Synthesis and cytotoxicity of novel 20-O-linked homocamptothecin ester derivatives as potent topoisomerase I inhibitors

Article abstract of DOI:10.1080/10286020.2013.855203

In an attempt to improve the antitumor activity of homocamptothecins (hCPTs), a series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized based on a synthetic route, by which hCPTs are acylated with different substituted pheno

Full text of DOI:10.1080/10286020.2013.855203

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Synthesis and cytotoxicity of novel
20-O-linked homocamptothecin ester
derivatives as potent topoisomerase I
inhibitors
Di-Zao Liab, Cun-Ying Wangc, Rui-Hua Liua, Yan-Ming Wanga, Teng-
Fei Jib, Yu-Rong Lid & Xian-Dao Panbd
a College of Pharmacy, State Key Laboratory of Medicinal
Chemical Biology, State Key Laboratory of Elemento-Organic
Chemistry and Tianjin Key Laboratory of Molecular Drug Research,
Nankai University, Tianjin, 300071, China
b State Key Laboratory of Bioactive Substance and Function of
Natural Medicines, Institute of Materia Medica, Chinese Academy
of Medical Sciences and Peking Union Medical College, Beijing,
100050, China
c Xuzhou College of Industrial Technology, Xuzhou, 221000, China
d Beijing Union Pharmaceutical Factory, Beijing, 100050, China
Published online: 11 Nov 2013.
To cite this article: Di-Zao Li, Cun-Ying Wang, Rui-Hua Liu, Yan-Ming Wang, Teng-Fei Ji, Yu-Rong
Li & Xian-Dao Pan (2013) Synthesis and cytotoxicity of novel 20-O-linked homocamptothecin ester
derivatives as potent topoisomerase I inhibitors, Journal of Asian Natural Products Research, 15:11,
1179-1188, DOI: 10.1080/10286020.2013.855203
To link to this article: http://dx.doi.org/10.1080/10286020.2013.855203
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Journal of Asian Natural Products Research, 2013
Vol. 15, No. 11, 1179–1188, http://dx.doi.org/10.1080/10286020.2013.855203
Synthesis and cytotoxicity of novel 20-O-linked homocamptothecin
ester derivatives as potent topoisomerase I inhibitors
Di-Zao Liab, Cun-Ying Wangc, Rui-Hua Liua, Yan-Ming Wanga, Teng-Fei Jib*,
Yu-Rong Lid and Xian-Dao Panbd*
aCollege of Pharmacy, State Key Laboratory of Medicinal Chemical Biology, State Key Laboratory
of Elemento-Organic Chemistry and Tianjin Key Laboratory of Molecular Drug Research, Nankai
University, Tianjin 300071, China; State Key Laboratory of Bioactive Substance and Function of
b
Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing 100050, China; cXuzhou College of Industrial Technology, Xuzhou
221000, China; dBeijing Union Pharmaceutical Factory, Beijing 100050, China
(Received 29 August 2013; final version received 10 October 2013)
In an attempt to improve the antitumor activity of homocamptothecins (hCPTs), a
series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized
based on a synthetic route, by which hCPTs are acylated with different substituted
phenoxyacetic acid ester derivatives. Most of the derivatives were assayed for in vitro
cytotoxicity against six human cancer cell lines KB, KB/VCR, A549, HCT-8, Bel7402,
and A2780, and most of the assayed compounds exhibited good antiproliferative
activity on these tumor cell lines especially on KB.
Keywords: 20-O-linked homocamptothecin ester; synthesis; cytotoxicity
1. Introduction
subject of ongoing clinical or preclinical
evaluation (Figure 1) [4,5].
(20S)-Camptothecin (CPT), a cytotoxic
quinoline alkaloid with topoisomerase I
(Topo I) inhibitory, is a potent anticancer
agent that was isolated from the Chinese
tree Camptotheca acumunata and its struc-
ture was confirmed by Wani and Wall [1]. It
has already been discovered that the
cytotoxicity of camptothecin is due to a
novel mechanism of action involving
selective inhibition of DNA Topo I [2,3].
As a consequence of its broad-spectrum
antitumour activity and particular cytotoxic
mechanism, there has been a substantial
effort toward the development of clinical
CPT analogs. Two of its water-soluble ana-
logs, topotecanandirinotecan(Figure 1),are
used in clinics as anticancer agents and are
now even being marketed in several coun-
tries, while several other analogs are the
However, the severe toxicities, such as
myelosuppression, nausea, vomiting, gas-
trointestinal disorders, and stomatitis [6,7]
as well as the instability of lactone and
other defects of CPTs [7], have promoted
intensive efforts to reduce their toxicity in
patients, increase the efficacy of these
agents, and overcome the tumor drug
resistance for this class of compounds. The
most important discovery would be to
modify the metabolically liable camp-
tothecin lactone ring from a six-membered
a-hydroxylactone ring to a seven-mem-
bered b-hydroxylactone ring, which leads
to the development of the homocamp-
tothecin (hCPT) family of compounds [8].
The hCPT is a semisynthetic analog
of camptothecin with a seven-membered
*Corresponding authors. Email: jitf@imm.ac.cn; xdp@imm.ac.cn
q 2013 Taylor & Francis

1180
D.-Z. Li et al.
