Synthesis and antitumor activity of 5'-demethyl-5'-trifluoromethyl-daunorubicin and -doxorubicin

Article abstract of DOI:10.1016/S0008-6215(99)00126-3

The title compounds were prepared by coupling phenyl 4-O-acetyl-2,3,6-trideoxy-6,6,6-trifluoro-1-thio-3-trifluoroacetamido-α-L- and β-L-lyxo-hexopyranoside with daunomycinone. The key step of this synthesis is the C-trifluoromethylation of a 1-protected 2,3-dideoxy-3-azido-D-erythro-pentodialdose, prepared from 2-deoxy-D-erythro-pentose, to give a 6,6,6-trifluoro-L-lyxo-hexose derivative. The synthetic products showed higher cytotoxicity than doxorubicin against most of the human tumor cell lines tested in vitro, possibly by the effect of the CF₃ group at C-5'. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00126-3

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Carbohydrate Research 320 (1999) 8–18
Synthesis and antitumor activity of
5%-demethyl-5%-trifluoromethyl-daunorubicin and
-doxorubicin
Ken Nakai b, Yasushi Takagi a,*, Seiichiro Ogawa b, Tsutomu Tsuchiya a
a Institute of Bioorganic Chemistry, 3-34-17 Ida, Nakahara-ku, Kawasaki 211-0035, Japan
b Department of Applied Chemistry, Faculty of Science and Technology, Keio Uni6ersity, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 8 February 1999; revised 3 May 1999; accepted 10 May 1999
Abstract
The title compounds were prepared by coupling phenyl 4-O-acetyl-2,3,6-trideoxy-6,6,6-trifluoro-1-thio-3-trifl-
uoroacetamido-a- - and b- -lyxo-hexopyranoside with daunomycinone. The key step of this synthesis is the
C-trifluoromethylation of a 1-protected 2,3-dideoxy-3-azido- -erythro-pentodialdose, prepared from 2-deoxy- -ery-
thro-pentose, to give a 6,6,6-trifluoro- -lyxo-hexose derivative. The synthetic products showed higher cytotoxicity
L
L
D
D
L
than doxorubicin against most of the human tumor cell lines tested in vitro, possibly by the effect of the CF3 group
at C-5%. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Anthracycline glycoside; Antitumor activity; Trifluoromethyl; 5%-demethyl-5%-trifluoromethyldoxorubicin
1. Introduction
In the course of our study to develop novel
anthracycline glycosides [1] having higher an-
titumor activity with lower toxicity than the
clinically used anthracycline antibiotics, such
as daunorubicin and doxorubicin (DOX), we
have recently reported 7-O-(2,6-dideoxy-6,6,6-
trifluoro - a - - lyxo - hexopyranosyl)adriamy-
L
cinone (1), which showed stronger antitumor
activity than DOX against murine leukemia
L1210 in vivo in a low dose range [2].
A characteristic chemical feature of 1 is that
it has the strongly electron-withdrawing CF3
group at C-5% instead of the CH3 group
present in normal anthracycline antibiotics;
this replacement stabilizes the glycosidic bond
against acidic hydrolysis by decreasing the
* Corresponding author. Tel.: +81-44-788-6821; fax: +
81-44-755-3099.
E-mail address: seiyuken@mxl.alpha-web.ne.jp (Y. Takagi)
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00126-3

K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
9
electron density at the glycosidic oxygen, and
thus restricting protonation. The high activity
of 1 may be attributed to this stabilization and
is also because of the high lipophilicity of the
CF3 group, which may enhance cellular up-
take of the compound. In pursuing our re-
search, we are interested in introducing a
3%-NH2 group instead of the 3%-OH group in 1
because the protonated 3%-NH2 group could
form a hydrogen bond with O-2 of thymidine
or with the O-4% atom (ring O) of deoxycy-
tidine in DNA, respectively, at the d(C-
GATCG) site of the substrate–DNA complex
[3], or could form a multiple water bridge with
a backbone phosphate oxygen of DNA, stabi-
lizing the complex, as reported on the DOX–
DNA complex [3]. Furthermore, the presence
of the 3%-NH2 group is expected to promote
the formation of ion-pair bonding with DNA,
which is acidic in nature, owing to the initial
adhesion mechanism [4] (which occurs before
the final complexing), facilitating the ap-
proach of 2 (or 3) to DNA. We report here
the preparation and antitumor activity of 7-O-
tion of 5 (to give 6) with subsequent desilyla-
tion gave an acyclic, 5-hydroxyl sugar 7.
Swern oxidation of 7 gave an unstable alde-
hyde 8, which was trifluoromethylated by
treatment with Me3SiCF3 in the presence of
a catalytic amount of Bu4NF (oxolane,
−40 °C) according to the procedure of
Prakash et al. [8]. Desilylation of the resulting
products gave a mixture of the desired 3-
azido-4-O-benzyl - 2,3,6 - trideoxy - 6,6,6 - trifl-
uoro -
acetal 9 (31%) and its epimer, 3-azido-4-O-
benzyl-2,3,6-trideoxy - 6,6,6 - trifluoro - - ribo -
L
- lyxo-hexose propane-1,3-diyl dithio-
D
hexose propane-1,3-diyl dithioacetal 10 (40%)
in approximately equal amounts. The configu-
rations of the newly introduced asymmetric
center at C-5 were determined after converting
the products into the corresponding pyra-
noses. The undesired isomer 10 could be con-
verted into 9 by treating the triflate of 10 with
NaNO2 in DMF [9], although the yield was
low. Deprotection of the dithioacetal group
[Hg(ClO4)2·3H2O and CaCO3] of 9 gave the
unstable cyclic sugar 11, which was isolated as
(3-amino-2,3,6-trideoxy-6,6,6-trifluoro-a- -
L
its 1-acetate 12 as an anomeric mixture. The
lyxo-hexopyranosyl)-daunomycinone (2) and
-adriamycinone (3), that is, 5%-demethyl-5%-
trifluoromethyl-daunorubicin and -doxoru-
bicin, respectively.
