Synthesis of functionalized carboranes as potential anticancer and BNCT agents

Article abstract of DOI:10.1021/ic061948i

Carboranyl aldehydes react with α,β-unsaturated esters, ketones, and nitriles in the presence of DABCO to provide functionalized carboranyl alcohols in good yields. Acetates of these alcohols undergo a facile isomerization with a variety of nucleophiles and afford structurally interesting carboranes. Biological evaluation of these molecules exhibited impressive antiproliferative activity for brain and breast cancer cells.

Full text of DOI:10.1021/ic061948i

Inorg. Chem. 2007, 46, 381−383
Synthesis of Functionalized Carboranes as Potential Anticancer and
BNCT Agents
Venkata Jaganmohan Reddy,† Matthew M. Roforth,‡ Chalet Tan,*,‡ and M. Venkat Ram Reddy*,†,‡
Departments of Chemistry and Biochemistry and of Pharmacy Practice and Pharmaceutical
Sciences, UniVersity of Minnesota at Duluth, Chem 233, 1039 UniVersity DriVe,
Duluth, Minnesota 55812
Received October 11, 2006
Scheme 1. Baylis-Hillman Reaction of m-Carboranyl Aldehyde
Carboranyl aldehydes react with
R,â-unsaturated esters, ketones,
and nitriles in the presence of DABCO to provide functionalized
carboranyl alcohols in good yields. Acetates of these alcohols
undergo a facile isomerization with a variety of nucleophiles and
afford structurally interesting carboranes. Biological evaluation of
these molecules exhibited impressive antiproliferative activity for
brain and breast cancer cells.
and amines in one step.4 The reaction is highly atom efficient,
and the products undergo a facile isomerization with a variety
of nucleophiles in SN2′ fashion to afford valuable synthons.
We envisaged that the Baylis-Hillman reaction of carboranyl
aldehyde with electron-deficient olefins in the presence of
tertiary amines like 1,4-diazabicyclo[2.2.2]octane (DABCO)
should provide a wide variety of functionalized carboranes
very easily. We also envisioned that these products could,
in turn, be converted into carboranes of structural and
biological interest.
For the present study, we chose carboranyl aldehydes 1
and 2 as the electrophiles and several activated olefins such
as acrylates, and acrylonitrile, as olefin partners. The required
aldehydes 1 and 2 were prepared according to a literature
procedure by treating the corresponding o- or m-carborane
with nBuLi and quenching with methyl formate at -78 °C.5
The initial reaction of 1 with 2 equiv of methyl acrylate in
the presence of 10% DABCO was sluggish, and only a partial
reaction took place to afford ∼20% of the alcohol 3 after
12 h. Prolonged continuation of the reaction for an additional
48 h did not improve the yield. However, usage of stoichio-
metric amounts of DABCO resulted in the complete con-
sumption of aldehyde 1, and compound 3a was obtained in