N
N
9
7
5
8
6
2
HO
4
N
O
O
N
10
11
N
O
C
3
A
B
O
16
17
N
D
13
N
1
N
O
12
E
20
N
O
14
O
15
19
O
Topotecan
18
CPT
Irinotecan
OH
O
OH
O
OH
O
Figure 1. Structures of camptothecin and its representative analogs.
b-hydroxylactone ring resulting from the
insertion of a methylene (ZCH2Z) spacer
between the alcohol moiety and the
carboxyl group of the classical six-
membered a-hydroxylactone ring of
CPT. The hCPT represents a promising
prototype for the next generation of Topo
I-targeting agents.
closed lactone form and the open carbox-
ylate form which is pH and also species
dependent (Figure 3). Particularly, human
serum albumin preferentially binds to the
carboxylate form of camptothecin deriva-
tives and shifts the equilibrium in favor of
the carboxylate [17]. Some 20-O-alkyl
esters [18] and amino acid esters of CPT
[19] have been prepared to improve
lactone ring stability and water solubility
of CPT.
Upgrading the highly reactive six-
membered lactone to a more stable
seven-membered ring is achieved without
compromising the antitumor activity of
hCPT, which not only retains superior
antitumor activity, but also enhances the
plasma stability of the drug and reinforces
its capacity to inhibit Topo I compared
with CPT [9]. Based on these encouraging
results, many hCPT analogs have been
synthesized and evaluated in vitro and
in vivo as antitumor agents [10–13].
Among them, diflomotecan (BN80915)
and elomotecan (BN80927) (Figure 2) are
the representative ones and have been in
clinical trials with encouraging results
being obtained [14–16].
2. Results and discussion
In previous studies, we prepared many
CPT oxyalkanoic acids [20] and substi-
tuted phenoxyacetic acid and phenoxybu-
tyl acid ester derivatives [21]. These
derivatives of hydroxyl group esterifica-
tion of 20th positions were not only found
to have better anticancer activities than
that of irinotecan in vitro and in vivo, but
also found to have much lower toxicities
than that of CPT in vivo. Here, we report
on the synthesis and the in vitro antitumor
evaluation of CPTs and substituted phe-
noxyacetic acid ester derivatives of
hCPTs, and several compounds that
For CPT derivatives, a major issue is
the opening of the lactone E-ring and the
formation of an equilibrium between the
N
Me
Cl
.HCl
O
O
F
F
O
N
N
N
N
N
N
O
O
O
O
hCPT
BN80927
O
Diflomotecan
O
OH
OH
OH
Figure 2. Structures of hCPT and its representative analogs.

Journal of Asian Natural Products Research
1181
O
O
N
N
N
N
OH
O
Na+
O
O
OH
OH
O
Figure 3. Structures of camptothecin (1a) and its water-soluble sodium salt.
showed superior activity would be chosen
to conduct further studies.
clinically effective CPT analog. CPT
possesses the best antitumor activity
in vitro in nanomolar concentration while
topotecan and hCPT have poorer cytotoxic
activity as compared with CPT. Most of
these synthesized ester compounds
(Table 1) showed good antiproliferative
activity on these tumor cell lines, and
several compounds showed comparable or
superior cytotoxic activity to topotecan.
The data in Table 1 exhibited the
cytotoxicity of ester dependent on that of
its parent compound. All of these assayed
camptothecin esters possessed the lowest
antitumor activity on vincristine-resistant
KB (KB/VCR) and the highest antitumor
activity on KB among these six human
cancer cell lines. Esters 6, 10, 11, 17, 18,
and 22 had cytotoxities that were higher
than toptecan (TPT) and hCPT and
comparable with CPT on KB, HCT-8,
Bel7402, and A2780. Ester 6 also pos-
sessed cytotoxity activity comparable with
CPT on A549. In addition, compounds 12
and 13 showed comparable or a little
Preparation (Scheme 1) and purifi-
cation of hCPTs 5 starting from CPT were
done according to the previously published
procedures [10,22]. hCPT ester derivatives
6–23 were prepared in proper yields by
the straightforward acylation of hCPTs
with the corresponding substituted phe-
noxyacetic acid and phenoxybutyl acid in
the presence of a coupling agent 1-[3-
(dimethylamino)propyl]-3-ethylcarbodii-
mide hydrochloride (EDCI) and a catalyst
4-(N,N-dimethylamino)pyridine
(4-
DMAP) at room temperature (Scheme 2).
Cytotoxicities of these hCPT ester
derivatives were evaluated on six human
cancer cell lines (KB, KB/VCR, A549,
HCT-8, Bel7402, and A2780) by using
3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide (MTT) assay
according to the previous method [23].
CPT, hCPT, and topotecan were used as
reference compounds. Topotecan was used
as a reference compound because it is a
O
O
O
(ii)
N
N
(i)
N
N
N
O
N
O
O
O
H
O
2
3
1
OH
O
OH
(iv)
OH
O
O
(iii)
N
N
OH
O
N
N
O
O
4
5
OH
OH
O
Scheme 1. Reagents and conditions: (i) NaBH4/CH3OH, r.t.; (ii) NaIO4, r.t.; (iii) Zn/Me3ClSi/
BrCH2COOCMe3/N2, reflux; (iv) CF3COOH.

1182
D.-Z. Li et al.