1
L
-lyxo structure with the C4(
L
) conformation
of 12 was supported by the large J2ax,3 (13 Hz)
and small coupling constants J4,5 (B2 Hz) in
1
its H NMR spectrum as well as the presence
of NOEs between H-3 and H-5 (for the a- and
b-
the b-
into the 1-acetate 14 via 13. Its structure was
L
anomers) and between H-1 and H-5 (for
2. Results and discussion
L
anomer). Similarly, 10 was converted
Synthesis.—We designed the synthesis of
compounds 2 and 3 by the coupling of a
suitably protected 5-demethyl-5-trifluorome-
thyldaunosamine with daunomycinone. Syn-
thesis of such 5-CF3 sugars has been rarely
reported, and although 3-(N-benzyltrifl-
uoroacetamido)-2,3,6-trideoxy-6,6,6-trifluoro-
4
determined to be b-
D
-ribo with the C1( )
D
conformation from the large coupling con-
stants of J1,2ax (7.5 Hz) and J4,5 (7.5 Hz) and
the existence of NOEs between H-1 and H-5,
and between H-2ax and H-4. Reduction of 12
with Raney nickel gave an amino sugar 15,
which was successively hydrogenolyzed over
Pd(OH)2 catalyst on carbon with cyclohexene
(catalytic hydrogen-transfer hydrogenolysis of
benzyl groups [10]) to give 16. Compound 16,
after 3-trifluoroacetylation (to give 17), was
acetylated to give a mixture of 1,4-diacetates
4-O-methoxymethyl-1-O-p-nitrobenzoyl-
lyxo-hexopyranose was prepared [5] from
L
-
-
D
glyceraldehyde in 14 steps, the coupling of this
synthetic sugar with daunomycinone has not
been described.
We
butyldiphenylsilyl-2,3-dideoxy-a-
pentofuranoside (4) [6,7] as the starting
material, prepared from 2-deoxy- -erythro-
with 1,3-pro-
chose
methyl
3-azido-5-O-tert-
18 (a-
L
) and 19 (b- ). The structures of the
L
D
-erythro-
1
compounds were confirmed by their H and
19F NMR spectra (Table 1).
D
Coupling of the 1-bromo (or 1-iodo) deriva-
tive of 18 and 19 with daunomycinone under
Koenigs–Knorr conditions [HgO (yellow),
pentose. Treatment of
4
panedithiol in the presence of BF3·OEt2 in
Cl(CH2)2Cl gave the dithioacetal 5. Benzyla-

Table 1
1
Selected H and 19F NMR data for compounds 5–12 and 14–21 in CDCl3
Compound Chemical shifts in ppm (J in Hz)
H-1
H-2a (or 2ax)
H-2b (or 2eq)
H-3
H-4
H-5
SCH2
PhCH2
Ac
CF3
5
6
4.17 dd
J1,2a 10.5
J1,2b 4.5
2.08 ddd
Je2a,2b 14.5
1.83 ddd
J2b,3 10.5
3.88 ddd
J3,4 5.5
3.67 ddt
3.78 (5a) dd
J5a,5b 10.5
3.74 (5b) dd
2.77–2.98 m
J4,5a
J4,5b
J4,OH
6
4
5
J2a,3
3
4.17 dd
J1,2a 10
’2.20–1.80“
4.06 dt
J2a,3 10
3.54 dt
3.80 (5a) dd
J5a,5b 11
3.75 (5b) dd
2.77–2.98 m
4.55 d
4.49 d
Jgem 12
J4,5a
J4,5b
5
5
J1,2b
5
J2b,3
J3,4
4
4
7
8
4.18 dd
J1,2a 10
J1,2b 4.5
4.12 dd
J1,2a 10
2.10 ddd
J2a,2b 14.5
J2a,3 3.5
1.85 ddd
J2b,3 10
4.03 ddd
J3,4
3.53 appar. q
J4,5a ꢀ4.5
J4,5b ꢀ4.5
3.87 dd
3.75 (5a,5b) br
9.68 d
2.79–2.99 m
2.79–2.97 m
4.70 d
4.63 d
Jgem 11.5
4.74 d
4.70 d
/
5
’2.19–1.81“
4.10 dt
J2a,3 10
J2b,3 3.5
J3,4 3.5
3.94 ddd
J4,5
2
J1,2b
5
Jgem 12
9
4.16 dd
J1,2a 10.5
2.11 ddd
J2a,2b 14.5
J2a,3 3
’2.21–1.80“
1.87 ddd
J2b,3 10.5
3.71 dd
J4,5
4.04 ddq
J5,OH 10.5
J5,CF 7.5
2.75–3.04 m
2.79–3.00 m
4.68 s
−77.9 d
−76.1 d
J3,4
6
1
320
J1,2b 4.5
3
a
a
a
10
11b
3.86 dd
J 7.5
J 2.5
4.75 d
4.63 d
Jgem 11
4.77 d
4.70 d
(
J5,CF 7
3
5.56 br s
2.34 ddt
1.98 ddt
J1,2eq ꢀ1
J2eq,3 4.5
J2eq,4 ꢀ1
3.76 ddd
J3,4 2.5
4.00 br s
4.33 dq
J4,5 ꢀ1
−73.6 (b-
(0.4 F)
L
) d
J1,2ax 3.5
J2ax,2eq 12.5
J2ax,3 12.5
J5,CF 6.5
Jgem 10.5
J5,CF 6.5
3
3
−74.0 (a-
(2.6 F)
−73.5 (b-
(0.8 F)
L
L
) d
) d
J2ax,OH
2
12b
14
6.40 br d
J1,2ax 3.5
2.48 dt
J2ax,2eq 13
J2ax,3 13
1.97 ddt
J1,2eq ꢀ1
J2eq,3 4.5
J2eq,4 ꢀ1
3.68 ddd
J3,4 2.5
4.04 br s
4.16 br q
4.77 d
4.71 d
Jgem 10.5
2.11 s
2.08 s
J5,CF 6.5
3
J5,CF 6
3
−74.0 (a-
(2.2 F)
−74.4 d
L
) d
6.02 dd
J1,2ax 7.5
J1,2eq 2.5
1.83 ddd
J2ax,2eq 13.5
J2ax,3 3.5
2.14 ddd
J2eq,3 5.5
4.00 dt
J3,4 3.5
3.83 dd
J4,5 7.5
4.33 dq
4.68 d
4.63 d
Jgem 11.5
J5,CF
7
3

Table 1 (Continued)
Compound Chemical shifts in ppm (J in Hz)
H-1
H-2a (or 2ax)
H-2b (or 2eq)
H-3
H-4
H-5
SCH2
PhCH2
Ac
CF3
15 b
16 b
