aspartic acid, glutamic acid,
cysteine, lysine and methionine, employing a slight ex-
cess of triethylborane or triphenylborane in tetrahydro-
furan.
O
R
δ
NH2
O
δ
B
Figure 1
To explore the scope of our reaction, fifteen a-amino ac-
ids were converted to oxazaborolidinones (Table 1). In
addition, compounds 3a, 3b, 3e, 3f, 3g, 3i, 3m, 3n and 3o,
were obtained in better yields when compared to previ-
ously reported procedures.7,8,12
O
R
δ
OH
B
O
NH2
δ
pH 7.5–8
reflux, 4 h
O
O
R
B
+
NH3
1
2
3a–o
Scheme 1
Flückiger et al.10 reported the use of the ethanolamine
complex of diphenylboronic acid in acidic conditions to
give a set of twenty 2,2-diphenyl-1,3,2-oxazaborolidin-5-
ones generated from the corresponding a-amino acids.
Strang et al.11 obtained various oxazaborolidinones using
the ethanolamine complex of diphenyl borinic acid in a
The corresponding spectroscopic data were used for the
structural attribution of 3a–o.18 In general, the signal be-
tween +3.0 and 6.7 ppm in the 11B NMR spectrum was as-
signed to a tetra-coordinated boron. In regard to the
carbon signals of the aromatic ring, the i-carbon atoms ap-
peared in the range 148–149 ppm, the o-carbons atoms at
131–132 ppm, the m-carbons atoms at 127–128 ppm and
the p-carbons atoms at 125–126 ppm. In general, a single
signal assigned to the carbon of the fourth position in the
SYNLETT 2007, No. 6, pp 0921–0924
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973886; Art ID: S14606ST
© Georg Thieme Verlag Stuttgart · New York

922
B. Velasco-Bejarano et al.
LETTER
oxazaborolidinonic moiety was present in the range 42– compounds showed the expected molecular ions as well
1
62 ppm and in the H NMR spectra, the proton at the as common ions; [M – 1]+, [M – 44]+, and [M – 77]+.
fourth position displayed common signals around 3.3–3.7
ppm. Finally, in the corresponding MS (EI), the target
Table 1 Production of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones 3a–3oa
Product
a-aa
Structure
pH
8.0
Yieldb (%)
Yieldc (%)
94
Mp (°C)
241–243
3a
Gly (G)
517
O
48.78
2612
454
δ
NH2
δ
B
O
3b
L-Ile (I)
7.5
8812
93
221–223
O
δ
NH2
O
δ
B
3c
L-Leu (L)
L-Met (M)
7.5
8.0
887
90
78
171–174
222–224
O
68.58
10012
δ
NH2
O
δ
B
3d
7812
S
O
δ
NH2
O
δ
B
3e
L-Thr (T)
8.5
12.68
5812
88
202–203
O
OH
δ
NH2
O
δ
B
3f
3g
3h
3i
L-Tyr (Y)
L-Ser (S)
L-Pro (P)
L-Orn
7.5
7.5
8.0
8.5
2112
91
93
98
90
149–150
259-260
268–269
213–215
O
δ
NH2
O
δ
B
43.48
3612
O
OH
δ
NH2
O
δ
B
10012
8715
O
δ
HN
δ
B
6013
NH2
O
δ
NH2
δ
O
B
Synlett 2007, No. 6, 921–924 © Thieme Stuttgart · New York

LETTER
Preparation of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones
923
Table 1 Production of 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones 3a–3oa (continued)
Product
a-aa
Structure
pH
8.5
Yieldb (%)
–
Yieldc (%)
89
Mp (°C)
244–246
3j
L-Arg (R)
HN
NH
NH2
O
δ
NH2
δ
O
B
3k
L-Val (V)
7.5
79.788
80
243–245
O
δ
NH2
δ
O
B
3l
L-Phe (F)
L-His (H)
8.0
8.0
709
65
92
222–224
275–277
O
δ
NH2
O
δ
OH
B
3m
45.998
N
NH
O
δ
NH2
O
δ
B
3n
3o
L-Asn (N)
8.5
8.5
–
–
76
83
150–151
240–242
NH2
O
O
δ
NH2
δ
O
B
L-Gln (Q)
O
NH2
O
δ
NH2
O
δ
B
a All the products were characterized by their spectroscopic data [1H NMR, 13C NMR, 11B NMR, MS (EI) and IR].
b Published procedure.
c Our procedure.
In addition, the cytotoxic effect of these compounds was In summary, this paper describes an efficient and conve-
studied using the Sulforhodamin assay on HCT-15 and nient procedure for the preparation of 2,2-diphenyl-1,3,2-
K-565 cell lines. The results show that compounds 3a–o oxazaborolidin-5-ones in good yields, under alkaline con-
exhibit a cytotoxic effect on both the HCT-15 and K-562 ditions. These compounds have shown themselves to be
cell lines. Meanwhile, 3a and 3j showed the best growth attractive molecules for further studies into their antineo-
inhibition in the HCT-15 cell line, while compounds 3a, plastic activity.
3b, 3c, 3g, 3j, 3l and 3n showed good inhibition in the
K-562 cell line (>70% growth inhibition).
Synlett 2007, No. 6, 921–924 © Thieme Stuttgart · New York