F
F
Cl
F
CH2O
CH2
CH2
O
O
12: R =
13: R =
19: R =
20: R =
CH2
O
6: R =
F
NO2
O
O
(v)
N
F
N
F
O
O
N
CH2O
N
Cl
7: R = CH2
S
O
O
CF3
O
CH2
CH2
O
O
14: R =
15: R =
16: R =
21: R = CH2O
CF3
Cl
O
O
8: R = CH2
O
O
O
5
OH
6 ~ 23
CH2O
22: R =
CH2
9: R =
R
(CH2)4O
F
CH2O
CN
23: R =
Br
Br
F
Br
F
CH2O
Cl
17: R =
18: R =
CH2
O
O
10: R =
F
F
CF3
CH2
O
CH2
11: R =
NO2
Br
CF3
Scheme 2. Reagents and conditions: (v) R0COOH/EDCI/DMAP/CH2Cl2, r.t.
superior cytotoxities to TPT and hCPT on
KB, A549, Bel7402, and A2780 with the
same results for 19 and 20 on KB and Bel
7402 and for 14 and 15 on Bel 7402.
Further investigations of the above esters
with good cytotoxities would be carried
out in the next step.
pronounced chemical consequences. One
effect is due to the removal of the elec-
tronic induction of the hydroxyl oxygen
atom on the carbonyl group, which results
in a lower reactivity of the carboxyl
function toward nucleophiles such as
water, alcohols, or amines. The second
effect stems from the thermodynamically
disfavored closure of a seven-membered
ring in comparison with a six-membered
The insertion of a methylene spacer
(ZCH2Z) between the alcohol moiety and
the carbonyl group of CPT lactone has two
Table 1. Cytotoxicities of 20(S)-O-linked hCPT ester derivatives against six human tumor cell
lines.
In vitro cytotoxicity (IC50, mmol l21
)
Compound
KB
KB/VCR
A549
HCT-8
Bel7402
A2780
CPT
Topotecan
hCPT
6
7
8
0.004
0.010
0.76
0.216
1.000
0.36
.1
.1
0.010
0.097
1.25
0.004
0.028
4.37
0.007
0.092
0.37
0.007
0.049
0.28
0.004
0. 051
0.029
0.059
0.005
0.005
0.010
0.008
0.027
0.051
0.410
0.005
0.006
0.008
0.007
0.056
0.006
0.009
1.000
0.093
0.776
0.082
0.100
0.086
0.097
0.100
0.510
1.000
0.170
0.279
0.206
0.484
.1
0.007
0.076
0.076
0.083
0.008
0.007
0.051
0.033
0.068
0.085
0.758
0.008
0.010
0.057
0.035
0.077
0.009
0.008
0.093
0.080
0.212
0.009
0.009
0.073
0.074
0.074
0.085
0.654
0.008
0.032
0.060
0.050
0.190
0.010
0.006
0.083
0.063
0.197
0.008
0.007
0.058
0.050
0.069
0.078
0.694
0.007
0.035
0.059
0.050
0.083
0.024
.1
9
0.900
0.846
0.476
0.697
0.548
0.846
.1
10
11
12
13
14
15
16
17
18
19
20
21
22
.1
0.641
0.401
.1
0.700
.1
0.326
0.280
Note: KB, human epidermoid carcinoma of the nasopharynx; KB/VCR, vincristine-resistant KB; A549, human
lung cancer; HCT-8, human colon cancer; Bel7402, human liver cancer; A2780, human ovarian cancer.

Journal of Asian Natural Products Research
ring [24]. Here, the esterification of 20-OH 3. Experimental
1183
of hCPT could strengthen these two
notable chemical effects and further
prohibit the seven-membered ring from
opening under the physiological conditions.
Taken together, these effects afford a
mechanistic explanation for the slow and
irreversible hydrolytic ring opening of
hCPT, in contrast to the rapid hydrolysis of
CPT to a pH-dependent equilibrium that
hinders the antitumor activity of CPT.
3.1 General experimental procedures
Melting points were determined on
an XT4-100X micro-melting apparatus
produced by Ningbo Biocotek Scientific
Instrument Co., Ltd (Ningbo, China) and
are uncorrected. The NMR spectra were
recorded on a Varian Mercury-300 spec-
1
trometer (300 MHz for H) produced by
Varian Medical Systems (Salt Lake City,
UT, USA). The mass spectra were
obtained on a Finnigan LTQ FTMS (ESI)
spectrometer produced by Thermo Elec-
tron Corporation (Waltham, MA, USA).
In conclusion, we synthesized a series
of 20-O-linked substituted phenoxyacetic
acid ester derivatives of hCPT by acylating
hCPT based on the expansion of the six-
membered lactone ring of CPT to a seven-
membered lactone ring and carried out the
in vitro antitumor evaluation of the most
esters by using MTT method. The above
preliminary biological results indicated
that the introduction of 20-O-phenoxyace-
tic acid esters of hCPT should lead CPT to
increase the anticancer activity. The
results provided further evidence for the
previous induction [24] that the highly
reactive a-hydroxylactone ring of CPT is
not an absolute requirement for good Topo
I-mediated activity, but homologation of
the E-ring followed with esterification
gives a more potent Topo I poison than
TPT, an outstanding representative of
CPTs, and exhibits high in vitro cytotoxi-
cities. This novel E-ring modification also
provides several more stable compounds
that hydrolyze more slowly than the
classical a-hydroxylactone of CPT.