17 b
6.31 br d
J1,2ax ꢀ3.5 J2ax,2eq 13.5
J2ax,3 12.5
2.02 ddd
1.75 ddt
J1,2eq ꢀ1
J2eq,3 4.5
J2eq,4 ꢀ1
3.14 ddd
J3,4 2.5
3.87 br s
4.19 br q
4.86 d
4.54 d
Jgem 11
2.09 s
−73.7 (b-
L
) d
J5,CF
7
(1 F)
3
J5,CF 6.5
3
−74.2 (a-
(2 F)
−74.1 (b-
(0.6 F)
L
L
) d
) d
6.32 br d
J1,2ax ꢀ3.5 J2ax,2eq 14
J2ax,3 12
2.00 ddd
1.76 ddt
J1,2eq ꢀ1
J2eq,3 4.5
J2eq,4 ꢀ1
3.31 ddd
3.95 br s
4.17 br q
2.11 s
2.15 s
J3,4
3
J5,CF 6.5
3
J5,CF 6.5
3
−74.6 (a-
(2.4 F)
−74.1 (b-
(0.7 F)
L
L
) d
) d
/
6.36 br d
J1,2ax ꢀ3.5 J2ax,2eq 14
J2ax,3 13
2.23 ddd
1.95 br dd
4.48 dddd 4.21 br d
J3,4 2.5
J3,NH 8.5
4.28 br q
J2eq,3
5
J5,CF 6.5
3
J5,CF 6
3
−74.6 (a-
(2.3 F)
L
) d
−76.35 s
(b-
−76.36 s
, COCF3)
−75.2 d
−76.43 s
(COCF3)
L, COCF3)
(a-L
320
18
6.43 br d
J1,2ax 3.5
2.18 ddd
J2ax,2eq 13.5
J2ax,3 12.5
2.06 dddd
J1,2eq 1.5
4.58 dddd 5.60 br s
J3,4 2.5
4.39 dq
2.18 s
2.16 s
J4,5 ꢀ1
(
J2eq,3
5
J3,NH
8
J5,CF 6
3
J2eq,4 ꢀ1
2.18 dddd
J2eq,3 4.5
J2eq,4 ꢀ1
2.26 ddt
J1,2eq ꢀ1
J2eq,3 4.5
J2eq,4 ꢀ1
2.26 dddd
J2eq,3 4.5
J2eq,4 ꢀ1
19
20
5.89 dd
2.02 dt
4.34 dddd 5.51 br d
J3,4
J3,NH 7.5
4.52 dddd 5.60 br d
J3,4 2.5
4.10 dq
J4,5
2.20 s
2.16 s
−74.6 d
−76.40 s
(COCF3)
−74.4 d
−76.38 s
(COCF3)
J1,2ax 9.5
J1,2eq 2.5
5.80 br d
J1,2ax 5.5
J2ax,2eq 12.5
J2ax,3 12.5
2.44 dt
J2ax,2eq 13
J2ax,3 13
3
1
J5,CF 6
4.91 3dq
2.17 s
J4,5 ꢀ1
J3,NH
7
J5,CF 6.5
3
21
4.90 dd
J1,2ax 11.5
J1,2eq 2.5
1.98 appar. q
J2ax,2eq 12.5
J2ax,3 12.5
4.28 dddd 5.48 br d
J3,4
J3,NH
3.98 dq
2.16 s
−74.9 d
−76.40 s
(COCF3)
3
J4,5
J5,CF
1
7
6
3
a l 4.22–4.11.
b 1H NMR data for the a-
L
anomer.

12
K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
Table 2
,
HgBr2 or HgI2, molecular sieves 3 A] was first
expected to be easy, since an analogous syn-
thesis of 1 with the corresponding 3,4-di-O-
acetyl-5-trifluoromethyl glycosyl bromide was
successful [2]; however, this mode of coupling
gave no product. The reason is not clear,
however it may be the formation of a
(F3CCO)N−(HgX)+ salt (X: Br or I) at N-3
of the sugar halides; the HgX2 catalyst is not
expected to approach Br(or I)-1 of the glyco-
syl halides because of positive charge repul-
sion between Hg and Hg. A similar coupling
using 4-O-acetyl-2,3,6-trideoxy-2-fluoro-3-tri-
13C NMR chemical shifts (l, ppm) and coupling constants
(JC,F, Hz in parentheses) of compounds 2 and 3 (both as
hydrochlorides) in D2O
a
C
2
3
1
2
3
4
4a
5
5a
6
6a
7
120.4 b
137.5
120.5 b
137.5
120.3 b
161.2
120.3 b
161.3
119.6
119.6
186.5 c
111.38 d
154.9 e
134.4 f
70.8
186.6 c
111.50 d
154.8 e
134.1 f
70.5
8
9
36.0
76.6
36.1
76.1
fluoroacetamido-
L
-talopyranosyl
bromide
with daunomycinone also gave the condensa-
tion product in only poor yield [11]. Coupling
of a mixture of 18 and 19 with daunomy-
cinone in the presence of Me3SiOSO2CF3 [12]
also failed. However, coupling of daunomy-
10
10a
11
11a
12
12a
13
14
OMe
1%
32.3
32.7
134.4 f
156.5 e
111.44 d
186.8 c
135.1 f
216.0
134.47 f
156.3 e
111.54 d
186.8 c
134.53 f
215.1
cinone with phenyl thioglycosides 20 (a-
L) and
25.0
57.2
65.0
57.3
21 (b-
L
), prepared from a mixture of 18 and
19 with Me3SiSPh and Me3SiOSO2CF3, in the
presence of N-iodosuccinimide and CF3SO3H
100.6
28.8
100.4
28.6
2%
3%
4%
46.8
62.6
46.8
62.4
[13], gave the a- -glycoside 22 (J1%,2%axB3 Hz)
L
in moderate yield. Alkaline deblocking of 22
gave desired 5%-demethyl-5%-trifluoromethyl-
daunorubicin 2. Compound 2 was next trans-
formed into the doxorubicin-type compound 3
according to, basically, the procedure of Arca-
mone et al. [14]. Bromination of 2 with Br2 in
the presence of HC(OMe)3 gave the 14-
bromo-13-dimethyl acetal, the dimethyl acetal
being removed subsequently by treatment with
acetone to give the 14-bromo derivative.
Treatment of the derivative with HCO2Na in
aqueous acetone gave the desired 5%-demethyl-
5%-trifluoromethyldoxorubicin 3 (49%). The
structures of 2 and 3 were confirmed by their
1H, 19F, and 13C NMR spectra (Table 2).
