New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5

Article abstract of DOI:10.1016/j.bmcl.2004.03.109

To improve the metabolic stability of 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, we designed and synthesized new taxane analogues. Most of the synthetic compounds maintained excellent antitum

Full text of DOI:10.1016/j.bmcl.2004.03.109

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3209–3215
New highly active taxoids from
9b-dihydrobaccatin-9,10-acetals. Part 5
Yasuyuki Takeda,a Kouichi Uoto,a Michio Iwahana,b Takeshi Jimbo,b
Motoko Nagata,b Ryo Atsumi,c Chiho Ono,c Noriko Tanaka,d Hirofumi Terasawab
and Tsunehiko Sogaa,*
aMedicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd, Tokyo R&D Center,
16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan
bNew Product Research Laboratories III, Daiichi Pharmaceutical Co., Ltd, Tokyo R&D Center,
16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan
cDrug Metabolism & Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd,
Tokyo R&D Center, 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan
dResearch Planning & Administration Department, Daiichi Pharmaceutical Co., Ltd, Tokyo R&D Center,
16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan
Received 1 March 2004; accepted 31 March 2004
Abstract—To improve the metabolic stability of 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv
and po administration, we designed and synthesized new taxane analogues. Most of the synthetic compounds maintained excellent
antitumor activity and were scarcely metabolized by human liver microsomes. And some compounds exhibited potent antitumor
effects against B16 melanoma BL6 in vivo by both iv and po administration similarly to 3.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
monkey or human liver microsomes rapidly provided
the metabolite M-1 (4). In our previous paper, to im-
prove the metabolic stability of 3, we synthesized taxane
analogues having substituents introduced onto the
metabolic position, exemplified by 5 and 6, which
maintained excellent antitumor activity and were scar-
cely metabolized by human liver microsomes.4
Paclitaxel (1, Taxolâ)1 and docetaxel (2, Taxotereâ)2
inhibit cell growth by interacting with microtubules and
are particularly effective against ovarian and breast
cancer and Kaposi’s sarcoma. However, their low water
solubility requires the co-injection of a detergent, such
as Cremophorâ EL or Tweenâ 80. These detergents
frequently cause untoward hypersensitivity reaction,
and patients receiving these drugs require premedica-
tion. In addition, neither is suitable for oral adminis-
tration because each has low oral bioavailability. Under
these circumstances, we had attempted to discover orally
active taxane analogues and found that a new taxane
analogue, 9-b-dihydro-9,10-O-acetal taxane 3, exhibited
marked in vivo efficacy by both iv and po administra-
tion.3 However, during our study of the biological
properties of 3, we found that the incubation of 3 with
We investigated yet another approach to obtain the
compound, which possessed potent antitumor efficacy
and high metabolic stability. We report here the syn-
thesis and antitumor activities of new taxane analogues
designed to improve the metabolic stability of 3.
2. Chemistry
Firstly, we tried to replace the morpholine moiety of 3
with the other amine groups. Oxidation of 7,3 the pre-
cursor of 3, with OsO4 followed by cleavage with NaIO4
gave the aldehyde, to which the amine moiety was
introduced by reductive amination to afford the targeted
compounds (8a–d)5 (Scheme 1).
* Corresponding author. Tel.: +81-3-3680-0151; fax: +81-3-5696-8344;
e-mail: sogatf7t@daiichipharm.co.jp
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.109

3210
Y. Takeda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3209–3215
R
O
O
O
O
Boc
Boc
a
NH
O
NH
O
N
O
N
O
O
H
O
H
OAc
OAc
HO OBz
OH
HO OBz
OH
7
8a (R = dimethylamino)
8b (R = methylamino)
8c (R = cyclopropylamino)
8d (R = cyclobutylamino)
Scheme 1. Reagents and conditions: (a) (i) OsO4, NMO, THF, acetone, H2O; (ii) NaIO4, THF, MeOH, H2O; (iii) amine, AcOH, NaBH3CN, EtOH
(82% for 8a, 12% for 8b, 60% for 8c, 56% for 8d).
Next, to avoid the formation of the hydroxypyridine
ring through metabolism by human liver microsomes,
we tried to replace the pyridine ring with tert-butyl,
3-fluoropyridyl, and thiazolyl groups. The synthesis of
the key b-lactam intermediates (13, 18a,b, 23, 27) is
shown in Scheme 2. The b-lactams (10, 15a,b) were
synthesized by the Staudinger reaction between the
imines, which were derived from the corresponding
aldehydes (9, 14a,b) and p-anisidine, and the ketene
derived in situ from 2-acetoxyacetyl chloride. The
p-methoxyphenyl moiety of 10 was removed with ceric
ammonium nitrate (CAN) and sequential deacetylation
and silylation gave the b-lactam 12. Finally, acylation of
12 was accomplished with di-tert-butyl dicarbonate
((Boc)2O) and 4-dimethylaminopyridine (DMAP)
to afford the targeted b-lactam 13 as a racemic mixture.
Compounds 15a and 15b were converted to 16a and
16b, respectively, by the sequential deacetylation and
silylation. After removal of the p-methoxyphenyl
moieties, the racemic mixtures were resolved by using a
chiral HPLC column to afford the optically pure b-lac-
tams ((+)-17a, (+)-17b). Acylations of chiral b-lactams
(17a,b) with (Boc)2O afforded the desired b-lactams
(18a,b) in good yield. The chiral b-lactam 23 was
obtained from 19 by following a procedure similar to
that described for the preparation of 18b from 14b by
replacing p-anisidine with 2,4-dimethoxybenzylamine.
The chiral b-lactam 27, possessing a 4-thiazolyl group,
was derived from the reported chiral b-lactam6 24 in
three steps.