Although a potential ring-opening reaction
with covalent binding to the enzyme is still
possible, the lower reactivity of hCPT
20-O-ester derivatives may have some
mechanistic implications. Furthermore,
this kind of modification should influence
the pharmacokinetics and pharmacody-
namics of the drugs, and it would represent
a promising template for the preparation of
improved anticancer agents.
3.2 General procedures for compounds
2–5
hCPTs 2–5 were prepared (Scheme 1)
according to the method reported by
Lavergne et al. [10].
3.2.1 Compound 2
Pale yellow solid (89.5%); m.p. 281–2838C
[lit. [24]: m.p. 280–2838C (dec.)], 1H NMR
(300MHz, DMSO-d6, d ppm): 8.64 (s, 1H,
Ar-H), 8.13 (q, 2H, J ¼ 7.5 Hz, Ar-H), 7.84
(t, 1H, J ¼ 7.5 Hz, Ar-H), 7.68 (t, 1H,
J ¼ 7.5 Hz, Ar-H), 7.36 (s, 1H, Ar-H), 5.23
(s, 2H, 17-H), 4.99 (s, 1H, 21-H), 4.58
(q, 2H, J ¼ 18.6Hz, 5-H), 1.69 (q, 2H,
J ¼ 7.5 Hz, 19-CH2), 0.90 (3H, t, J ¼
10.5Hz, 18-CH3).
3.2.2 Compound 3
Pale yellow solid (87.7%); m.p. 192–
1938C [lit. [24]: m.p. 192–1948C (dec.)];
1H NMR (300 MHz, CDCl3, d ppm): 8.42
(s, 1H, Ar-H), 8.22 (d, 1H, J ¼ 8.1 Hz, Ar-
H), 8.09 (s, 1H, HCOO), 7.97 (d, 1H,
J ¼ 8.1 Hz, Ar-H), 7.85 (t, 1H, J ¼ 8.1 Hz,
Ar-H), 7.69 (t, 1H, J ¼ 8.1 Hz, Ar-H), 7.33
(1H, s, Ar-H), 5.35 (s, 2H, 17-H), 5.32 (s,
2H, 5-H), 2.96 (q, 2H, J ¼ 7.5 Hz,
19-CH2), 1.27 (t, 3H, J ¼ 7.5 Hz, 18-CH3).

1184
D.-Z. Li et al.
3.2.3 Compound 4
3.3.1 Compound 6
Pale yellow solid (57.7%); m.p. 143–
1458C [lit. [24]: m.p. 146–1498C]; 1H
NMR (300 MHz, CDCl3, d ppm): 8.38 (s,
1H, Ar-H), 8.22 (d, 1H, J ¼ 8.4 Hz, Ar-H),
7.92 (d, 1H, J ¼ 8.4 Hz, Ar-H), 7.82 (t,
1H, J ¼ 8.4 Hz, Ar-H), 7.65 (t, 1H,
J ¼ 8.4 Hz, Ar-H), 7.43 (s, 1H, Ar-H),
5.28 (s, 2H, 17-H), 5.10 (m, 2H, 5-H),
3.08, 2.87 (d, 2H, J ¼ 16.2 Hz, 20-
CH2COO), 1.99 (m, 2H, 19-CH2), 1.38
(s, 9H, OZC(CH3)3), 0.93 (t, 3H,
J ¼ 8.4 Hz, 18-CH3).
Pale yellow solid (57.7%); m.p. 165–
1678C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.46 (s, 1H, Ar-H), 8.30 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.96 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.88 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.71
(t, 1H, J ¼ 8.4 Hz, Ar-H), 7.38 (s, 1H,
Ar-H), 5.83, 5.49 (dd, 2H, J ¼ 15.6Hz,
17-H), 5.29 (s, 2H, 5-H), 4.89 (m, 2H,
20-OZCOCH2ZOZ), 4.37, 3.15 (dd, 2H,
J ¼ 13.2Hz, 21-H), 2.31, 1.98 (m, 2H,
19-CH2), 1.16 (t, 3H, J ¼ 7.2 Hz, 18-CH3);
HR-ESI-MS: m/z 587.1227 [M þ H]þ
(calcd for C29H20F5N2O6, 587.1242).
3.2.4 Compound 5
3.3.2 Compound 7
Pale yellow solid (85.0%); m.p. 288–2908C
1
(dec.) [lit. [24]: m.p. . 3008C]; H NMR
Pale yellow solid (72.9%); m.p. 258–2608C
(dec.); 1H NMR (300MHz, CDCl3, d ppm):
8.39 (s, 1H, Ar-H), 8.19 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.94 (d, 1H, J ¼ 7.8 Hz, Ar-H), 7.85
(t, 1H, J ¼ 8.4 Hz, Ar-H), 7.68 (t, 1H,
J ¼ 7.8 Hz, Ar-H), 7.31 (d, 2H, J ¼ 7.5 Hz,
Ar-H), 7.24 (s, 1H, Ar-H), 7.07 (d, 2H,
J ¼ 7.5 Hz, Ar-H), 5.79, 5.46 (d, 2H, J ¼
15.6Hz, 17-H), 5.25 (s, 2H, 5-H), 4.28,3.02
(dd, 2H, J ¼ 13.2Hz, 21-H), 3.66 (t, 2H,
J ¼ 11.7 Hz, 20-OZCOCH2ZSZ), 2.19,
1.88 (m, 2H, 19-CH2), 1.09 (t, 3H,
J ¼ 7.2 Hz, 18-CH3); HR-ESI-MS: m/z
547.1090[M þ H]þ (calcd for C29H24ClN2-
O5S, 547.1095).