Antitumor acti6ity.—The DOX-type com-
pound 3 showed antitumor activity compara-
ble with that of DOX against murine leukemia
L1210 in vivo, although it is slightly more
toxic in a high dose range (Table 3). Com-
pound 2 was less active. However, both 2 and
3 (especially 3) showed stronger growth in-
hibitory activity than DOX against various
human tumor cell lines in vitro (Table 4). It
should be stressed that these compounds dis-
played 60–70 fold stronger activity against
human epithelioid carcinoma (HeLa) and hu-
man leukemia (HL60), suggesting that the 5%-
5%
6%
69.9 q (30.5)
124.3 q (279.5)
69.9 q (30)
124.3 q (280)
a Measured at 45 °C.
b ,c,d,e,f
Figs. in the same column may be interconvertible.
CF3 group plays a notable role in eliciting the
antitumor activity in comparison with the 5%-
CH3 group.
3. Experimental
General methods.—Melting points were de-
termined on a Kofler block, and are uncor-
rected. Optical rotations were measured with a
Perkin–Elmer 241 polarimeter. NMR spectra
(1H at 250 and 500 MHz, 13C at 125.8 MHz,
and 19F at 235.3 MHz) were recorded with
Bruker AC-250P and AMX-500 spectrome-
ters, using Me4Si and CFCl3 (for 19F) as the
internal standards. TLC was performed on
Kieselgel 60 F254 (E. Merck), column chro-
matography on Kieselgel 60, and flash column
chromatography on Wakogel C-300. Solvent
A for TLC is a solution of 20:3.8:0.45
CHCl3–MeOH–aq 17% NH4OH.

K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
13
Table 3
Antitumor activities a of 2 and 3 in comparison with DOX against the murine L1210 cell line [T/C b (%); 60-day survivor
numbers/treated numbers of mice]
c
Compound
Dose (mg kg−1 day−1
)
5
2.5
1.25
0.6
0.3
0.15
2
92 d
0/4
129 d
0/4
169 d
0/4
227
0/4
\559
2/4
\451
1/4
146
0/4
\302
1/4
\519
2/4
132
0/4
329
0/4
\312
1/4
3
132 d
0/4
176 d
0/4
\481 d
1/4
DOX
190 d
0/4
\603
2/4
\529
2/4
a Leukemia L1210 cells (105) were inoculated into CDF1 mice (2091 g) i.p. Drugs were administered daily, starting 24 h after
inoculation, from day 1 to 9 i.p.
b (Mean survival days of treated mice/mean survival days of control mice) ×100.
c Hydrochloride.
d More than 10% weight decrease in the treated mice was observed.
3 - Azido - 5 - O - tert - butyldiphenylsilyl - 2,3-
dideoxy- -erythro-pentose propane-1,3-diyl
3-Azido-4-O-benzyl-2,3-dideoxy- -erythro-
D
D
pentose propane-1,3-diyl dithioacetal (7).—To
a solution of 6 (17.69 g, 30.6 mmol) in ox-
olane (120 mL) was added Bu4NF·3H2O
(10.10 g, 32 mmol) and the solution was kept
for 1.5 h at room temperature (rt). After
concentration of the solution, the residue was
chromatographed (toluene“12:1 toluene–
EtOAc) to give 7 as a colorless syrup, 8.86 g
(85%), [h]1D9 +23° (c 1.5, CHCl3); IR (liquid
film): w 2110 cm−1 (N3). Anal. Calcd for
C15H21N3O2S2: C, 53.07; H, 6.23; N, 12.38; S,
18.89. Found: C, 53.19; H, 6.31; N, 12.12; S,
18.64.
dithioacetal (5).—A solution of 4 (18.96 g, 46
mmol), 1,3-propanedithiol (6.8 mL, 68 mmol),
and BF3·OEt2 (1.7 mL, 14 mmol) in dry
Cl(CH2)2Cl (150 mL) was kept for 70 min at
50 °C. After dilution with CHCl3, the solution
was washed with aq 5% NaOH and water,
dried (MgSO4), and concentrated. The residue
was
chromatographed
(toluene“25:1
toluene–EtOAc) to give 5 as a colorless syrup,
19.62 g (87%), TLC (toluene): Rf 0.2 (cf 4: Rf
0.35), [h]2D0 −22° (c 1, CHCl3); IR (liquid
film): w 2100 cm−1 (N3). Anal. Calcd for
C24H33N3O2S2Si: C, 59.10; H, 6.82; N, 8.62.
Found: C, 59.44; H, 6.93; N, 8.20 (Scheme 1).
3-Azido-4-O-benzyl-5-O-tert-butyldiphenyl-
3-Azido-4-O-benzyl-2,3,6-trideoxy-6,6,6-
trifluoro- -lyxo-hexose propane-1,3-diyl dithio-
L
acetal (9) and 3-azido-4-O-benzyl-2,3,6-tride-
oxy-6,6,6-trifluoro- -ribo-hexose propane-1,3-
silyl-2,3-dideoxy-D-erythro-pentose propane-
D
1,3-diyl dithioacetal (6).—To a cold (−40 °C)
suspension of NaH (1.72 g, 60% NaH in
mineral oil, 43 mmol) in dry DMF (70 mL)
was added a solution of 5 (19.52 g, 40 mmol)
and PhCH2Br (5.0 mL, 42 mmol) in DMF (80
mL) over 5 min, and the mixture was stirred
for 4 h at 0 °C. After addition of AcOH (2.5
mL) followed by water (1 L), the mixture was
extracted with CHCl3. The extracts were
washed with aq NaHCO3 (saturated) and wa-
ter, dried (Na2SO4), and concentrated. The
residue was chromatographed (1:2 hexane–
toluene) to give 6 as a colorless syrup, 17.69 g
(77%), [h]2D1 −15° (c 1, CHCl3); IR (liquid
film): w 2100 cm−1 (N3). Anal Calcd for
C31H39N3O2S2Si: C, 64.43; H, 6.80; N, 7.27.
Found: C, 64.68; H, 6.92; N, 7.34.
diyl dithioacetal (10).—To a cold (−78 °C)
solution of (COCl)2 (1.55 mL, 18 mmol) in
dry CH2Cl2 (24 mL) was added (CH3)2SO (1.9
mL, 27 mmol) and 7 (3.02 g, 8.9 mmol) in
CH2Cl2 (42 mL), and the mixture was stirred
for 40 min at the same temperature under the
atmosphere of Ar. Ethyldiisopropylamine (7.8
mL, 45 mmol) was added, and the mixture
was stirred for 30 min, then for 1.5 h at 0 °C.