PMP
Boc
d
a
O
O
O
O
b
c
CHO
N
HN
HN
N
(
OAc
OAc
OTES
OTES
9
(
)-10
(
)-11
)-13
(
)-12
CHO
14a
F
N
S
PMP
PMP
Boc
a
O
O
O
O
d
e
f
N
N
HN
N
CHO
R
OAc
)-15a
R
OTIPS
)-16a
R
OTIPS
(+)-17a
(+)-17b
R
OTIPS
14b
N
(+)-18a
(
(
(
(
(+)-18b
)-15b
)-16b
Boc
O
O
DMB
N
DMB
N
O
O
d
g
h
HN
N
e
S
CHO
S
S
N
N
S
S
OTIPS
(+)-22
OTIPS
(+)-23
OAc
OTIPS
19
(
)-20
(
)-21
N
N
N
Boc
O
O
PMP
N
PMP
N
O
O
d
f
HN
N
i
OTIPS
( )-26
OTIPS
OBn
(+)-24
OTIPS
( )-25
S
S
S
S
N
N
N
N
+
(+)-27
+
Scheme 2. Reagents and conditions: (a) (1) 4-anisidine, Na2SO4, benzene, (2) 2-AcOCH2COCl, Et3N, CH2Cl2 (54% for 10, 61% for 15a, 41% for
15b); (b) CAN, CH3CN, H2O (72%); (c) (1) K2CO3, THF, MeOH, (2) TESCl, imidazole, DMF (71%); (d) (Boc)2O, DMAP, THF (97% for 13, quant.
for 18a, 96% for 18b, 98% for 23, 98% for 27); (e) (1) K2CO3, THF, MeOH, (2) TIPSCl, imidazole, DMF (74% for 16a, 70% for 16b, 38% for 21); (f)
(1) CAN, CH3CN, H2O, (2) Chiralcel OD (24% for 17a, 31% for 17b, 56% for 26 from 24); (g) (1) 2,4-dimethoxylbenzylamine, Na2SO4, benzene, (2)
2-AcOCH2COCl, Et3N, CH2Cl2 (48%); (h) (1) K2S2O8, Na2HPO4, CH3CN, H2O, (2) Chiralcel OD (20%); (i) (1) BC13, CH2Cl2, (2) TIPSCl,
imidazole, DMF.

Y. Takeda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3209–3215
3211
O
O
O
O
O
O
a
b
Boc
Boc
NH
O
NH
O
O
HO
H
O
O
O
OAc
H
O
HO OBz
28
H
OAc
HO OBz
OAc
OTES
HO OBz
OH
29
30
R
O
O
c
Boc
31a (R = morpholino)
31b (R = dimethylamino)
NH
O
O
O
H
OAc
HO OBz
OH
Scheme 3. Reagents and conditions: (a) 13, LiHMDS, THF (86%); (b) TBAF, THF (96%); (c) (1) OsO4, NMO, THF, acetone, H2O, (2) NaIO4,
THF, MeOH, H2O, (3) amine, AcOH, NaBH3CN, EtOH(73% for 31a, 96% for 31b).
The synthesis of the taxane analogues possessing a tert-
butyl group at the C-13 side chain is depicted in Scheme
3. The coupling of 283 with the 3 equiv of the racemic b-
lactam 13 was carried out following a procedure similar
to that reported by Ojima et al.7 to afford the single
isomer 29 in good yield. Subsequent removal of the
protecting group at C-20 gave the compound 30. Oxi-
dation of 30 with OsO4 followed by cleavage with
NaIO4 gave the aldehyde, which was converted to the
desired compounds 31a and 31b by reductive amina-
tion.8
3. Results and discussion
Activities of the synthetic compounds were evaluated in
cytotoxicity assays against five cell lines (P388, PC-6,
PC-12, PC-6/VCR29-9, and PC-6/VP1-1), and activities
were compared with those of paclitaxel, docetaxel, and 3
(Table 1). Among the compounds having another amine
group than the morpholine of 3, the methylamino
derivative 8b exhibited significantly decreased cytotox-
icity against cancer cell lines expressing P-glycoprotein
(PC-12, PC-6/VCR29-9, and PC-6/VP1-1). It should be
noted that compounds in which the pyridine ring of 3
was replaced by a tert-butyl or other hetero ring groups
exhibited nearly the same cytotoxicity as 3 and good
metabolic stability. The cytotoxicity of the other three
compounds (8a,c,d) was slightly weaker than that of 3,
but stronger than those of paclitaxel and docetaxel.
The targeted compounds (34a–i) were synthesized
according to a procedure similar to that described for
the preparation of 31a utilizing 28 and the 1.2 equiv of
corresponding chiral b-lactams (18a,b, 23, 27) (Scheme
4).9
O
O
O
O
O
O
Boc
Boc
b
NH
O
NH
O
a
O
O
R1
O
OTIPS
R1
O
H
H
O
OAc
OAc
HO OBz
HO
HO OBz
H
OH
OAc
HO OBz
33a (R1 = 3-fluoro-2-pyridyl)
33b (R1 = 2-thiazolyl)
33c (R1 = 4-thiazolyl)
33d (R1 = 5-thiazolyl)
32a (R1 = 3-fluoro-2-pyridyl)
32b (R1 = 2-thiazolyl)
32c (R1 = 4-thiazolyl)
32d (R1 = 5-thiazolyl)
28
R2
34a (R1 = 3-fluoro-2-pyridyl, R2 = morpholino)
34b (R1 = 3-fluoro-2-pyridyl, R2 = dimethylamino)
34c (R1 = 2-thiazolyl, R2 = morpholino)
O
O
34d (R1 = 2-thiazolyl, R2 = dimethylamino)
34e (R1 = 2-thiazolyl, R2 = cyclopropylamino)
34f (R1 = 4-thiazolyl, R2 = morpholino)
Boc
c
NH
O
O
R1
O
34g (R1 = 4-thiazolyl, R2 = dimethylamino)
34h (R1 = 5-thiazolyl, R2 = morpholino)
34i (R1 = 5-thiazolyl, R2 = dimethylammino)
H
OAc
HO OBz
OH
Scheme 4. Reagents and conditions: (a) 18a, 18b, 23, or 27, LiHMDS, THF (97% for 32a, 77% for 32b, 57% for 32c, 84% for 32d); (b) TBAF, THF
(94% for 33a, 98% for 33b, 84% for 33c, 95% for 33d); (c) (1) OsO4, NMO, THF, acetone, H2O, (2) NaIO4, THF, MeOH, H2O, (3) amine, AcOH,
NaBH3CN, EtOH(78% for 34a, 78% for 34b, 70% for 34c, 64% for 34d, 69% for 34e, 57% for 34f, 88% for 34g, 54% for 34h, 51% for 34i).