(300MHz, DMSO-d6, d ppm): 8.68 (s, 1H,
Ar-H), 8.13 (t, 2H, J ¼ 8.1 Hz, Ar-H), 7.86
(t, 1H, J ¼ 8.1 Hz, Ar-H), 7.71 (t, 1H,
J ¼ 8.1 Hz, Ar-H), 7.41 (s, 1H, Ar-H), 5.50,
5.41 (dd, 2H, J ¼ 15.0Hz, 17-H), 5.26 (s,
2H, 5-H), 3.44, 3.07 (dd, 2H, J ¼ 13.2Hz,
21-H), 1.84 (q, 2H, J ¼ 8.1 Hz, 19-CH2),
0.86 (t, 3H, J ¼ 7.2 Hz, 18-CH3).
3.3 General procedures for compounds
6–23
Taking compound 6 for example, a mixture
of hCPT (15 mg, 0.041 mmol); 2,3,4,5,6-
pentafluorophenoxyacetic acid (30 mg,
0.124 mmol); EDCI (30 mg, 0.157 mmol);
4-DMAP(12 mg, 0.098 mmol);and dichlor-
omethane (5 ml) was stirred at room
temperature for 8–12h. The reaction was
monitored by thin layer chromatography
until the end. Then, chloroform (40 ml) was
added, and organic phase was washed with
water (35 ml), saturated sodium bicarbonate
aqueous solution (35 ml) and brine (35 ml),
and then dried over magnesium sulfate.
After the solvent was removed under
reduced pressure, the residue was taken up
inchloroformandchromatographed(eluent:
CHCl3–CH3OH 98:2) on silica gel to give
14mg of compound 6 as a pale yellow solid.
3.3.3 Compound 8
Pale yellow solid (41.8%); m.p. 112–
1148C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.44 (s, 1H, Ar-H), 8.30 (d, 1H,
J ¼ 8.7 Hz, Ar-H), 7.96 (d, 1H, J ¼ 8.7 Hz,
Ar-H), 7.88 (t, 1H, J ¼ 8.7 Hz, Ar-H), 7.71
(t, 1H, J ¼ 8.7 Hz, Ar-H), 7.41 (s, 1H,
Ar-H), 7.22 (t, 2H, J ¼ 6.9 Hz, Ar-H), 6.91
(t, 2H, J ¼ 7.5 Hz, Ar-H), 6.78 (s, 1H,
Ar-H), 5.84, 5.46 (dd, 2H, J ¼ 15.6Hz,
17-H), 5.28 (s, 2H, 5-H), 4.73 (d, 2H, J ¼
7.8 Hz, 20-OZCOCH2ZO), 4.37, 3.09 (dd,
2H, J ¼ 13.2Hz, 21-H), 2.28, 1.93 (m, 2H,
19-CH2), 1.12 (t, 3H, J ¼ 6.9 Hz, 18-CH3);
HR-ESI-MS: m/z 497.1703 [M þ H]þ
(calcd for C29H25N2O6, 497.1713).

Journal of Asian Natural Products Research
1185
3.3.4 Compound 9
3.3.7 Compound 12
Pale yellow solid (60.8%); m.p. 227–
2298C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.44 (s, 1H, Ar-H), 8.30 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.99 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.91 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.72
(t, 2H, J ¼ 8.4 Hz, Ar-H), 7.57 (d, 1H,
J ¼ 9.3 Hz, Ar-H), 7.38 (t, 2H, J ¼ 8.4 Hz,
Ar-H), 7.22 (d, 1H, J ¼ 2.4 Hz, Ar-H), 7.02
(m, 2H, Ar-H), 5.80–5.49 (m, 2H, 17-H),
5.24 (d, 2H, J ¼ 3.0 Hz, 5-H), 4.91, 4.83 (d,
2H, J ¼ 16.2 Hz, 20-OZCOCH2ZOZ),
4.36, 3.14 (dd, 2H, J ¼ 13.8Hz, 21-H),
2.32, 1.97 (m, 2H, 19-CH2), 1.13 (t, 3H,
J ¼ 7.8 Hz, 18-CH3); HR-ESI-MS: m/z
Pale yellow solid (66.8%); m.p. 246–
2488C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.43 (s, 1H, Ar-H), 8.24 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.95 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.85 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.77
(d, 2H, J ¼ 8.4 Hz, Ar-H), 7.69 (t, 1H,
J ¼ 7.8 Hz, Ar-H), 7.44 (t, 2H, J ¼ 6.3 Hz,
Ar-H), 7.36 (s, 1H, Ar-H), 7.20 (t, 1H,
J ¼ 7.8 Hz, Ar-H), 7.07 (t, 1H, J ¼ 8.4 Hz,
Ar-H), 6.97 (d, 2H, J ¼ 8.4 Hz, Ar-H), 5.85,
5.49 (dd, 2H, J ¼ 15.6Hz, 17-H), 5.28
(d, 2H, J ¼ 6.9 Hz, 5-H), 4.81 (dd, 2H,
J ¼ 16.2Hz, 20-OZCOCH2O), 4.33, 3.14
(d, 2H, J ¼ 13.2 Hz, 21-H), 2.27, 1.95
(m, 2H, 19-CH2), 1.11 (t, 3H, J ¼ 6.9 Hz,
18-CH3); HR-ESI-MS: m/z 619.1865
[M þ H]þ (calcd for C35H28N3O8,
619.1832).
