First synthesis of novel spin-labeled derivatives of camptothecin as potential antineoplastic agents

Article abstract of DOI:10.1016/j.ejmech.2008.01.008

In an effort to improve the stability of labile lactone ring and water solubility of camptothecin, five novel spin-labeled camptothecin derivatives were synthesized in quantitative yield by a simple modification of the carbodiimide method using the combination of scandium triflate (Sc(OTf)₃) and 4-dimethylaminopyridine (DMAP), and the in vitro pharmacokinetic determination of the lactones of representative compound 13a showed that the biological life span of their lactone forms in human and mouse plasma significantly increased when compared with their mother compound camptothecin. Also, the in vitro cytotoxicity of compounds 13a-13e against human bladder cancer T-24 showed either similar or better activity than that of the parent drug, camptothecin, and clinically available drug, irinotecan.

Full text of DOI:10.1016/j.ejmech.2008.01.008

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 2610e2614
http://www.elsevier.com/locate/ejmech
Preliminary communication
First synthesis of novel spin-labeled derivatives of
camptothecin as potential antineoplastic agents
c
b,**
, Liu Yang , Zong-Cheng Zhan
c
Ying-Qian Liu a, , Xuan Tian
*
a School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
c Analytic Center of Environment Engineering, Environmental and Municipal Engineering School, Lanzhou Jiaotong University,
Lanzhou 730000, PR China
Received 12 August 2007; received in revised form 12 December 2007; accepted 10 January 2008
Available online 25 January 2008
Abstract
In an effort to improve the stability of labile lactone ring and water solubility of camptothecin, five novel spin-labeled camptothecin deriv-
atives were synthesized in quantitative yield by a simple modification of the carbodiimide method using the combination of scandium triflate
(Sc(OTf)3) and 4-dimethylaminopyridine (DMAP), and the in vitro pharmacokinetic determination of the lactones of representative compound
13a showed that the biological life span of their lactone forms in human and mouse plasma significantly increased when compared with their
mother compound camptothecin. Also, the in vitro cytotoxicity of compounds 13ae13e against human bladder cancer T-24 showed either sim-
ilar or better activity than that of the parent drug, camptothecin, and clinically available drug, irinotecan.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Camptothecin; Antineoplastic properties; Spin-labeled
1. Introduction
prolong the biological life span of lactone in human and
mouse plasma compared with their parent compounds. And
meanwhile the overall toxicity of tested ester prodrugs against
nude mice was much lower and their antitumor activity against
human tumor xenografts in nude mice was maintained via
enzymatical cleavage [11e14]. Simultaneous efforts to improve
water solubility have resulted in development of water-soluble
adducts, such as prothecan, afeletecan and camptothecin poly-
glutamate [15e17].
Furthermore, the nitroxyl free radicals have a wide range of
activities in biology. Some studies have shown that the intro-
duction of nitroxyl moiety can lead to a fast decomposition,
higher alkylating, lower carbamoylating activity, better anti-
melanomic activity, lower general toxicity, and through cell
membranes as a transport and while the nitroxyl free radicals
possess low toxicity and are not mutagenic or carcinogenic by
themselves [18e25]. In previous studies, a series of spin-la-
beled podophyllotoxin analogues, by modifying different posi-
tions, have been prepared by our group and these compounds
showed significant antitumor activity with marked decrease in
Camptothecin (1) is a potent antineoplastic compound with
selectively targeting topoisomerase I by trapping the catalytic
intermediate of the TopIeDNA reaction, the cleavage complex
[1e4]. Hydrophilization of the camptothecin molecules results
in the identification and development of topotecan (2) and iri-
notecan (3) (Fig. 1), which have been clinically approved for
treatment of ovarian and colon cancers, respectively [5e8].
However, the therapeutic use of unmodified CPT has been
severely hindered by toxicity stemming in part from instability
of the active lactone form due to preferential binding of the
carboxylate to serum albumin and problems with delivery
due to poor water solubility [9,10]. Ever since esterification of
the 20-hydroxy group of camptothecin was demonstrated to
* Corresponding author. Tel.: þ86 931 8912410; fax: þ86 931 8912582.
** Corresponding author.
E-mail addresses: yqliu@lzu.edu.cn, yangliu1104@mail.lzjtu.cn (Y.-Q.
Liu).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.01.008