3212
Y. Takeda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3209–3215
Table 1. Cytotoxicity and metabolic stability of 7-deoxy-9,10-O-acetal taxane analogues
Compd
Cytotoxicity GI50 (ng/mL)a
Remaining rate (%)b
P388
PC-6
PC-12
PC-6/VCR29-9
455
62.1
2.43
PC-6/VP1-1
1
2
3
2.93
0.78
0.18
1.27
0.26
0.26
539
1000
442
NT
19.1
0.13
88.7
60.2
19.3
8a
8b
0.41
0.60
0.17
0.56
0.34
0.73
0.20
0.67
0.06
0.25
0.06
0.03
0.06
0.04
0.07
0.38
0.54
0.54
0.83
0.70
0.67
0.29
0.38
0.12
0.27
0.42
0.65
0.35
0.07
0.30
0.74
5.82
0.30
1.45
0.13
0.50
0.14
0.62
0.13
0.35
0.12
0.08
0.19
0.12
0.17
4.04
43.2
54.2
265
84.8
NT
8c
8d
2.22
4.88
0.85
1.42
0.96
2.58
1.37
2.81
1.16
1.02
1.10
0.66
1.63
49.4
81.7
5.56
15.7
13.7
21.3
19.7
39.1
39.4
9.13
17.3
20.5
23.8
94.4
92.0
92.1
93.1
85.2
91.4
94.8
91.4
84.9
91.2
91.2
86.4
87.4
31a
31b
34a
34b
34c
34d
34e
34f
34g
34h
34i
NT: not tested.
a Concentration that inhibited the growth of cells by 50% at 72 h continuous exposure for the five cell lines [mouse leukemia (P388), human lung
cancer cell lines (PC-6 and PC-12), and resistant cancer cell lines (PC-6/VCR29-9 and PC-6/VP1-1)].11 Resistance factors (GI50 of the drug for the
selection for the resistance cell line/that for the parent cell line) of PC-6/VCR29-9 and PC-6/VP1-1 were 842 and 20, respectively.
b Remaining rate of the substrate after 5 min of incubation with human liver microsomes.
Comparing the cytotoxicity of 8c and 8d, 8d exhibited
weaker cytotoxicity against all cell lines than 8c. This
decrease in cytotoxicity might be due to a steric hin-
drance. As compared with the cytotoxicity of com-
pounds possessing the dimethylamino moiety on their
acetal moiety, the compounds possessing the morphol-
ine moiety on their acetal moiety showed slightly
stronger cytotoxicity.
35 (Fig. 1),3 whose C-13 side chain is the same as that of
docetaxel, got worse.10 These results clarify that the
substitution of the pyridine ring, which is considered
main metabolic position, with a suitable moiety such as
a tert-butyl or other hetero ring groups may contribute
to the improvement of metabolic stability. Interestingly,
the compounds in which the morpholine moiety of 3,
which was not the metabolic position, was replaced by
another amine group exhibited good metabolic stability.
Hence, it was elucidated that the modification of the
pyridine ring was not the only method to improve the
metabolic stability of 3.
The metabolic stability of all the synthetic compounds
except 8b was examined, and the results were shown as
the rate remaining after 5 min of incubation with human
liver microsomes. All compounds in which the pyridine
ring was replaced by a tert-butyl or other hetero ring
groups also exhibited good metabolic stability as we had
expected. On the other hand, the metabolic stability of
To evaluate the antitumor effects in vivo, we used B16
melanoma BL6 cells subcutaneously implanted into
mice, and the activities of all the synthetic compounds
R2O O
OH
O
O
N
7
R1 NH
O
O
13
O
O
O
H
OAc
HO OBz
OH
Boc
N
paclitaxel (1 : R1 = Ph, R2 = Ac)
NH
O
docetaxel (2 : R1 = tBuO, R2 = H)
O
O
H
OAc
HO OBz
OH
O
N
R
3 (R = H)
4 (R = OH)
5 (R = F)
O
O
6 (R = OMe)
Boc
NH
O
O
O
H
OAc
HO OBz
OH
35
Figure 1. Structures of taxane analogues.

Y. Takeda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3209–3215
Table 2. Antitumor activity against B16 melanoma BL6a
3213
except 8b,c and 34e,g,i were compared with those of
docetaxel and 3 when administered intravenously (iv)
and orally (po) (Table 2). Our synthetic compounds
exhibited potent antitumor effects by both iv and po
administration; however, the effective dose ranges of
some compounds, including 5 and 6, were narrow. They
showed potent antitumor activity at only one dosage by
oral administration; whereas the higher dosage resulted
in death and the lower dosage did not exhibit the high
antitumor effect. On the other hand, compounds 8a,
31a, and 34a,b,c exhibited potent antitumor effects over
a wide dosage range by both iv and po administration as
3. The detailed data of these six compounds (3, 8a, 31a,
and 34a,b,c) are shown in Table 3. Compounds 8a and
34a,b could be assumed to have good oral bioavaila-
bilities, because these compounds administered orally
gave nearly the same antitumor effects and body weight
losses as compared with those when they were admin-
istered intravenously. In contrast, docetaxel when
administered orally at a dose of 600 mg/kg exhibited no
antitumor effect and no body weight loss as a result of
its poor oral bioavailability.
Compd
Effective dose range (mg/kg)b
iv
po
3
12.0–27.0
7.9
13.3
5.3–18.0
3.5
5.9
5
6
8a
7.9–17.8
NTc
7.9–17.8
NTc
7.9
8c
8d
11.9–27.6
11.9–17.8
11.9
31a
31b
34a
34b
34c
34d
34e
34f
34g
34h
34i
7.8–11.9
11.9
11.9–17.8
7.9–11.0
11.9–26.7
11.9
11.9–17.8
5.3–11.9
7.9–17.8
7.8–17.8
NTc
NTc
7.9
3.5–5.3
NTc
7.9
NTc
None
NTc
NTc
a Cultured B16 melanoma BL6 was kindly provided by Dr. Tsuruo
(Institute of Molecular and Cellular Biosciences, University of
Tokyo) by courtesy of Dr. Fidler (The University of Texas M. D.
Andersen Cancer Center).12 B16 melanoma BL6 cells were subcuta-
neously inoculated into C57BL/6 mice (six mice per group) on day 0.
Compounds were administered intravenously or orally on day 4
(single administration). Tumor masses were weighed on day 15.
b Effective dose range means that the doses resulted in inhibition rate of
more than 58% without both body weight loss of less than 20% and
no death due to toxicity.
In summary, we designed and synthesized new taxane
analogues to improve the metabolic stability of 3, and it
was suggested that some compounds had nearly the
same biological properties as 3 and were scarcely
metabolized by human liver microsomes. We expect to
find an optimal compound to be selected for clinical
development among these compounds.
c NT: not tested. Compounds 8c and 34e could not be administered due
to their low solubility. Maximum tolerated dose (MTD) of 34g and
34i were significantly decreased in a preliminary test.