625.0961
[M þ H]þ
(calcd
for
C33H26BrN2O6, 625.0974).
3.3.5 Compound 10
Pale yellow solid (48.0%); m.p. 162–
1648C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.43 (s, 1H, Ar-H), 8.24 (d, 1H,
J ¼ 8.7 Hz, Ar-H), 7.95 (d, 1H, J ¼ 8.7 Hz,
Ar-H), 7.86 (t, 1H, J ¼ 8.7 Hz, Ar-H), 7.69
(t, 1H, J ¼ 8.7 Hz, Ar-H), 7.33 (s, 1H,
Ar-H), 7.17 (m, 3H, Ar-H), 5.84–5.48 (dd,
2H, J ¼ 15.3Hz, 17-H), 5.28 (s, 2H, 5-H),
4.83 (d, 2H, J ¼ 7.8 Hz, 21-H), 4.40, 3.07
(dd, 1H, J ¼ 13.2 Hz, 20-OZCOCH2-
ZOZ), 2.32, 1.96 (m, 2H, 19-CH2), 1.13
(t, 3H, J ¼ 6.9 Hz, 18-CH3); HR-ESI-MS:
m/z 583.1481 [M þ H]þ (calcd for
C30H23F4N2O6, 583.1414).
3.3.8 Compound 13
Pale yellow solid (57.4%); m.p. 139–
1418C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.38 (s, 1H, Ar-H), 8.23 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.93 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.84 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.67
(t, 1H, J ¼ 8.4 Hz, Ar-H), 7.27 (s, 1H,
Ar-H), 6.79 (d, 2H, J ¼ 8.4 Hz, Ar-H), 6.72
(d, 2H, J ¼ 6.3 Hz, Ar-H), 5.82, 5.46 (dd,
2H, J ¼ 16.5Hz, 17-H), 5.24 (s, 2H, 5-H),
4.67 (d, 2H, J ¼ 2.4 Hz, 20-OZCOCH2-
OZ), 4.38, 3.08 (dd, 2H, J ¼ 13.8Hz, 21-
H), 3.52(s, 3H, 40-OCH3),2.28, 1.93(m, 2H,
19-CH2), 1.13 (t, 3H, J ¼ 7.8 Hz, 18-CH3);
HR-ESI-MS: m/z 527.1814 [M þ H]þ
(calcd for C30H27N2O7, 527.1818).
3.3.6 Compound 11
Pale yellow solid (60.5%); m.p. 190–
1928C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.46 (1H, s, Ar-H), 8.26 (d, 1H,
J ¼ 8.7 Hz, Ar-H), 7.89 (d, 1H, J ¼ 7.8 Hz,
Ar-H), 7.81 (t, 1H, J ¼ 8.7 Hz, Ar-H), 7.72
(t, 1H, J ¼ 7.8 Hz, Ar-H), 7.30 (s, 1H, Ar-
H), 7.13 (m, 3H, Ar-H), 5.73, 5.54 (d, 2H,
J ¼ 15.3Hz, 17-H), 5.29 (s, 2H, 5-H), 4.86
(m, 2H, 20-OZCOCH2ZO), 4.22, 3.23 (dd,
2H, J ¼ 13.8Hz, 21-H), 2.34, 2.03 (m, 2H,
19-CH2), 1.13 (t, 3H, J ¼ 7.8 Hz, 18-CH3);
HR-ESI-MS: m/z 610.1424 [M þ H]þ
(calcd for C30H23F3N3O8, 610.1437).
3.3.9 Compound 14
Pale yellow solid (70.5%); m.p. 163–
1658C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.41 (s, 1H, Ar-H), 8.23 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.95 (d, 1H, J ¼ 8.7 Hz,
Ar-H), 7.86 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.69
(t, 1H, J ¼ 8.7 Hz, Ar-H), 7.03 (d, 2H,
J ¼ 9.3 Hz, Ar-H), 7.26 (s, 1H, Ar-H), 6.89
(d, 2H, J ¼ 9.3 Hz, Ar-H), 5.81, 5.49 (dd,
2H, J ¼ 16.5Hz, 17-H), 5.27 (s, 2H, 5-H),

1186
D.-Z. Li et al.