Y.-Q. Liu et al. / European Journal of Medicinal Chemistry 43 (2008) 2610e2614
2611
OH
R3
R2
O
OH
NHNHCNH
R1
O
N O
N
O
N
O
O
O
O
OCH3
H3CO
OH
OCH3
Camptothecin(1): R1=R2=R3=H
GP-11(4)
Topotecan(2):
Irinotecan(3):
R1=OH, R2=(CH3)2NHCH2, R3=H
O
C
R2=H, R3=CH2CH3
O
,
R1=
N
N
Fig. 1. Structure of camptothecin (1), topotecan (2), irinotecan (3) and GP-11 (4).
toxicity when compared with the parent compound
[20,23,26e34]; in particular, GP-11 (4) was reported as low
immunosuppressive antitumor agent, which increased the mi-
totic index and resulted in G2/M phase, and to a lesser extent,
S arrest. It has the possibility of becoming a promising new
antitumor drug. Inspired by previous work as well as the
fact that L-amino acids are actively transplanted into mamma-
lian tissue have good water solubility, and are often used as
carrier vehicles for some drugs, our approach to the above
chemical stability/water solubility problems is to introduce
the nitroxyl radical moiety into the molecule of camptothecin
at its 20-hydroxyl via hydrophilic amino acid spacer that to-
gether provide (i) enhanced water solubility and (ii) improved
stability of the lactone ring.
further converted by 25% aqueous ammonia to the carboxa-
mide 7 [35]; catalytic oxidation of 7 with hydrogen peroxide
in the presence of sodium tungstate and catalytic amount of
trylon-B yielded 1-oxyl-2,2,5,5-tetramethylpyrroline-3-car-
bamide 8; alkaline hydrolysis of 8 led to amide cleavage to
1-oxyl-2,2,5,5-tetramethylpyrroline-3-carboxylic
acid
9
[36,37], which on esterification with ethyl chloroformate in
the presence of catalytic amount of triethylamine gave quanti-
tative yields of its higher reactive mixed anhydride 10; without
isolation, the active anhydride 10 can be readily converted into
the corresponding acid azide 11 [38,39] when dissolved in an
aqueous acetone solution of sodium azide within a few min-
utes at 0 ꢀC; without further purification, reaction of the
free-radical acid azide 11 with the corresponding amino acids
in the presence of magnesium oxide at room temperature af-
forded
N-(1-oxyl-3-carbonyl-2,2,5,5-tetramethylpyrroline)
2. Chemistry
amino acids 12ae12e. Spectral data for 12ae12e are identical
to the data reported by Hankovszky [40] (Fig. 2).
Facile stereoselective esterification of the hindered tertiary
alcohol 20(S )-camptothecin with N-(1-oxyl-3-carbonyl-
2,2,5,5-tetramethylpyrroline) amino acids 12ae12e has been
achieved in quantitative yield by a simple modification of
Camptothecin 1 was isolated from a Chinese medicinal
plant Camptotheca acuminata and served as the starting mate-
rial for the preparation of all the derivatives.
Compound 6 was prepared quite readily in quantitative
yield by addition of bromine to the ketone 5, which was
COOH
CONH2
O
CONH2
O
Br
Br
i
ii
iii
iv
N
O
N
O
N
H
N
H
6
N
H
5
9
8
7
R
O
OH
CON3
COOCOOC2H5
N
H
vii
vi
v
O
No.
12a
12b
12c
R
N
O
N
O
N
O
H
CH3
CH2Ph
10
11
12a-12e
12d
12e
CH2CH2SCH3
CH2CH(CH3)2
Fig. 2. Reagents and conditions: (i)e(iii) Na2WO4/H2O2/EDTA; (iv) 10% aqueous NaOH, reflux, stir; (v) ethyl chloroformate/NEt3; (vi) NaN3/water, stir; (vii)
amino acids/MgO, stir, 24 h.