70% yield after silica gel column chromatography. The
reaction with m-carboranyl aldehyde 2 was also equally
facile, and the alcohol 4 was obtained in 70% yield (Scheme
1).
Carboranes are a very good source of multiple boron atoms
with a wide variety of potential applications in medicinal
chemistry.1 The carborane moiety could also be introduced
to study the hydrophobic interactions between a drug
molecule and the enzyme/receptor.1c Carboranes and other
polyhedral boranes have also been extensively studied for
Boron Neutron Capture Therapy (BNCT).2 Functionalization
of carboranes is an extremely important transformation to
achieve all of these goals.3
The Baylis-Hillman reaction is an important C-C bond-
forming reaction, and it offers densely functionalized alcohols
* To whom correspondence should be addressed. E-mail: vmereddy@
d.umn.edu.
† Department of Chemistry and Biochemistry, University of Minnesota
at Duluth.
‡ Department of Pharmacy Practice and Pharmaceutical Sciences,
University of Minnesota at Duluth.
(1) (a) Bregadze, V. I.; Sivaev, I. B.; Glazun, S. A. Anti-Cancer Agents
Med. Chem. 2006, 6, 75. (b) Hosmane, N. S.; Maguire, J. A.
Organometallics 2005, 24, 1356. (c) Valliant, J. F.; Guenther, K. J.;
King, A. S.; Morel, P.; Schaffer, P.; Sogbein, O. O.; Stephenson, K.
A. Coord. Chem. ReV. 2002, 232, 173. (d) Salt, C.; Lennox, A. J.;
Takagaki, M.; Maguire, J. A.; Hosmane, N. S. Russ. Chem. Bull. 2004,
53, 1871. (e) Rana, G.; Vyakaranam, K.; Maguire, J. A.; Hosmane,
N. S. In Metallotherapeutic Drugs and Metal-Based Diagnostic
Agents: The Use of Metals in Medicine; Gielen, M., Tiekink, E., Eds.;
John Wiley & Sons: New York, 2005; Chapter 2, pp 19-49. (f)
Yinghuai, Z.; Peng, A. T.; Chong, L. S.; Carpenter, K.; Maguire, J.
S.; Hosmane, N. S.; Takagaki, M. J. Am. Chem. Soc. 2005, 127, 9875.
(2) (a) Wu, G.; Barth, R. F.; Yang, W.; Lee, R. J.; Tjarks, W.; Backer,
M. V.; Backer, J. M. Anti-Cancer Agents Med. Chem. 2006, 6, 167.
(b) Barth, R. F.; Coderre, J. A.; Vicente, M.; Graca, H.; Blue, T. E.
Clin. Cancer Res. 2005, 11, 3987. (c) Soloway, A. H.; Tjarks, W.;
Barnum, B. A.; Rong, F. G.; Barth, R. F.; Codogni, I. M.; Wilson, J.
G. Chem. ReV. 1998, 98, 1515.
Similarly, the reaction of o-carboranyl aldehyde 1 with
olefins such as ethyl, benzyl, and phenyl acrylates proceeded
satisfactorily to yield the corresponding alcohols 3b-d in
(3) (a) Ma, L.; Hamdi, J.; Wong, F.; Hawthorne, M. F. Inorg. Chem. 2006,
45, 278. (b) Li, T.; Hamdi, J.; Hawthorne, M. F. Bioconjugate Chem.
2006, 17, 15.
(4) Review: Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV.
2003, 103, 811.
(5) Dozzo, P.; Kasar, R. A.; Kahl, S. B. Inorg. Chem. 2005, 44, 8053.
10.1021/ic061948i CCC: $37.00
Published on Web 12/16/2006
© 2007 American Chemical Society
Inorganic Chemistry, Vol. 46, No. 2, 2007 381