Ice-cooled aq NH4Cl (saturated) was added,
and the mixture was extracted with CH2Cl2.
The extracts were washed with cold water,
dried (MgSO4), and concentrated to give
crude aldehyde 8 as a yellowish brown syrup,
3.08 g, which was positive to the Tollens
reaction; TLC: Rf 0.2 (100:1 toluene–EtOAc).
To a cold (−40 °C) mixture of the syrup

14
K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
(3.08 g) and Me3SiCF3 (2.4 mL, 16 mmol) in
oxolane (30 mL) was added a 0.6 M solution
of Bu4NF·3H2O in oxolane (1.5 mL) and the
solution was kept for 10 min at the same
temperature. TLC (100:1 toluene–EtOAc)
showed two major spots at Rf 0.7 and 0.8
(trimethylsilyl ethers of 9 and 10). After addi-
tion of a 0.6 M solution of Bu4NF·3H2O in
oxolane (15 mL) the mixture was kept for 10
min at 0 °C. Concentration gave a residue, to
which water (100 mL) was added, and the
mixture was extracted with CHCl3. The ex-
tracts were dried (MgSO4), and concentrated.
Flash chromatography (100:1 toluene–
EtOAc) of the residue gave 9 as a colorless
syrup (chromatographically homogeneous),
0.26 g (7%), along with crude 9 (1.05 g), and
10 as a colorless syrup, 1.45 g (40%), the last
being crystallized from EtOAc–hexane to af-
ford plates. Flash chromatography (2:1 hex-
ane–iPr2O) of crude 9 afforded 0.88 g (24%)
of pure material. The total yield of 9 was 1.14
g (31%). Compound 9, TLC: Rf 0.2 (100:1
toluene–EtOAc), [h]1D9 +9° (c 1, CHCl3); IR
(liquid film): w 2125 cm−1 (N3). Anal. Calcd
for C16H20F3N3O2S2: C, 47.16; H, 4.95; N,
10.31. Found: C, 47.42; H, 5.02; N, 10.39.
Compound 10, TLC: Rf 0.15 (100:1 toluene–
EtOAc), mp 90–91 °C, [h]2D2 −3° (c 1,
CHCl3); IR (KBr): w 2120 cm−1 (N3). Anal.
Calcd for C16H20F3N3O2S2: C, 47.16; H, 4.95;
N, 10.31. Found. C, 47.17; H, 5.00; N, 10.38.
Preparation of 9 from 10.—A mixture of 10
(416 mg, 1.02 mmol), (CF3SO2)2O (0.22 mL,
1.3 mmol), and pyridine (0.41 mL, 5.1 mmol)
in dry CH2Cl2 (6 mL) was kept for 1 h at 0 °C.
MeOH was added, and the solution, after
dilution with CH2Cl2, was washed with aq
NaHCO3 (saturated), aq 20% KHSO4, and
water, dried (Na2SO4), and concentrated to
give the 5-triflate as a chromatographically
homogeneous syrup, 593 mg; 19F NMR
(CDCl3): l −72.0 (br dq, J5,F-6 ꢀ6,
JF-6,SO CF(F%,F¦) 3 Hz, CF3-5), −74.1 (q,
2
CF3SO2). A mixture of the syrup, NaNO2 (315
mg, 4.6 mmol), and 15-crown-5 (0.40 mL, 2.0
mmol) in DMF (5.6 mL) was stirred for 4 h at
rt. After dilution with water, the mixture was
extracted with CHCl3. The extracts were
washed with water, dried (Na2SO4), and con-
centrated. Chromatography (100:1 toluene–
EtOAc) of the residue gave 9, 158 mg (38%),
which was identical with the specimen ob-
tained from 8.
1 - O - Acetyl - 3 - azido - 4 - O - benzyl - 2,3,6-
trideoxy-6,6,6-trifluoro- -lyxo-hexopyranose
L
(12).—To a mixture of 9 (1.83 g, 4.5 mmol)
and CaCO3 (2.74 g, 27 mmol) in aq oxolane
(1:3.8, 26 mL) was added Hg(ClO4)2·3H2O
(10.86 g, 22.5 mmol) in oxolane (16 mL) and
the mixture was stirred for 1 h at rt. After
addition of aq NaHCO3 (saturated, 30 mL)
followed by CH2Cl2, the mixture was filtered
through a Celite bed, which was repeatedly
washed with CH2Cl2. The filtrate and wash-
ings combined were washed with aq NaHCO3
(saturated), aq 10% KI, and water, dried
(MgSO4), and concentrated to give 11 as a
pale yellowish–green syrup, 1.51 g, which was
positive to the Tollens reagent; TLC: Rf 0.05
(toluene). A solution of the syrup and Ac2O
(0.70 mL, 7.4 mmol) in pyridine (9.5 mL) was
kept for 15 h at rt. Water was added, the
solution was concentrated with the aid of
toluene, and the residue was subjected to flash
chromatography (toluene) to give an anomeric
Table 4
Growth-inhibitory effect of 2 and 3 in comparison with DOX against various human cell lines a in vitro
b
c
Compound
IC50 (mg mL−1
)
HeLa
HL60
PC3
A431
PC6
MCF7
TT
DLD-1
2
0.47
0.18
12.2
0.025
0.032
1.54
0.79
1.52
10.3
0.49
0.086
0.73
0.48
0.11
0.78
0.32
0.11
0.47
0.56
0.23
0.46
0.83
0.26
0.77
3
DOX
a HeLa, human epithelioid carcinoma; HL60, human leukemia; PC3, human prostatic adenocarcinoma; A431, human
epidermoid carcinoma; PC6, human lung carcinoma; MCF7, human breast adenocarcinoma; TT, human esophageal carcinoma;
DLD-1, human colon carcinoma.
b Hydrochloride.
c IC50 values (50% inhibition concentration) were determined by MTT assay [15] on day-3 culture.

K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
15
Scheme 1.
mixture of 12 as a colorless syrup, 1.09 g
(68%). From other fractions, crude 12 (pale-
yellow syrup, 310 mg) and the 5-acetate of 9
[colorless syrup, 71 mg (3.5%)] were obtained.
