A general, convenient way to carborane-containing amino acids for boron neutron capture therapy

Article abstract of DOI:10.1016/S0040-4039(00)60803-1

A general, convenient procedure for the synthesis of carborane-containing amino acids in good yield has been developed. The synthesis of o-carboranylalanine 1, O-(o-carboran-1-ylmethyl)-tyrosine 2 and p-(o-carboran-1-yl)-phenylalanine 3 is reported.

Full text of DOI:10.1016/S0040-4039(00)60803-1

00404039192
+
Vol. 33, No. 49,
Britain
7489-7490.1992
in
A General, Convenient Way to Carborane-Containing
Amino Acids for Boron Neutron Capture Therapy
Iwona M.
and Albert
of
Ohio State University,
West
Avenue, Columbus,
USA
A general, convenient
developed. The synthesis of
for
of
acids in good yield has been
2 and
is
1.
p-Boronophenylalanhte
treatment of melanoma by means of Boron Neutron Capture Therapy
is the
boron-containing amino acid that has been used in
However, them is only a single
boron atom in this amino acid and the structure appears to be metabolically unstable. This is rationale for the
synthesis of carborane-containing analogues (10 boron atoms) of aromatic amino acids, which from metabolic
studies with related compounds, might be highly resistant to oxidative changes.
this letter! we describe a new, convenient procedure to previously synthesized
total yield) and two new boron-containing amino acids,
2 (77% total
yield) and
3 (71% total yield).
1 is a potential analogue of phenylalanine and might be useful for BNCT. The
dimensions of the cage am only slightly larger than space occupied by a benzene ring rotating about its C(l)-
C(4) axis, and its two carbon atoms participate in the delocalized bonding.‘.
The synthesis of
1
involves a phase transfer
4. with propargyl bromide to yield monoalkylated product 5. Boronation of
with a decaborane-acetonitrile complex followed by the partial hydrolysis of the alkylated s base, 6, with
function stronger acidic conditions (70%
of commercially available
6N
affords the aminonitrile 7. In order to hydrolyze the
24h) are required to obtain
1.
7489

7490
same
have been used in
has also been applied to the synthesis of
3. corresponding carborane-containing
4, followed by acid hydrolysis to produce the
2 and
bromides
amino acids. This
procedure yields a racemic mixture of the carboranecontaining amino acids and these are now beiig separated
into their enantiomers for biological evaluation.
summary, a practical method for the synthesis of carborane-containing amino acids, has been
reported. This procedure can be used for the synthesis of the other boron-containing amino acids that might be
potentially useful in treatment of cancer by means of BNCT.
This research has been supported by the U.S.
of
and contract
National Cancer Institute of the U.S. Public Health Service
CA 538%.
Snyder.
a) Barth, RF.;
Reedy, A.J.;
Wm.J.
R.G.
2.
3.
J.A.;
c)
J.A.;
Fairchild, R.G.;
P.L.;
LE.;
M.; Honda, C;
S.;
J.D.
M.;
Y.;
M.; Tsui, M.; Sasumu H.;
Y.; M.;
0.; M.;
T.
1989. 388-389.
C.; Susuki, T.
A.; R
a)
A.; Escher, E.;
S.
c)
P.:
S.
4.
5.
a) O’Donnell, M.J.:
1982, 47.2663.
T.M.
(1): m.p.
b)
MS
232
Anal.
NMR
C.
7.41; N, 6.06; B, 46.77. Found: C. 25.78: H. 7.30: N. 5.99; B, 46.50.
1.1-3.4
m,
B-H);
(d of
JAB
is bidden under
(2): m.p.
Jax 5.4,
5.6); 3.67
solvent.
J
5.3): the proton
bonded to carbon atom of
6.
7.
MS
3-NBA) 338
6.77; N,
+
for
C, 42.71;
m,
6.87; N, 4.15;
B-H);
Found: C. 42.45:
B. 31.91.
NMR
4.5): 3.73 (dd,
1.1-3.3
(d of
14.6, Jax 8.4,
4.51
J
8.6); the proton bonded to carbon atom of
cage is hidden under the
from the solvent.
(3): m.p.
MS
308
6.67; N, 4.41: B, 35.20.
14.5. 8.3, = 4.7); 3.78 (dd.
8.4).
+
Anal. Calcd for
C. 42.98;
1.2-3.3
6.89: N.4.56; B, 35.17. Found: C. 42.68;
3.04.3.27 (d of
JAB
5.11
7.32.7.53
J
(Received in USA 30 July 1992; accepted 9 September 1992)