4.72 (d, 2H, J ¼ 3.9 Hz, 20-OZCOCH2-
OZ), 4.34, 3.13 (dd, 2H, J ¼ 13.8 Hz,
21-H), 2.29, 1.96 (m, 2H, 19-CH2), 1.12
(t, 3H, J ¼ 7.8 Hz, 18-CH3); HR-ESI-MS:
m/z 581.1525 [M þ H]þ (calcd for
C30H24F3N2O7, 581.1536).
ppm): 8.53 (s, 1H, Ar-H), 8.44 (d, 1H,
J ¼ 6.3 Hz, Ar-H), 8.01 (d, 1H, J ¼ 6.3 Hz,
Ar-H), 7.93 (t, 1H, J ¼ 6.0 Hz, Ar-H), 7.76
(t, 1H, J ¼ 6.0 Hz, Ar-H), 7.62 (s, 1H, Ar-
H), 7.50 (d, 1H, J ¼ 1.5 Hz, Ar-H), 7.14 (d,
1H, J ¼ 5.1 Hz, Ar-H), 6.84 (d, 1H,
J ¼ 6.6 Hz, Ar-H), 5.81, 5.48 (dd, 2H,
J ¼ 12.0 Hz, 17-H), 5.31 (s, 2H, 5-H),
4.94, 4.78 (dd, 2H, J ¼ 12.0 Hz, 20-
OZCOCH2OZ), 4.35, 3.13 (dd, 2H,
J ¼ 10.2Hz, 21-H), 2.30, 1.95 (m, 2H, 19-
CH2), 1.15(t, 3H, J ¼ 5.7 Hz, 18-CH3);HR-
ESI-MS: m/z 609.0425 [M þ H]þ (calcd for
C29H24BrClN2O6, 609.0428).
3.3.10 Compound 15
Pale yellow solid (84.1%); m.p. 142–
1448C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.40 (s, 1H, Ar-H), 8.25 (d, 1H,
J ¼ 8.7 Hz, Ar-H), 7.94 (d, 1H, J ¼ 8.7 Hz,
Ar-H), 7.85 (t, 1H, J ¼ 8.7 Hz, Ar-H), 7.68
(t, 1H, J ¼ 8.7 Hz, Ar-H), 7.33 (s, 1H, Ar-
H), 6.98 (d, 2H, J ¼ 8.7 Hz, Ar-H), 6.80 (t,
2H, J ¼ 8.7 Hz, Ar-H), 5.84, 5.45 (d, 2H,
J ¼ 15.6Hz, 17-H), 5.24 (s, 2H, 5-H), 4.72
(m, 2H, 20-OZCOCH2O), 4.40, 3.08 (dd,
2H, J ¼ 13.2Hz, 21-H), 2.70 (m, 1H, 40-
CHMe2), 2.34, 1.94 (m, 2H, 19-CH2), 1.13
(t, 3H, J ¼ 6.9 Hz, 18-CH3), 1.01 (d, 6H,
J ¼ 7.2 Hz, 40-CH(CH3)2); HR-ESI-MS:
m/z 539.2174 [M þ H]þ (calcd for
C32H31N2O6, 539.2182).
3.3.13 Compound 18
Pale yellow solid (43.6%); m.p. 206–
2088C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.44 (s, 1H, Ar-H), 8.26 (d, 1H,
J ¼ 6.3 Hz, Ar-H), 7.95 (d, 1H, J ¼ 6.3 Hz,
Ar-H), 7.87 (t, 1H, J ¼ 6.3 Hz, Ar-H), 7.70
(t, 1H, J ¼ 6.3 Hz, Ar-H), 7.34 (s, 1H,
Ar-H), 6.87 (t, 1H, J ¼ 5.4 Hz, Ar-H), 6.79
(d, 1H, J ¼ 4.5 Hz, Ar-H), 5.83, 5.49 (dd,
2H, J ¼ 12.0Hz, 17-H), 5.29 (s, 2H, 5-H),
4.80 (q, 2H, J ¼ 12.6Hz, 20-OZCOCH2-
OZ), 4.38, 3.14 (d, 2H, J ¼ 10.2Hz, 21-H),
2.33, 1.98 (m, 2H, 19-CH2), 1.15 (t, 3H,
J ¼ 5.7 Hz, 18-CH3); HR-ESI-MS: m/z
611.0625 [M þ H]þ (calcd for C29H22BrF2-
N2O6, 611.0629).
3.3.11 Compound 16
Pale yellow solid (48.0%); m.p. 169–
1718C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.37 (s, 1H, Ar-H), 8.14 (d, 1H,
J ¼ 7.8 Hz, Ar-H), 7.91 (d, 1H, J ¼ 7.8 Hz,
Ar-H), 7.80 (t, 1H, J ¼ 7.8 Hz, Ar-H), 7.65
(t, 1H, J ¼ 7.8 Hz, Ar-H), 7.17 (m, 1H,
Ar-H), 6.84 (m, 2H, Ar-H), 6.71 (m, 1H,
Ar-H), 5.79, 5.45 (dd, 1H, J ¼ 15.6Hz, 17-
H), 5.27 (s, 2H, 5-H), 4.33, 3.09 (dd, 2H,
J ¼ 13.2Hz, 21-H), 3.93 (t, 2H, J ¼ 5.4 Hz,
ArOCH2C), 2.54 (t, 2H, J ¼ 3.6 Hz,
20-OZCOCH2OZ), 2.26, 1.86 (m, 2H,
19-CH2), 1.94 (m, 4H, ZCH2CH2Z),1.16
(t, 3H, J ¼ 7.2 Hz, 18-CH3); HR-ESI-MS:
m/z 635.1187 [M þ H]þ (calcd for C32H29-
BrFN2O6, 635.1115).