Table 3. Antitumor activity of selected five compounds against B16 melanoma BL6
Compd Route
Dose (mg/kg) IR (%)a BWLmax (%)b Mortality Route Dose (mg/kg) IR (%)a BWLmax (%)b
Mortality
0/6
2
3
po
po
600.0
6.2
<0
0/6
iv
iv
100.0
95.1
<0
27.0
18.0
12.0
8.0
97.3
93.3
84.9
27.2
4.5
0.3
<0
0/6
0/6
0/6
0/6
18.0
12.0
8.0
95.6
94.4
87.2
62.4
3.7
0/6
0/6
0/6
0/6
<0
<0
<0
<0
5.3
8a
po
po
po
po
po
26.7
17.8
11.9
7.9
97.5
97.0
88.8
72.8
13.1
8.8
<0
1/6
0/6
0/6
0/6
iv
iv
iv
iv
iv
26.7
17.8
11.9
7.9
––
––
6/6
0/6
0/6
0/6
97.7
95.0
82.3
8.6
1.0
<0
<0
31a
34a
34b
34c
26.7
17.8
11.9
7.9
––
––
6/6
0/6
0/6
0/6
17.8
11.9
7.8
––
––
6/6
0/6
0/6
0/6
90.3
63.4
25.5
11.7
0.4
<0
93.8
71.9
28.6
10.5
1.2
<0
5.3
26.7
17.8
11.9
7.9
97.4
88.5
16.6
2.2
1/6
0/6
0/6
0/6
26.7
17.8
11.9
7.9
––
––
6/6
0/6
0/6
0/6
94.7
85.7
28.6
11.9
<0
65.9
)16.3
<0
0.8
0.3
17.8
11.9
7.9
94.8
97.4
91.5
42.4
13.9
12.9
3.8
5/6
0/6
0/6
0/6
17.8
11.9
7.9
––
––
6/6
0/6
0/6
0/6
95.6
91.5
67.6
12.0
2.9
2.0
5.3
<0
5.3
40.0
26.7
17.8
11.9
––
––
6/6
0/6
0/6
0/6
26.7
17.8
11.9
7.9
98.3
96.9
85.7
79.1
15.0
7.1
2/6
0/6
0/6
0/6
97.8
97.0
77.9
10.0
8.8
<0
<0
1.5
a IR(%) ¼ (1 ) TWt/TWc)Â100. TWt: the mean tumor weight of the treated group. TWc: the mean tumor weight of the control group.
b BWLmax (%): Maximum rate of body weight loss (<0 indicates no body weight loss).

3214
Y. Takeda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3209–3215
pound 8d: mp 211–212 °C. 1HNMR (CDCl 3) d: 1.26 (3H,
Acknowledgements
s), 1.44 (9H, s), 1.47 (3H, s), 1.61 (3H, s), 1.72 (3H, s),
1.65–2.31 (13H, m), 2.35 (3H, s), 2.87 (2H, d, J ¼ 5:4 Hz),
2.94 (1H, d, J ¼ 5:4 Hz), 3.33–3.36 (1H, m), 4.15 (1H, d,
J ¼ 7:3 Hz), 4.22 (1H, d, J ¼ 8:3 Hz), 4.33 (1H, d,
J ¼ 8:3 Hz), 4.90–4.92 (2H, m), 4.95 (1H, t, J ¼ 4:9 Hz),
5.24 (1H, d, J ¼ 6:8 Hz), 5.35 (1H, d, J ¼ 7:9 Hz), 5.94–
6.00 (2H, m), 6.09 (1H, t, J ¼ 8:3 Hz), 7.22–7.25 (1H, m),
7.42 (1H, d, J ¼ 7:8 Hz), 7.47 (2H, t, J ¼ 7:8 Hz), 7.60
(1H, t, J ¼ 7:8 Hz), 7.72 (1H, t, J ¼ 7:8 Hz), 8.13 (2H, d,
J ¼ 7:8 Hz), 8.54 (1H, d, J ¼ 3:9 Hz); FAB-MS (m=z): 890
(M+H)þ. Anal. Calcd for C48H63N3O13Æ0.25H2O: C,
64.45; H, 7.15; N, 4.70. Found: C, 64.29; H, 7.15; N,
The authors are greatly indebted to Drs. T. Tsuruo,
Institute of Molecular and Cellular Biosciences, Uni-
versity of Tokyo and I. J. Fidler, the University of Texas
M. D. Anderson Cancer Center for their kind supply of
B16 melanoma BL6.
References and notes
1. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
MacPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325.
4.89; IR: 3264, 2983, 1735, 1698, 1596, 1529, 1479,
22
D
1446 cmÀ1; ½aꢀ )6.0 (c 0.27, CHCl3).
ꢀ
ꢀ
2. Gueritte-Voegelein, F.; Guenard, D.; Lavelle, F.; Le Goff,
M.-T.; Mangatal, L.; Potier, P. J. Med. Chem. 1991, 34,
992.
6. Li, L.; Thomas, S. A.; Klein, L. L.; Yeung, C. M.; Maring,
C. J.; Grampovnik, D. J.; Lartey, P. A.; Plattner, J. J. J.
Med. Chem. 1994, 37, 2655.
3. Takeda, Y.; Yoshino, T.; Uoto, K.; Chiba, J.; Ishiyama,
T.; Iwahana, M.; Jimbo, T.; Tanaka, N.; Terasawa, H.;
Soga, T. Bioorg. Med. Chem. Lett. 2003, 13, 185.
4. Takeda, Y.; Uoto, K.; Chiba, J.; Horiuchi, T.; Iwahana,
M.; Atsumi, R.; Ono, C.; Terasawa, H.; Soga, T. Bioorg.
Med. Chem. 2003, 11, 4431.
7. Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.;
Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985.