924
B. Velasco-Bejarano et al.
LETTER
(15) Rettig, S. J.; Trotter, J. Can. J. Chem. 1977, 55, 958.
Acknowledgment
(16) Typical procedure (Table 1, entry 1, 3a): Glycine (0.5g,
6.6 mmol) was dissolved in H2O (3 mL) and the pH was ad-
justed to 8 with NaOH (5%, 2 mL). A solution of diphenyl-
borinic acid was prepared from 2-aminoethyl-diphenyl-
borinate (1.59 g, 6.6 mmol) as described in the literature.14
The solutions were mixed together and heated at reflux for
4 h. The solvent was evaporated slowly and the product was
filtered and washed with cold H2O and n-hexane, yielding
1.49 g of 3a (6.26 mmol, 94%).
(17) Cytotoxicity in K-562 and HCT-15 cell lines, using the
sulforhodamine B assay: Skehan P., Storeng R., Scudiero
D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesh
H., Kenney S., Boyd M.R.; J. Natl. Cancer Inst.; 1990, 82:
1107; 24 h after treatment, the treated and control cell
cultures were fixed with ice-cold 10% CCl3COOH for 30
min. The 96-well plates were washed in H2O and then
sulforhodamine (SRB, 100 mL, 0.4%) dissolved in AcOH
(1%) was added to each well and left for 15 min. The SRB
was removed, washed in AcOH (1%) and allowed to air-dry.
Then aqueous Tris base [tris(hydroxymethyl)aminoethane]
(100 mL, 10 mM) was added to each well to solubilize the
cell-bound dye and the absorbance at 550 nm was measured.
The results are expressed as a percentage of control cell
growth.
B.V.B. thanks CONACyT, México, for a scholarship, and Cátedra
IN1-71 FESC-UNAM for financial support. The authors acknow-
ledge financial support from COFAA-IPN and EDI-IPN, México.
References and Notes
(1) Dembitsky, V. M.; Srebnik, M. Tetrahedon 2003, 59, 579.
(2) Jabbour, A.; Steinberg, D.; Dembitsky, V. M.; Moussaieff,
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Agents Chemother. 1980, 17, 549.
(4) Dobrydneva, Y.; Abelt, C. J.; Dovel, B.; Thadigiri, C. M.;
Williams, R. L.; Blackmore, P. F. Mol. Pharmacol. 2006, 69,
247.
(5) Velasco, B.; Trujillo-Ferrara, J. G.; Fabila, L. H.; Miranda,
R.; Sánchez-Torres, L. E. Life Sci. 2007, 80, 1007.
(6) Lang, K.; Nuetzel, K.; Schubert, F. German Patent 1130445,
1962; Chem. Abstr. 1963, 58, 1488a.
(7) Skoog, I. H. J. Org. Chem. 1964, 29, 492.
(8) Shih-Hua, T.; Kuo-Min, C.; Shih-Lu, T.; Chia-Chun, L.;
Shih-Lin, C. Chem. Abstr. 1967, 66, 37990m.
(9) Nefkens, G. H. L.; Zwanenburg, B. Tetrahedron 1983, 39,
2995.
(18) 2,2-Diphenyl-1,3,2-oxazaborolidin-5-one (3a): White
solid; mp 241–243 °C (Lit. 242–245 °C); IR (KBr): 3428,
3243, 3074, 1720, 1604, 1434, 1302, 1217, 963, 702 cm–1;
1H NMR (DMSO-d6): d = 7.35 (d, J = 7 Hz, 4 H), 7.22 (t,
J = 7 Hz, 4 H), 7.16 (t, J = 7 Hz, 4 H), 7.07 (br t, 2 H, NH),
3.43 (t, J = 6 Hz, 2 H); 13C NMR (DMSO-d6): d = 42.9,
126.1, 127.1, 131.0, 147.8, 172.5; 11B NMR (DMSO-d6):
d = +5.03; MS (EI): m/z = 239, 238, 162 (base peak), 161,
132, 104, 77.
(10) Flückinger, R.; Henson, E.; Hess, G. M.; Gallop, P. M.
Biomed. Mass Spectrom. 1984, 11, 611.
(11) Strang, C. J.; Henson, E.; Okamoto, Y.; Paz, M. A.; Gallop,
P. M. Anal. Biochem. 1989, 178, 276.
(12) Farfán, N.; Silva, D.; Santillan, R. Heteroat. Chem. 1993, 4,
533.
(13) Trujillo, J.; Höpfl, H.; Castillo, D.; Santillan, R.; Farfán, N.
J. Organomet. Chem. 1998, 571, 21.
(14) Chremos, G. N.; Weidmann, H.; Zimmerman, H. K. J. Org.
Chem. 1961, 26, 1683.
Synlett 2007, No. 6, 921–924 © Thieme Stuttgart · New York

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