3.3.14 Compound 19
Pale yellow solid (43.8%); m.p. 152–
1548C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.40 (s, 1H, Ar-H), 8.20 (d, 1H,
J ¼ 6.3 Hz, Ar-H), 7.94 (d, 1H, J ¼ 6.3 Hz,
Ar-H), 7.84 (t, 1H, J ¼ 6.3 Hz, Ar-H), 7.68
(t, 1H, J ¼ 6.3 Hz, Ar-H), 7.26 (s, 1H,
Ar-H), 6.59 (s, 2H, Ar-H), 5.82, 5.48 (dd,
2H, J ¼ 12.0Hz, 17-H), 5.26 (s, 2H, 5-H),
4.68 (d, 2H, J ¼ 3.0 Hz, 20-OZCOCH2-
OZ), 4.37, 3.10 (dd, 2H, J ¼ 10.5Hz,
21-H), 2.33, 1.95 (m, 2H, 19-CH2), 2.20
(6H, s, 30-CH3 and 40-CH3), 1.13 (t, 3H,
3.3.12 Compound 17
J ¼ 5.4 Hz,
18-CH3);
HR-ESI-MS:
Pale yellow solid (43.8%); m.p. 181–
1838C; 1H NMR (300 MHz, CDCl3, d
m/z 559.1630 [M þ H]þ (calcd for
C31H28ClN2O6, 559.1636).

Journal of Asian Natural Products Research
1187
3.3.15 Compound 20
3.3.18 Compound 23
Pale yellow solid (70.4%); m.p. 132–
1348C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.40 (s, 1H, Ar-H), 8.24 (d, 1H,
J ¼ 7.8 Hz, Ar-H), 7.94 (d, 1H, J ¼ 7.5 Hz,
Ar-H), 7.86 (t, 1H, J ¼ 7.5 Hz, Ar-H), 7.69
(t, 1H, J ¼ 7.5 Hz, Ar-H), 7.24 (s, 1H, Ar-
H), 6.84 (d, 2H, J ¼ 4.2 Hz, Ar-H), 6.82
(d, 2H, J ¼ 4.2 Hz, Ar-H), 5.86, 5.49 (dd,
2H, J ¼ 15.9Hz, 17-H), 5.26 (s, 2H, 5-H),
4.68 (d, 2H, J ¼ 6.0 Hz, 20-OZCOCH2-
OZ), 4.35, 3.11 (dd, 2H, J ¼ 13.5 Hz,
21-H), 2.24, 1.94 (m, 2H, 19-CH2), 1.12 (t,
3H, J ¼ 7.5 Hz, 18-CH3); HR-ESI-MS:
m/z 515.1610 [M þ H]þ (calcd for
C29H24FN2O6, 515.1618).
Pale yellow solid (65.0%); m.p. 200–
2028C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.42 (d, 1H, J ¼ 11.4Hz, Ar-H),
8.21 (d, 1H, J ¼ 8.4 Hz, Ar-H), 7.95 (d, 1H,
J ¼ 7.8 Hz, Ar-H), 7.69 (t, 1H, J ¼ 8.4 Hz,
Ar-H), 7.43 (t, 1H, J ¼ 7.8 Hz, Ar-H), 7.22
(s, 1H, Ar-H), 6.73(m, 3H, Ar-H), 5.73, 5.53
(dd, 2H, J ¼ 15.9Hz, 17-H), 5.27 (s, 2H, 5-
H), 4.77 (d, 2H, J ¼ 5.4 Hz, 20-OZCOCH2-
OZ), 4.24, 3.20 (dd, 2H, J ¼ 14.1Hz,
21-H), 2.31, 2.00 (m, 2H, 19-CH2), 1.11
(t, 3H, J ¼ 7.2 Hz, 18-CH3); HR-ESI-MS:
m/z 540.1563 [M þ H]þ (calcd for
C30H23FN3O6, 540.1571).
Acknowledgments
This research was supported in part by the
Fundamental Research Funds for the Central
Universities of China (Grant No. 65011141)
and the Research Fund for the Doctoral
Program of Higher Education of China (Grant
No. 20110031120048).
3.3.16 Compound 21
Pale yellow solid (51.8%); m.p. 103–
1058C; 1H NMR (300 MHz, CDCl3, d
ppm): 8.41 (s, 1H, Ar-H), 8.24 (d, 1H,
J ¼ 8.4 Hz, Ar-H), 7.95 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.86 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.70
(t, 1H, J ¼ 8.4 Hz, Ar-H), 7.58 (m, 2H, Ar-
H), 7.28 (s, 1H, Ar-H), 6.98 (m, 2H, Ar-H),
5.79, 5.49 (dd, 2H, J ¼ 15.3Hz, 17-H), 5.26
(s, 2H, 5-H), 4.79 (d, 2H, J ¼ 6.0 Hz, 20-
OZCOCH2OZ), 4.77, 4.32 (dd, 2H,
J ¼ 13.5Hz, 21-H), 2.32, 1.97 (m, 2H, 19-
CH2), 1.10(t, 3H, J ¼ 4.5 Hz, 18-CH3);HR-
ESI-MS: m/z 565.1581 [M þ H]þ (calcd for
C30H24F3N2O6, 565.1587).
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