8. Spectral data of 31a and 31b are as follows. Compound
31a: mp 159–160 °C. 1HNMR (CDCl 3) d: 1.05 (9H, s),
1.25 (3H, s), 1.39 (9H, s), 1.49 (3H, s), 1.60 (3H, s), 1.79
(3H, s), 1.64–2.03 (5H, m), 2.31–2.38 (2H, m), 2.34 (3H, s),
2.59–2.68 (4H, m), 2.70–2.82 (2H, m), 2.92 (1H, d,
J ¼ 4:8 Hz), 3.74 (4H, t, J ¼ 4:9 Hz), 3.93 (1H, d,
J ¼ 10:3 Hz), 4.07 (1H, s), 4.13 (1H, d, J ¼ 6:8 Hz), 4.24
(1H, d, J ¼ 8:3 Hz), 4.33 (1H, d, J ¼ 8:3 Hz), 4.60 (1H, s),
4.93 (1H, s), 5.06 (1H, t, J ¼ 4:9 Hz), 5.10 (1H, d,
J ¼ 10:3 Hz), 5.24 (1H, d, J ¼ 6:3 Hz), 6.00 (1H, d,
J ¼ 4:8 Hz), 6.05 (1H, t, J ¼ 8:3 Hz), 7.48 (2H, t,
J ¼ 7:8 Hz), 7.61 (1H, t, J ¼ 7:8 Hz), 8.13 (2H, d,
J ¼ 7:8 Hz); FAB-MS (m=z): 885 (M+H)þ. Anal. Calcd
for C47H68N2O14ÆH2O: C, 62.51; H, 7.81; N, 3.10. Found:
5. Spectral data of 8a–d are as follows. Compound 8a: mp
1
148–149 °C. HNMR (CDCl ) d: 1.26 (3H, s), 1.44 (9H,
3
s), 1.48 (3H, s), 1.61 (3H, s), 1.72 (3H, s), 1.88–1.94 (3H,
m), 2.05–2.13 (2H, m), 2.32–2.39 (2H, m), 2.38 (6H, s),
2.38 (3H, s), 2.63–2.76 (2H, m), 2.93 (1H, d, J ¼ 4:4 Hz),
4.12 (1H, d, J ¼ 7:3 Hz), 4.22 (1H, d, J ¼ 8:3 Hz), 4.33
(1H, d, J ¼ 7:2 Hz), 4.90–4.92 (2H, m), 5.01 (1H, t,
J ¼ 5:4 Hz), 5.24 (1H, d, J ¼ 6:4 Hz), 5.36 (1H, d,
J ¼ 9:3 Hz), 5.94–5.99 (2H, m), 6.09 (1H, t, J ¼ 8:7 Hz),
7.23 (1H, dd, J ¼ 4:9, 7.3 Hz), 7.41 (1H, d, J ¼ 7:8 Hz),
7.47 (2H, t, J ¼ 7:8 Hz), 7.60 (1H, t, J ¼ 7:3 Hz), 7.72 (1H,
t, J ¼ 7:3 Hz), 8.12 (2H, d, J ¼ 7:8 Hz), 8.54 (1H, d,
J ¼ 4:9 Hz), FAB-MS (m=z): 864 (M+H)þ. Anal. Calcd
for C46H61N3O13Æ0.5H2O: C, 63.29; H, 7.16; N, 4.81.
C, 62.70; H, 7.73; N, 2.99; IR: 3450, 2956, 1712, 1602,
25
1492, 1452, 1367 cmÀ1; ½aꢀ )10.6 (c 0.39, CHCl3).
D
Compound 31b: mp 142–144 °C. 1HNMR (CDCl 3) d:
1.05 (9H, s), 1.25 (3H, s), 1.39 (9H, s), 1.49 (3H, s), 1.62
(3H, s), 1.80 (3H, s), 1.86–2.06 (5H, m), 2.30–2.38 (2H, m),
2.34 (3H, s), 2.38 (6H, s), 2.66 (1H, dd, J ¼ 5:4, 13.2 Hz),
2.75 (1H, dd, J ¼ 3:9, 13.2 Hz), 2.93 (1H, d, J ¼ 4:9 Hz),
3.93 (1H, d, J ¼ 10:8 Hz), 4.14 (1H, d, J ¼ 7:4 Hz), 4.25
(1H, d, J ¼ 8:3 Hz), 4.33 (1H, d, J ¼ 8:3 Hz), 4.60 (1H, s),
4.94 (1H, s), 5.04 (1H, t, J ¼ 4:9 Hz), 5.09 (1H, d,
J ¼ 10:8 Hz), 5.26 (1H, d, J ¼ 6:9 Hz), 6.00 (1H, d,
J ¼ 4:9 Hz), 6.05 (1H, t, J ¼ 7:8 Hz), 7.48 (2H, t,
J ¼ 7:8 Hz), 7.61 (1H, t, J ¼ 7:8 Hz), 8.13 (2H, d,
J ¼ 7:8 Hz); FAB-MS (m=z): 843 (M+H)þ. Anal.
Calcd for C45H66N2O13ÆH2O: C, 62.77; H, 7.96; N,
Found: C, 63.12; H, 7.06; N, 4.70; IR: 3450, 2946, 1722,
25
1712, 1592, 1506, 1469, 1452, 1438 cmÀ1; ½aꢀ )4.6 (c 0.5,
D
CHCl3). Compound 8b: mp 139–142 °C. 1HNMR
(CDCl3) d: 1.27 (3H, s), 1.44 (9H, s), 1.49 (3H, s), 1.61
(3H, s), 1.72 (3H, s), 1.84–2.13 (5H, m), 2.26–2.39 (2H, m),
2.35 (3H, s), 2.55 (3H, s), 2.94–2.95 (3H, m), 4.16 (1H, d,
J ¼ 7:3 Hz), 4.22 (1H, d, J ¼ 8:3 Hz), 4.33 (1H, d,
J ¼ 8:3 Hz), 4.90–4.92 (2H, m), 5.00 (1H, br s), 5.26
(1H, d, J ¼ 6:4 Hz), 5.36 (1H, d, J ¼ 8:3 Hz), 5.94–5.99
(2H, m), 6.09 (1H, t, J ¼ 8:3 Hz), 7.22–7.25 (1H, m), 7.42
(1H, d, J ¼ 7:8 Hz), 7.47 (2H, t, J ¼ 7:8 Hz), 7.60 (1H, t,
J ¼ 7:8 Hz), 7.72 (1H, t, J ¼ 7:8 Hz), 8.12 (2H, d,
J ¼ 7:8 Hz), 8.54 (1H, d, J ¼ 3:9 Hz); FAB-MS (m=z):
850 (M+H)þ; HR-MS Calcd for C45H60N3O13: 850.4126.
3.25. Found: C, 62.97; H, 7.94; N, 2.98; IR: 3450, 2954,
24
D
1712, 1602, 1492, 1452, 1367 cmÀ1; ½aꢀ )21.2 (c 0.2,
CHCl3).