2612
Y.-Q. Liu et al. / European Journal of Medicinal Chemistry 43 (2008) 2610e2614
O
O
No.
R
N
i
N
13a
13b
13c
13d
13e
H
N
N
O
O
O
O
CH3
R
CH2Ph
CH2CH2SCH3
CH2CH(CH3)2
O
OH
O
N
H
O
1
N
O
13a-13e
Fig. 3. Reagents and conditions: (i) DIPC/DMAP/Sc(OTf)3, ꢁ10 ꢀC, stir.
the carbodiimide method using the combination of scandium
triflate (Sc(OTf)3) and 4-dimethylaminopyridine (DMAP) to
give the desired camptothecin esters 13ae13e under an atmo-
sphere of nitrogen at ꢁ20 ꢀC (Fig. 3). Synthesized target com-
pounds 13ae13e were characterized by melting point, ESR,
IR and HRMS spectral analyses.
The synthetic methodology for the preparation of N-(1-
oxyl-3-carbonyl-2,2,5,5-tetramethylpyrroline) amino acids
12ae12e is depicted in Fig. 2.
Furthermore, the in vitro cytotoxicity of compounds 13ae
13e against human bladder cancer T-24 was tested based on
MTT assay. The results are summarized in Table 2.
As illustrated in Table 2, compounds 13ae13e showed
more significant cytotoxicity against T-24 in vitro than its pa-
rental compound of CPT. Among them, compound 13a ex-
hibited most potent cytotoxicity against T-24 cell (inhibition
rate is 34.5%), while the inhibition rate values of these ana-
logues were either similar or better than those of the prototyp-
ical inhibitor irinotecan. Examination of the different amino
acid linkages and the resulting activity in the inhibition of hu-
man bladder cancer T-24 in vitro reveal the following order of
The synthetic methodology for the preparation of spin-la-
beled camptothecin derivatives 13ae13e is depicted in Fig. 3.
activity:
L-glycine > L-phenyl
alanine > L-alanine > L-
methionine > L-leucine. These results indicated that the struc-
tures of L-amino acids have potential effects on the bioactivity
of these compounds. Hence, a systemic, predictable correla-
tion could be made between the nature of amino acids and an-
ticancer activities. As can be seen, as a whole, the introduction
of a stable nitroxyl radical into the molecule of camptothecin
with L-amino acids led to potentiate their antitumor activity,
which also indicated that the design and synthesis of these
compounds should be beneficial for therapeutic values of
camptothecin and they probably have synergistic action to tu-
mor cell lines.
3. Results and discussion
For the challenging acylation of the tertiary and unreactive
20-hydroxyl group, especially with bulky amino acid residues,
we have developed an efficient route using a modified version
of Greenwald’s method [41] by the combination of scandium
triflate (Sc(OTf)3) and 4-dimethylaminopyridine (DMAP).
The desired compounds have been obtained by facile acylation
of the 20-hydroxyl group with N-(1-oxyl-3-carbonyl-2,2,5,5-
tetramethylpyrroline) amino acids 12ae12e.
The in vitro determination, based on literature method [42],
of lactone levels in human and mouse plasma for camptothecin
and compound 13a is shown in Table 1. As shown in Table 1,
the percent of the lactone of CPT in human plasma is 28.4%
after 4 h, 14.6% after 8 h, and only 3.8% after 24 h. In other
words, the active form of CPT is lost in a short time period af-
ter oral administration. This is opposite to what is observed in
mice, in which the active lactone form lasts for relatively long
time period. For example, the closed lactone form of CPT in
mouse plasma is 40.5% after 4 h. The closed lactone form
of 13a in human plasma is much stable than its mother com-
pound 1. For example, 65.2% of 13a is still detected as the
closed lactone form even after 4 h. The results were further ev-
ident that the biological life span of lactone forms of their
camptothecin esters in human and mouse plasma significantly
increased when compared with their mother compound camp-
tothecin. And the cleavage of 13a in both mouse and human
plasma was monitored by HPLC, which was clearly shown
that compound 13a was cleaved to afford mainly its parental
compound of CPT in both mouse and human plasma. It was
also the case in pH 7.4 phosphate buffer (data not shown).
4. Conclusions
To improve the biological profile of the potent anticancer
compound camptothecin, five novel spin-labeled derivatives
of camptothecin have been synthesized by a modified version
of Greenwald’s method. The compounds selected for the in vi-
tro determination of lactone levels showed that their biological
Table 1
Comparison of percent lactone of prodrug 13a and camptothecin (CPT) in hu-
man and mouse plasma
Time (h)
0
2
4
6
8
24
Human plasma
% Lactone for 13a
% Lactone for CPT
100.0
100.0
78.7
61.4
65.2
28.4
56.1
19.4
34.4
14.6
7.8
3.8
Mouse plasma
% Lactone for 13a
% Lactone for CPT
100.0
100.0
76.3
55.1
57.6
40.5
43.9
24.5
31.8
10.9
10.8
5.3