Flash chromatography (toluene) of crude 12
afforded 160 mg (10%) of pure material and
the 5-acetate of 9, 80 mg (4.4%). Total yield of
12 was 1.25 g (78%). Compound 12, TLC: Rf
0.2 (toluene); IR (liquid film): w 2110 (N3),
1770 cm−1 (CꢀO). Anal. Calcd for
C15H16F3N3O4: C, 50.14; H, 4.49; F, 15.86; N,
11.70. Found: C, 50.29; H, 4.31; F, 16.21; N,
11.73.
CHCl3, was washed with aq 20% KHSO4, aq
NaHCO3 (saturated), and water, dried
(MgSO4), and concentrated to give 14 as a
colorless syrup, 85 mg (96%), which was crys-
tallized from CHCl3–hexane to give prisms,
TLC: Rf 0.4 (30:1 toluene–EtOAc), mp 90–
90.5 °C, [h]2D3 +21° (c 1, CHCl3); IR (KBr): w
2090 (N3), 1760 cm−1 (CꢀO). Anal. Calcd for
C15H16F3N3O4: C, 50.14; H, 4.49; N, 11.70,
Found: C, 50.06; H, 4.54; N, 11.65.
1-O-Acetyl-3-amino-2,3,6-trideoxy-6,6,6-
trifluoro- -lyxo-hexopyranose (16).—To a so-
L
lution of 12 (498 mg, 1.4 mmol) in 1,4-dioxane
(6 mL) was added Raney Ni (thick suspension
in water, ꢀ4 mL) portionwise over 1 h,
whereupon the spot of 12 (Rf 0.9) in TLC
(10:1 CHCl3–MeOH) disappeared. After dilu-
tion with EtOAc, the mixture was filtered
through a Celite bed and washed thoroughly
with EtOAc. The filtrate and washings com-
bined were washed with brine, dried (Na2SO4),
and concentrated to give crude 15 as a syrup,
386 mg, which contained ꢀ10% of 16. A
mixture of the syrup, cyclohexene (4.7 mL, 46
mmol), and 20% Pd(OH)2 on carbon (Pearl-
man’s catalyst, 103 mg) in EtOH (9.6 mL) was
stirred for 15 h at 75 °C. Additional cyclohex-
ene (twice; each 1.2 mL, 12 mmol) was added
1 - O - Acetyl - 3 - azido - 4 - O - benzyl - 2,3,6-
trideoxy-6,6,6-trifluoro-i- -ribo-hexopyranose
D
(14).—To a mixture of 10 (100 mg, 0.25
mmol) and CaCO3 (149 mg, 1.5 mmol) in aq
oxolane (1:4, 1.5 mL) was added
Hg(ClO4)2·3H2O (607 mg, 1.3 mmol) in ox-
olane (0.8 mL) and the mixture was stirred for
30 min at rt. Successive processing as de-
scribed for 11 gave 13 as a pale yellowish–
green syrup, 80 mg, which was unstable and
positive to the Tollens reaction; TLC: Rf 0.1
(30:1 toluene–EtOAc). A solution of the
syrup and Ac2O (0.05 mL, 0.5 mmol) in
pyridine (0.5 mL) was kept for 2 h at rt. After
addition of water, the solution was concen-
trated. The residue, after dissolution in

16
K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
halfway. The mixture was filtered through a
Celite bed and washed thoroughly with 1:2
cyclohexene–EtOH. The filtrate and washings
were concentrated and the turbid solution of
the residue in EtOAc containing the catalyst
particles accompanied was filtered through a
Celite bed with successive washing with
EtOAc, then the solution was concentrated.
This procedure was repeated twice to obtain
an anomeric mixture of 16 as yellow–green
foam, 251 mg (75%). An analytical sample
was prepared by flash chromatography (sol-
vent A) to give a colorless solid, TLC: Rf 0.1
(10:1 CHCl3–MeOH). Anal. Calcd for
C8H12F3NO4: C, 39.51; H, 4.97; N, 5.76.
Found: C, 39.83; H, 5.14; N, 5.89.
3.38; N, 3.53. Compound 19, TLC: Rf 0.21
(12:1 toluene–acetone), [h]1D9 −34° (c 0.6,
CHCl3). Anal. Calcd for C12H13F6NO6: C,
37.81; H, 3.44; N, 3.67. Found: C, 38.14; H,
3.39; N, 3.60.
Phenyl 4-O-acetyl-2,3,6-trideoxy-6,6,6-trifl-
uoro-1-thio-3-trifluoroacetamido-h-
L
- (20) and
-i-L
-lyxo-hexopyranoside (21).—To a solu-
tion of a mixture of 18 and 19 (596 mg, 1.56
mmol) in dry CH2Cl2 (12 mL) were added
Me3SiSPh (1.2 mL, 6.2 mmol) and
Me3SiOSO2CF3 (0.34 mL, 1.9 mmol) and the
solution was refluxed for 15 h. After dilution
with EtOAc, the solution was washed with
cold aq 5% NaOH and cold brine, dried
(Na2SO4), and concentrated. Flash chro-
matography (50:1 CH2Cl2–EtOAc) of the
residue gave an anomeric mixture of 20 and
21, in a 54:46 ratio, as a solid (488 mg, 72%).
The anomers were resolved by flash chro-
matography (25:1 toluene–acetone). Crystal-
lization of each anomer from EtOAc–hexane
afforded 20 as needles and 21 as an amor-
phous solid. Compound 20 sublimes at ꢀ
170 °C, TLC: Rf 0.15 (25:1 toluene–acetone),
[h]2D1 −184° (c 0.85, CHCl3). Anal. Calcd for
C16H15F6NO4S: C, 44.55; H, 3.50; N, 3.25.
Found: C, 44.65; H, 3.48; N, 3.21. Compound
21, TLC: Rf 0.25 (25:1 toluene–acetone), [h]D21
+34° (c 1, CHCl3). Anal. Calcd for
C16H15F6NO4S: C, 44.55; H, 3.50; N, 3.25.
Found: C, 44.67; H, 3.66; N, 3.27.
1,4-Di-O-acetyl-2,3,6-trideoxy-6,6,6-trifl-
uoro-3-trifluoroacetamido-h-
L
- (18) and i- -
L
lyxo-hexopyranose (19).—To an ice-cold
solution of 16 (1.02 g, 4.2 mmol) and pyridine
(1.9 mL, 23.6 mmol) in dry CH2Cl2 (18.5 mL)
was added (CF3CO)2O (1.2 mL, 8.5 mmol)
and the solution was kept for 1 h at 0 °C.