9. Spectral data of 34a–i are as follows. Compound 34a: mp
Found, 850.4165; IR: 3423, 2931, 1712, 1592, 1492, 1434,
24
1
1367 cmÀ1; ½aꢀ )4.8 (c 0.1, CHCl3). Compound 8c: mp
166–167 °C. HNMR (CDCl ) d: 1.29 (3H, s), 1.40 (9H,
3
D
210–212 °C. 1HNMR (CDCl 3) d: 0.37–0.41 (2H, m), 0.44–
0.48 (2H, m), 1.26 (3H, s), 1.43 (9H, s), 1.49 (3H, s), 1.61
(3H, s), 1.72 (3H, s), 1.78–2.11 (6H, m), 2.25–2.34 (2H, m),
2.35 (3H, s), 2.93 (1H, d, J ¼ 4:9 Hz), 3.04 (2H, d,
J ¼ 4:9 Hz), 4.15 (1H, d, J ¼ 6:8 Hz), 4.22 (1H, d,
J ¼ 8:3 Hz), 4.32 (1H, d, J ¼ 8:8 Hz), 4.90–4.92 (2H, m),
4.97 (1H, t, J ¼ 4:9 Hz), 5.25 (1H, d, J ¼ 6:8 Hz), 5.35
(1H, d, J ¼ 9:3 Hz), 5.94–5.99 (2H, m), 6.09 (1H, t,
J ¼ 8:3 Hz), 7.22–7.25 (1H, m), 7.42 (1H, d, J ¼ 7:8 Hz),
7.47 (2H, t, J ¼ 7:8 Hz), 7.60 (1H, t, J ¼ 7:8 Hz), 7.72 (1H,
t, J ¼ 7:8 Hz), 8.12 (2H, d, J ¼ 7:8 Hz), 8.53 (1H, d,
J ¼ 4:4 Hz); FAB-MS (m=z): 876 (M+H)þ. Anal. Calcd
for C47H61N3O13Æ0.5H2O: C, 63.79; H, 7.06; N, 4.75.
s), 1.49 (3H, s), 1.61 (3H, s), 1.79 (3H, s), 1.70–2.03 (5H,
m), 2.30–2.44 (2H, m), 2.35 (3H, s), 2.61–2.65 (4H, m),
2.70–2.82 (2H, m), 2.94 (1H, d, J ¼ 4:8 Hz), 3.75 (4H, t,
J ¼ 4:9 Hz), 4.14 (1H, d, J ¼ 7:3 Hz), 4.23 (1H, d,
J ¼ 8:3 Hz), 4.33 (1H, d, J ¼ 7:8 Hz), 4.67 (1H, s), 4.92
(1H, s), 5.05 (1H, t, J ¼ 4:9 Hz), 5.25 (1H, d, J ¼ 7:3 Hz),
5.65 (1H, d, J ¼ 7:8 Hz), 5.99 (1H, d, J ¼ 5:4 Hz), 6.09
(1H, t, J ¼ 7:8 Hz), 6.20 (1H, d, J ¼ 8:3 Hz), 7.29–7.33
(1H, m), 7.43–7.49 (3H, m), 7.60 (1H, t, J ¼ 7:3 Hz), 8.13
(2H, d, J ¼ 7:3 Hz), 8.40 (1H, d, J ¼ 4:9 Hz); FAB-MS
(m=z):
924
(M+H)þ.
Anal.
Calcd
for
C48H62FN3O14Æ0.25H2O: C, 62.09; H, 6.78; N, 4.53; F,
2.05. Found: C, 62.09; H, 6.77; N, 4.61; F, 2.01; IR: 3565,
24
D
Found: C, 63.73; H, 7.01; N, 4.58; IR: 3542, 2973, 1724,
2950, 1722, 1693, 1600, 1500, 1448 cmÀ1; ½aꢀ )17.9 (c
22
D
1
1596, 1529, 1442 cmÀ1; ½aꢀ )8.2 (c 0.34, CHCl3). Com-
0.45, CHCl3). Compound 34b: mp 147–149 °C. HNMR

Y. Takeda et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3209–3215
3215
(CDCl3) d: 1.29 (3H, s), 1.41 (9H, s), 1.49 (3H, s), 1.63
(3H, s), 1.79 (3H, s), 1.86–2.08 (5H, m), 2.32–2.38 (2H, m),
2.34 (3H, s), 2.38 (6H, s), 2.66 (1H, dd, J ¼ 5:4, 13.6 Hz),
2.75 (1H, dd, J ¼ 3:9, 13.6 Hz), 2.94 (1H, d, J ¼ 4:9 Hz),
4.14 (1H, d, J ¼ 6:9 Hz), 4.23 (1H, d, J ¼ 8:3 Hz), 4.33
(1H, d, J ¼ 8:3 Hz), 4.68 (1H, d, J ¼ 2:9 Hz), 4.92 (1H, s),
5.02 (1H, t, J ¼ 4:9 Hz), 5.25 (1H, d, J ¼ 6:8 Hz), 5.65
(1H, d, J ¼ 8:3 Hz), 6.00 (1H, d, J ¼ 4:9 Hz), 6.09 (1H, t,
J ¼ 7:8 Hz), 6.21 (1H, d, J ¼ 8:3 Hz), 7.28–7.33 (1H, m),
7.43–7.49 (3H, m), 7.60 (1H, t, J ¼ 7:3 Hz), 8.14 (2H, d,
J ¼ 7:3 Hz), 8.40 (1H, d, J ¼ 4:4 Hz); FAB-MS (m=z): 882
(M+H)þ. Anal. Calcd for C46H60FN3O13Æ1.5H2O: C,
60.78; H, 6.99; N, 4.62; F, 2.09. Found: C, 60.86; H,
J ¼ 7:3 Hz), 4.22 (1H, d, J ¼ 8:8 Hz), 4.32 (1H, d,
J ¼ 8:3 Hz), 4.56 (1H, br s), 4.92 (1H, s), 4.93 (1H, d,
J ¼ 2:4 Hz), 5.04 (1H, t, J ¼ 4:9 Hz), 5.23 (1H, d,
J ¼ 6:8 Hz), 5.49 (1H, d, J ¼ 9:2 Hz), 5.75 (1H, d,
J ¼ 9:8 Hz), 5.99 (1H, d, J ¼ 4:9 Hz), 6.10 (1H, t,
J ¼ 7:8 Hz), 7.32 (1H, s), 7.47 (2H, t, J ¼ 7:8 Hz), 7.60
(1H, t, J ¼ 7:8 Hz), 8.12 (2H, d, J ¼ 7:8 Hz), 8.80 (1H, d,
J ¼ 1:9 Hz); FAB-MS (m=z): 912 (M+H)þ. Anal. Calcd