COMMUNICATION
Scheme 2. Acetylation of Baylis-Hillman Alcohols
Table 1. Baylis-Hillman Reaction of o-Carboranyl Aldehyde
Scheme 3. Nucleophilic Allylic Rearrangement of Baylis-Hillman
Acetates
no.
EWG
R
3
DABCO (%) time (h) yield (%)
1
2
3
4
5
6
7
8
9
COOMe
COOEt
COOBn
COOPh
CHO
COCH3
COOCH2CF3
CN
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
70
70
70
70
10
10
10
30
c
12
12
12
12
1
70
75
71
60
60a
63b
81
90
65
6
3g
3h
0.5a
2.0
c
COOMe
Ph 3i
a The reaction was performed at 0 °C. b Isolated as its acetate. c â-
Substituted acrylates fail to undergo the Baylis-Hillman reaction; hence,
3i was synthesized via an alternate protocol involving vinylalumination.6
good yield (entries 2-4). Acrolein is an extremely sensitive
monomer, polymerizes instantaneously in the presence of
amines, and generally is not a good substrate for unreactive
Baylis-Hillman electrophiles. Fortunately, aldehyde 1 is
sufficiently reactive so as to afford the corresponding
hydroxyl aldehyde 3e in good yield (entry 5). The reaction
was done in THF as the solvent at 0 °C to minimize the
polymerization of acrolein. The reaction of 1 with methyl
vinyl ketone took place smoothly, but the product alcohol
3f could not be obtained in very pure form. Accordingly,
we characterized 3f via conversion to its acetate (entry 6).
In the cases of 2,2,2-trifluoroethylacrylate and acrylonitrile
(entries 7 and 8), the reaction went to completion within half
an hour using 30% DABCO, affording the alcohols 3g and
3h in 81% and 90% yield, respectively. â-Phenyl-substituted
alcohol 3i was prepared via the reaction of methyl 3-phenyl-
2-propynoate with DIBAL-H/NMO followed by treatment
with carboranyl aldehyde 1 (entry 9, Table 1).6
MeMgBr was very facile, and R,â-unsaturated ester 7 was
formed in 78% yield. Treatment with 4-methylbenzenethiol
was also very smooth, and the thioether 8 was obtained in
80% yield. We have also performed the isomerization with
lithiated benzophenone glycinimine 9. This afforded the
R-diphenylimino ester that upon acidic hydrolysis afforded
the amino acid 10 in very good yield (Scheme 3). This
particular reaction could be useful because of the easy access
of carborane containing functionalized amino acids.2c
Owing to the importance of carboranes in medicinal
chemistry, some of these compounds have been evaluated
as potential anticancer agents, and preliminary results are
highly encouraging for brain and breast cancer cells. The
antiproliferative activity of these compounds was tested in
human LN229 gliomablastoma cells, MCF-7 (estrogen
receptor-positive), and MDA-MB-231 (estrogen receptor-
negative) breast carcinoma cells. The cells were incubated
at 37 °C in 96-well plates for 3 days in the presence or
absence of the compounds. The cell numbers were quantified
by a crystal violet assay9 and normalized to the untreated
cells. At 25 µM, both 3a and 3h exhibited over 95%
inhibition of cell proliferation in all three cell lines.
Compounds 3a and 3h were also active at lower concentra-
tions (5-15 µM), whereas the corresponding Baylis-
Hillman product obtained from benzaldehyde and methyl
acrylate was totally inactive.
After successfully synthesizing the functionalized carbo-
ranyl alcohols, we carried out further studies to synthesize
some useful and structurally interesting functionalized car-
boranyl intermediates via nucleophilic allylic substitution.
As a representative example, we took the acetate 6 derived
from alcohol 3a. The acetate formation under standard basic
conditions resulted in the formation of o-carborane via
elimination. Similar observations were made by Yamamoto
et al., wherein o-carborane was used as a protecting group
for the hydroxyl moiety and was subsequently deprotected
under basic conditions.7 Fortunately, acetate formation under
Lewis acidic conditions took place very smoothly. Treatment
of 3a with Ac2O in the presence of a catalytic amount of
In conclusion, we have carried out a systematic study of
the Baylis-Hillman reaction on carboranyl aldehydes with
electron-deficient olefins and obtained functionalized car-
boranyl alcohols in a single step. The acetate of hydroxy
ester has been successfully isomerized with a variety of
nucleophiles in SN2′ fashion, and several functionalized
carboranes of structural and biological interest were obtained
in good yields. Preliminary biological evaluation showed
8
Mg(ClO4)2 furnished acetate 6 in 90% yield (Scheme 2).
After obtaining the acetate, we carried out the isomeriza-
tion with several nucleophiles. The reaction of 6 with
(6) Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Reddy, M. V.
R. J. Org. Chem. 2003, 68, 9310.
(7) Nakamura, H.; Aoyagi, K.; Yamamoto, Y. J . Org. Chem. 1997, 62,
780.
(8) Chakraborti, A. K.; Sharma, L.; Gulhane, R.; Shivani. Tetrahedron
2003, 59, 7661.
(9) Kueng, W.; Silber, E.; Eppenberger, U. Anal. Biochem. 1989, 182,
16.
382 Inorganic Chemistry, Vol. 46, No. 2, 2007

COMMUNICATION
impressive antiproliferative activity for the brain and breast
cancer cells. A detailed biological evaluation of these
compounds is in progress and will be reported in due course.
Owing to the significance of the Baylis-Hillman reaction,
the ease of functionalization, and the importance of carbo-
ranes in various fields, we believe that the present study
would be of interest to inorganic, organic, and medicinal
chemists.
Acknowledgment. We thank the Department of Chem-
istry and Biochemistry and College of Pharmacy, University
of Minnesota at Duluth, for the facilities and funding.
Supporting Information Available: Experimental and spectral
1
data along with H and 13C NMR spectra for various compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
IC061948I
Inorganic Chemistry, Vol. 46, No. 2, 2007 383