TLC (10:1 CHCl3–MeOH) showed two spots
corresponding to 17 (Rf 0.5, major) and to the
4-O-trifluoroacetyl derivative of 17 (Rf 0.9).
After addition of MeOH (1 mL) followed by
EtOAc (60 mL), the solution was poured into
20% NaCl in aq NaHCO3 (saturated, 120 mL)
and the mixture was stirred vigorously for 30
min at rt, whereupon the spot at Rf 0.9 disap-
peared. The aqueous layer separated was re-
peatedly extracted with EtOAc. The extracts
and the original organic layer combined were
washed with brine, dried (Na2SO4), and con-
centrated to give 17 as a yellow–brown foam,
1.45 g. A solution of this and Ac2O (0.8 mL,
8.5 mmol) in pyridine (13 mL) was kept for 15
h at rt, concentrated, and the residue was
subjected to flash chromatography (12:1
toluene–acetone) to give a mixture of 18 and
19 as a solid, 1.13 g (71%). Analytical samples
were prepared by further flash chromatogra-
phy (12:1 toluene–acetone) of the solid fol-
lowed by crystallization (CHCl3 –hexane) of
the separated products to give 18 as needles
and 19 as an amorphous solid, respectively.
Compound 18, TLC: Rf 0.18 (12:1 toluene–
acetone), mp 138.5–141 °C, [h]2D0 −107° (c
0.5, CHCl3). Anal. Calcd for C12H13F6NO6: C,
37.81; H, 3.44; N, 3.67. Found: C, 37.67; H,
7-O-(4-O-Acetyl-2,3,6-trideoxy-6,6,6-trifl-
uoro-3-trifluoroacetamido-h- -lyxo-hexopyran-
L
osyl)daunomycinone (22).—To an ice-cold sus-
pension of an anomeric mixture of 20 and 21
(368 mg, 0.85 mmol), daunomycinone (548
,
mg, 1.38 mmol), and powdered 4 A molecular
sieves (594 mg, activated at 350 °C under a
stream of N2) in dry Cl(CH2)2Cl (60 mL) were
added N-iodosuccinimide (200 mg, 0.89
mmol) and a 0.09 M solution of CF3SO3H in
Cl(CH2)2Cl (0.3 mL), and the mixture was
stirred at 0 °C. After 20 min, additional
CF3SO3H solution (0.5 mL) was poured, and
the stirring was continued for 30 min at the
temperature. Triethylamine (0.04 mL) was
added, and the mixture was filtered through
Celite together with CHCl3. The organic solu-
tion was washed with aq NaHCO3 (saturated),
aq 10% Na2S2O3, and water, dried (Na2SO4),

K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
17
2.15 (apparently dt, 1 H, J1%,2%ax 4, J2%ax,2%eq 13.5,
J2%ax,3% 13 Hz, H-2%ax), ꢀ2.08 (1 H, over-
lapped with the signals of H-2%eq, H-8b), 2.06
(br dd, 1 H, H-2%eq). 19F NMR (D2O): l
−74.9 (d, J5%,F 6.5 Hz, CF3). Anal. Calcd for
C27H26F3NO10·HCl·1.5 H2O: C, 50.28; H,
4.69; N, 2.17. Found: C, 50.29; H, 4.79; N,
2.18.
and concentrated. Flash chromatography (6:1
CH2Cl2 –EtOAc) of the residue followed by
precipitation from EtOAc–hexane gave 22 as
a red solid, 245 mg (40%), TLC: Rf 0.3 (6:1
CH2Cl2 –EtOAc), [h]2D3 +225° (c 0.1, CHCl3);
1H NMR (CDCl3): l 14.00, 13.25 (each 1 H s,
OH–6,11), 8.04 (dd, 1 H, J1,2 7.5, J1,3 ꢀ1 Hz,
H-1), 7.79 (dd, 1 H, J1,2 7.5, J2,3 8.5 Hz, H-2),
7.40 (dd, 1 H, H-3), 6.29 (br d, 1 H, J3%,NH ꢀ7
Hz, NH), 5.71 (br s, 1 H, H-1%), 5.60 (br d, 1
H, J3%,4% 2.5 Hz, H-4%), 5.28 (dd, 1 H, J7,8ax 4.5,
J7,8eq 2 Hz, H-7), 4.69 (br q, 1 H, J5%,F 6.5 Hz,
H-5%), 4.44–4.31 (m, 1 H, H-3%), 4.08 (s, 3 H,
OMe-4), 3.79 (s, 1 H, OH-9), 3.19 (dd, 1 H,
J10ax,10eq 19, J10eq,8eq 1.5 Hz, H-10eq), 3.01 (d, 1
H, H-10ax), 2.39 (s, 3 H, H-14), 2.17 (s, 3 H,
OAc), 2.47–2.37 and 2.23–2.03 (each m of 1
H and 3 H, respectively, H-2%ax, 2%eq, 8ax,
8eq). 19F NMR (CDCl3): l −74.9 (d, 3 F,
J5%,F 6.5 Hz, CF3-5%), −76.5 (s, 3 F, COCF3).
Anal. Calcd for C31H27F6NO12·1.5 H2O: C,
49.87; H, 4.05; N, 1.88. Found: C, 49.93; H,
3.92; N, 1.90.
7-O-(3-Amino-2,3,6-trideoxy-6,6,6-trifluoro-
h- -lyxo-hexopyranosyl)adriamycinone (3).—
L
To a suspension of 2 (hydrochloride, 31 mg,
50 mmol) in dry 1,4-dioxane (1.1 mL) was
added a 5% solution of HC(OMe)3 in dry
MeOH (0.76 mL), and the solution was kept
for 45 min at rt. After cooling (ice bath), 2.1%
Br2 in dry CH2Cl2 (0.17 mL; Br2, 66 mmol)
was added, and the solution was kept for 30
min at 0 °C, and then 2 h at rt. TLC (solvent
A) of the solution showed a main spot at Rf
0.53 (the 14-bromo-13-dimethyl acetal, cf 2: Rf
0.48). The solution was poured into diiso-
propyl ether (4 mL) with subsequent addition
of hexane (10 mL) to give a red precipitate,
which was collected (centrifugation) and
washed with hexane. A solution of the solid in
acetone (1.8 mL) was kept for 1 h at rt,
whereupon a spot at Rf 0.48 (solvent A) (13-
dedimethyl acetal) became a major one. After
concentration, a mixture of the residue and
HCO2Na (65 mg, 0.96 mmol) in 1:1.5 aq
acetone (3 mL) was stirred vigorously for 15 h
at rt. An additional amount of HCO2Na (18
mg, 0.26 mmol) was added and stirring was
continued further 5 h. TLC (solvent A) of the
mixture showed a main spot at Rf 0.35 (3).