for C46H61N3O14Sꢁ0.5H2O: C, 59.98; H, 6.78; N, 4.56; S,
3.48. Found: C, 60.04; H, 6.58; N, 4.56; S, 3.60; IR: 3559,
24
2948, 1720, 1697, 1687, 1600, 1500, 1452 cmÀ1; ½aꢀ )5.2 (c
D
1
0.42, CHCl3). Compound 34g: mp 141–144 °C. HNMR
(CDCl3) d: 1.26 (3H, s), 1.43 (9H, s), 1.48 (3H, s), 1.62
(3H, s), 1.72 (3H, s), 1.82–2.12 (6H, m), 2.34–2.38 (1H, m),
2.34 (3H, s), 2.38 (6H, s), 2.66 (1H, dd, J ¼ 4:9, 13.2 Hz),
2.75 (1H, dd, J ¼ 3:9, 13.2 Hz), 2.93 (1H, d, J ¼ 4:9 Hz),
4.12 (1H, d, J ¼ 6:9 Hz), 4.22 (1H, d, J ¼ 8:3 Hz), 4.32
(1H, d, J ¼ 8:3 Hz), 4.92 (1H, s), 4.93 (1H, d, J ¼ 1:9 Hz),
5.02 (1H, t, J ¼ 4:9 Hz), 5.24 (1H, d, J ¼ 6:8 Hz), 5.49
(1H, d, J ¼ 9:2 Hz), 5.75 (1H, d, J ¼ 9:8 Hz), 5.99 (1H, d,
J ¼ 4:9 Hz), 6.10 (1H, t, J ¼ 8:3 Hz), 7.31 (1H, d,
J ¼ 1:4 Hz), 7.47 (2H, t, J ¼ 7:8 Hz), 7.60 (1H, t,
J ¼ 7:8 Hz), 8.13 (2H, d, J ¼ 7:8 Hz), 8.80 (1H, d,
J ¼ 1:4 Hz); FAB-MS (m=z): 870 (M+H)þ. Anal. Calcd
for C44H59N3O13Sꢁ0.75H2O: C, 59.81; H, 6.90; N, 4.76; S,
6.94; N, 4.54; F, 2.17; IR: 3575, 2946, 1722, 1702, 1602,
22
1492, 1446 cmÀ1; ½aꢀ )18.9 (c 1.0, CHCl3). Compound
D
34c: mp 152–156 °C. 1HNMR (CDCl 3) d: 1.25 (3H, s),
1.21–1.73 (2H, m), 1.45 (9H, s), 1.48 (3H, s), 1.60 (3H, s),
1.73 (3H, s), 1.78–2.11 (3H, m), 2.34 (3H, s), 2.31–2.37
(2H, m), 2.57–2.68 (4H, m), 2.70–2.82 (2H, m), 2.93 (1H,
d, J ¼ 4:9 Hz), 3.74 (4H, t, J ¼ 4:9 Hz), 4.12 (1H, d,
J ¼ 6:8 Hz), 4.22 (1H, d, J ¼ 8:3 Hz), 4.32 (1H, d,
J ¼ 7:8 Hz), 4.92 (1H, br s), 5.00 (1H, d, J ¼ 2:0 Hz),
5.04 (1H, t, J ¼ 4:4 Hz), 5.23 (1H, d, J ¼ 6:8 Hz), 5.60
(1H, d, J ¼ 9:3 Hz), 5.92 (1H, d, J ¼ 9:3 Hz), 5.99 (1H, d,
J ¼ 4:9 Hz), 6.12 (1H, t, J ¼ 7:8 Hz), 7.31 (1H, d,
J ¼ 3:4 Hz), 7.47 (2H, t, J ¼ 7:8 Hz), 7.60 (1H, t,
J ¼ 7:8 Hz), 7.76 (1H, d, J ¼ 3:4 Hz), 8.12 (2H, d,
J ¼ 7:8 Hz); FAB-MS (m=z): 912 (M+H)þ. Anal. Cacld
for C46H61N3O13ÆH2O: C, 59.40; H, 6.83; N, 4.52; S, 3.45.
3.63. Found: C, 59.84; H, 6.75; N, 4.48; S, 3.56; IR: 3423,
24
2948, 1712, 1602, 1492, 1452, 1367 cmÀ1; ½aꢀ )16.3 (c
D
1
0.15, CHCl3). Compound 34h: mp 152–155 °C. HNMR
(CDCl3) d: 1.23 (3H, s), 1.19–1.72 (2H, m), 1.42 (9H, s),
1.47 (3H, s), 1.60 (3H, s), 1.63 (3H, s), 1.75–2.06 (3H, m),
2.31 (3H, s), 2.32–2.38 (2H, m), 2.57–2.68 (4H, m), 2.70–
2.82 (2H, m), 2.91 (1H, d, J ¼ 4:9 Hz), 3.74 (4H, t,
J ¼ 4:9 Hz), 4.09 (1H, d, J ¼ 6:8 Hz), 4.24 (1H, d,
J ¼ 8:4 Hz), 4.33 (1H, d, J ¼ 8:4 Hz), 4.60 (1H, br s),
4.94 (1H, br s), 5.04 (1H, t, J ¼ 4:9 Hz), 5.22 (1H, d,
J ¼ 6:9 Hz), 5.62–5.68 (2H, m), 6.00 (1H, d, J ¼ 4:9 Hz),
6.10 (1H, t, J ¼ 7:8 Hz), 7.48 (2H, t, J ¼ 7:8 Hz), 7.59 (1H,
t, J ¼ 7:8 Hz), 7.92 (1H, s), 8.12 (2H, d, J ¼ 7:8 Hz), 8.75
(1H, s); FAB-MS (m=z): 912 (M+H)þ. Anal. Calcd for
C46H61N3O14Sꢁ1.25H2O: C, 59.12; H, 6.85; N, 4.50; S,
Found: C, 59.53; H, 6.82; N, 4.23; S, 3.51; IR: 3438, 2956,
25
1718, 1602 cmÀ1; ½aꢀ )9.0 (c 0.25, CHCl3). Compound
D
34d: mp 151–154 °C. 1HNMR (CDCl 3) d: 1.25 (3H, s),
1.21–1.75 (2H, m), 1.45 (9H, s), 1.48 (3H, s), 1.61 (3H, s),
1.74 (3H, s), 1.75–2.08 (3H, m), 2.32–2.39 (2H, m), 2.34
(3H, s), 2.38 (6H, s), 2.66 (1H, dd, J ¼ 5:4, 13.6 Hz), 2.75
(1H, dd, J ¼ 3:9, 13.6 Hz), 2.93 (1H, d, J ¼ 4:9 Hz), 4.12
(1H, d, J ¼ 6:8 Hz), 4.22 (1H, d, J ¼ 8:3 Hz), 4.32 (1H, d,
J ¼ 8:3 Hz), 4.92 (1H, s), 4.99–5.03 (2H, m), 5.24 (1H, d,
J ¼ 6:8 Hz), 5.60 (1H, d, J ¼ 9:3 Hz), 5.92 (1H, d,
J ¼ 9:3 Hz), 5.99 (1H, d, J ¼ 4:9 Hz), 6.13 (1H, t,
J ¼ 7:8 Hz), 7.31 (1H, d, J ¼ 2:9 Hz), 7.47 (2H, t,
J ¼ 7:8 Hz), 7.60 (1H, t, J ¼ 7:8 Hz), 7.76 (1H, d,
J ¼ 2:9 Hz), 8.12 (2H, d, J ¼ 7:8 Hz); FAB-MS (m=z):
870 (M+H)þ. Anal. Calcd for C44H59N3O13SꢁH2O: C,
59.51; H, 6.92; N, 4.73; S, 3.61. Found: C, 59.56; H, 6.71;
3.43. Found: C, 59.16; H, 6.58; N, 4.51; S, 3.47; IR: 3423,
24
2956, 1712, 1600, 1490, 1452, 1367 cmÀ1; ½aꢀ )3.4 (c 0.1,
D
CHCl3). Compound 34i: mp 153–157 °C. 1HNMR
(CDCl3) d: 1.23 (3H, s), 1.20–1.69 (2H, m), 1.42 (9H, s),
1.47 (3H, s), 1.61 (3H, s), 1.65 (3H, s), 1.75–2.05 (3H, m),
2.30–2.39 (2H, m), 2.31 (3H, s), 2.38 (6H, s), 2.66 (1H, dd,
J ¼ 4:9, 13.5 Hz), 2.75 (1H, dd, J ¼ 3:9, 13.5 Hz), 2.91
(1H, d, J ¼ 4:9 Hz), 4.10 (1H, d, J ¼ 6:8 Hz), 4.24 (1H, d,
J ¼ 8:3 Hz), 4.33 (1H, d, J ¼ 8:3 Hz), 4.60 (1H, br s), 4.94
(1H, br s), 5.02 (1H, t, J ¼ 4:4 Hz), 5.23 (1H, d,
J ¼ 6:8 Hz), 5.62–5.71 (2H, m), 6.01 (1H, d, J ¼ 4:9 Hz),
6.10 (1H, t, J ¼ 7:8 Hz), 7.48 (2H, t, J ¼ 7:8 Hz), 7.61 (1H,
t, J ¼ 7:8 Hz), 7.92 (1H, s), 8.12 (2H, d, J ¼ 7:8 Hz), 8.75
(1H, s); FAB-MS (m=z): 870 (M+H)þ. Anal. Calcd for
C44H59N3O13SꢁH2O: C, 59.51; H, 6.92; N, 4.73; S, 3.61.
N, 4.76; S, 3.60; IR: 3409, 2948, 1712, 1602, 1490, 1452,
24
D
1367 cmÀ1; ½aꢀ )13.8 (c 0.2, CHCl3). Compound 34e: mp
1
209–210 °C. HNMR (CDCl ) d: 0.37–0.51 (4H, m), 1.25
3
(3H, s), 1.45 (9H, s), 1.49 (3H, s), 1.61 (3H, s), 1.74 (3H, s),
1.82–2.12 (6H, m), 2.25–2.29 (1H, m), 2.33–2.37 (1H, m),
2.35 (3H, s), 2.94 (1H, d, J ¼ 5:4 Hz), 3.04 (2H, d,
J ¼ 4:9 Hz), 4.15 (1H, d, J ¼ 7:3 Hz), 4.23 (1H, d,
J ¼ 8:3 Hz), 4.33 (1H, d, J ¼ 8:3 Hz), 4.92 (1H, br s),
4.97–5.00 (2H, m), 5.26 (1H, d, J ¼ 7:3 Hz), 5.59 (1H, d,
J ¼ 9:8 Hz), 5.93 (1H, d, J ¼ 9:8 Hz), 6.00 (1H, d,
J ¼ 4:9 Hz), 6.13 (1H, t, J ¼ 8:3 Hz), 7.31 (1H, d,
J ¼ 2:9 Hz), 7.47 (2H, t, J ¼ 7:8 Hz), 7.60 (1H, t,
J ¼ 7:8 Hz), 7.76 (1H, d, J ¼ 2:9 Hz), 8.12 (2H, d,
J ¼ 7:8 Hz); FAB-MS (m=z): 882 (M+H)þ. Anal. Calcd
for C45H59N3O13Sꢁ0.5H2O: C, 60.66; H, 6.79; N, 4.72; S,
Found: C, 59.37; H, 6.67; N, 4.77; S, 3.57; IR: 3430, 2948,
24
1710, 1600, 1490, 1452, 1367 cmÀ1; ½aꢀ )18.7 (c 0.2,
D
CHCl3).
10. The condition of the metabolic stability test of 35 differed
from those of the other compounds. Under this condition,
the remaining rates of 35 and 3 after 5 min of incubation
with human liver microsomes were about 66% and 84%,
respectively.
11. PC-6/VCR29-9: PC-6 cell line, which is resistant to
Vincristineâ. PC-6/VP1-1: PC-6 cell line, which is resistant
to VP-16 (Etoposideâ).
3.60. Found: C, 60.61; H, 6.59; N, 4.74; S, 3.59; IR: 3490,
24
2967, 1741, 1706, 1602, 1531, 1454, 1369 cmÀ1; ½aꢀ )12.4
D
(c 0.21, CHCl3). Compound 34f: mp 159–160 °C. 1H
NMR (CDCl3) d: 1.26 (3H, s), 1.43 (9H, s), 1.48 (3H, s),
1.60 (3H, s), 1.71 (3H, s), 1.82–2.12 (6H, m), 2.31–2.39
(1H, m), 2.35 (3H, s), 2.59–2.67 (4H, m), 2.72 (1H, dd,
J ¼ 4:9, 13.2 Hz), 2.80 (1H, dd, J ¼ 3:9, 13.2 Hz), 2.92
(1H, d, J ¼ 4:9 Hz), 3.74 (4H, t, J ¼ 4:9 Hz), 4.12 (1H, d,
12. Poste, G.; Doll, J.; Hart, I. R.; Fidler, I. J. Cancer Res.
1980, 40, 1636.