Concentration gave a residue, which was di-
luted with water and the mixture was washed
with CHCl3. To the aqueous solution was
added NaHCO3 (920 mg) and the product was
extracted with CHCl3. The organic solution
was dried (Na2SO4) and concentrated. To the
residue dissolved in 0.24 M methanolic HCl
(0.27 mL) was added toluene, and the result-
ing precipitate was collected (centrifugation)
and washed thoroughly with toluene to give a
red solid of 3 as the hydrochloride, 16 mg
7-O-(3-Amino-2,3,6-trideoxy-6,6,6-trifluoro-
h- -lyxo-hexopyranosyl)daunomycinone (2).—
L
A suspension of 22 (45 mg, 0.063 mmol) in aq
0.2 M NaOH (4.6 mL) was stirred for 2.5 h at
0 °C. After addition of water (2 mL), the
deep-purple solution was neutralized with aq
0.1 M HCl (10.7 mL) and the aq solution was
washed with CHCl3. Aqueous NaHCO3 (satu-
rated, 2 mL) was added, and the aqueous
solution was repeatedly extracted with CHCl3.
The organic solution was dried (Na2SO4), and
concentrated. To a solution of the residue in
CHCl3 (0.15 mL)–MeOH (0.15 mL)–0.3 M
methanolic HCl (0.25 mL) was added diiso-
propyl ether, and the resulting precipitate was
collected (centrifugation) and thoroughly
washed with diisopropyl ether. A red solid of
2 (hydrochloride) was obtained, 31 mg (79%),
TLC: Rf 0.45 (solvent A), [h]2D2 +240° (c 0.1,
1
MeOH); H NMR (D2O): l 7.58 (apparently
t, 1 H, J1,2 =J2,3ꢀ8 Hz, H-2), 7.35–7.29 (m,
2 H, H-1, 3), 5.63 (br d, 1 H, J1%,2%ax 4 Hz,
H-1%), 4.76 (br, 1 H, H-7), 4.69 (br q, 1 H, J5%,F
6.5 Hz, H-5%), 4.36 (br s, 1 H, H-4%), 3.86 (s, 3
H, OMe), 3.75 (ddd, 1 H, J2%ax,3% 13, J2%eq,3% 4.5,
J3%,4% 3 Hz, H-3%), 2.85 (br d, 1 H, J10a,10b 18 Hz,
H-10a), 2.67 (br d, 1 H, H-10b), 2.43 (s, 3 H,
H-14), 2.22 (br d, 1 H, J8a,8b 14.5 Hz, H-8a),
1
(49%), [h]2D2 +243° (c 0.1, MeOH); H NMR
(D2O, 45 °C): l 7.62 (br t, 1 H, J1,2=J2,3
8
Hz, H-2), 7.39–7.34 (m, 2 H, H-1,3), 5.68 (br
d, 1 H, J1%,2%ax 4 Hz, H-1%), 4.80 (s, 2 H, H-14),
4.78 (br, 1 H, H-7), 4.69 (br q, 1 H, J5%,F 6.5
Hz, H-5%), 4.38 (br s, 1 H, H-4%), 3.90 (s, 3 H,

18
K. Nakai et al. / Carbohydrate Research 320 (1999) 8–18
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[3] C.A. Frederick, L.D. Williams, G. Ughetto, G.A. van
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Biochemistry, 29 (1990) 2538–2549.
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11–24.
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OMe), 3.77 (ddd, 1 H, J2%ax,3% 13, J2%eq,3% 5, J3%,4%
2.5 Hz, H-3%), 2.93 (d, 1 H, J10a,10b 18 Hz,
H-10a), 2.65 (d, 1 H, H-10b), 2.28 (br d, 1 H,
J8a,8b 15 Hz, H-8a), 2.18 (apparently dt, 1 H,
J1%,2%ax 4, J2%ax,2%eq 13.5, J2%ax,3% 13 Hz, H-2%ax),
2.08 (dd, 1 H, H-2%eq), 2.04 (dd, 1 H, J8a,8b 15,
J7,8b 5 Hz, H-8b). 19F NMR (D2O): l −74.9
(d, J5%,F 6.5 Hz, CF3). Anal. Calcd for
C27H26F3NO11·HCl·H2O: C, 49.74; H, 4.48; N,
2.15. Found: C, 50.10; H, 4.70; N, 2.03.
[7] P. Hansen, E.B. Pedersen, Acta Chem. Scand., 44 (1990)
522–523.
[8] G.K.S. Prakash, R. Krishnamurti, G.A. Olah, J. Am.
Chem. Soc., 111 (1989) 393–395.
Acknowledgements
[9] R. Albert, K. Dax, R.W. Link, A.E. Stu¨tz, Carbohydr.
Res., 118 (1983) C5–C6.
[10] S. Hanessian, T.J. Liak, B. Vanasse, Synthesis, (1981)
396–397.
[11] Y. Takagi, H. Park, T. Tsuchiya, unpublished results.
[12] Y. Kimura, M. Suzuki, T. Matsumoto, R. Abe, S.
Terashima, Bull. Chem. Soc. Jpn., 59 (1986) 423–431.
[13] P. Konradsson, U.E. Udodong, B. Fraser-Reid, Tetrahe-
dron Lett., 31 (1990) 4313–4316.
[14] F. Arcamone, L. Bernardi, P. Giardino, A. Di Marco,
Ger. Offen. 2652391, May 26, 1977; Chem. Abstr., 87
(1977) 152,522f.
The authors are grateful to Dr Tomio
Takeuchi (the director) and Ms Chisato
Nosaka of the Institute of Microbial Chem-
istry for the antitumor assay in vivo. We also
express deep thanks to Drs Masaaki Ishizuka
and Katsuhisa Yamazaki of the Institute for
Chemotherapy for carrying out the bioassay
(Table 4).
[15] M.C. Alley, D.A. Scudiero, A. Monks, M.L. Hursey,
M.J. Czerwinski, D.L. Fine, B.J. Abbott, J.G. Mayo,
R.H. Shoemaker, M.R. Boyd, Cancer Res., 48 (1988)
589–601.
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