Y.-Q. Liu et al. / European Journal of Medicinal Chemistry 43 (2008) 2610e2614
2613
Table 2
In vitro cytotoxicity activity of compounds 13ae13e
separated with chloroformemethanol as eluent. Synthesized
target compounds 13ae13e were characterized by melting
point, ESR, IR and HRMS spectral analyses.
Compounds
Inhibition rate (%)
T-24
13a
13b
34.5
25.9
26.4
25.5
16.4
15.4
23.8
5.1.1. Camptothecin-20-O-[N-(10-oxyl-30-carbonyl-
20,20,50,50-tetramethylpyrroline)]-glycinoate (13a)
13c
13d
Yellow powder, isolated yield: 50%; m.p. 168e170 ꢀC;
[a]2D0 ¼ ꢁ91ꢀ (c ¼ 0.5, DMF); IR (KBr, cmꢁ1): 3366 (NH),
1754 (NHCO), 3063, 1615, 1557 (ArH), 1662 (C]O), 1131,
1159, 1233 (CeO), 1356 (NOꢂ); ESR: g0 ¼ 2.0055,
AN ¼ 14.62 Gs (triplet peak in 1 ꢃ 10ꢁ4 M, DMF); HRMS:
m/z calcd for C31H31N4O7: 572.2266 [M þ H]þ, Found:
572.2260 [M þ H]þ.
13e
CPT
Irinotecan
life span in human and mouse plasma was much longer than
that of the parent compound camptothecin. Meanwhile, all
of these target compounds exhibited either similar or better cy-
totoxicity against T-24 in vitro than that of the prototypical in-
hibitor irinotecan. As can be seen, as a whole, the introduction
of a stable nitroxyl radical into the molecule of camptothecin
with L-amino acids led to enhanced stability of the lactone ring
and improvement of their antitumor activity. Further biological
evaluation is in progress to define their DNA topoisomerase I
inhibition activity and to clarify whether spin-labeled campto-
thecin analogues might counteract the toxicity of this class an-
titumor drug.
5.1.2. Camptothecin-20-O-[N-(10-oxyl-30-carbonyl-
20,20,50,50-tetramethylpyrroline)]-alaninoate (13b)
Yellow powder, isolated yield: 46%; m.p. 166e168 ꢀC;
[a]2D0 ¼ ꢁ87ꢀ (c ¼ 0.5, DMF); IR (KBr, cmꢁ1): 3429 (NH),
1751 (NHCO), 3056, 1603, 1552 (ArH), 1662 (C]O), 1127,
1154, 1228 (CeO), 1358 (NOꢂ); ESR: g0 ¼ 2.0058,
AN ¼ 14.62 Gs (triplet peak in 1 ꢃ 10ꢁ4 M, DMF); HRMS:
m/z calcd for C32H33N4O7: 586.2422 [M þ H]þ, Found:
586.2416 [M þ H]þ.
5. Experimental
5.1.3. Camptothecin-20-O-[N-(10-oxyl-30-carbonyl-
20,20,50,50-tetramethylpyrroline)]-phenylalaninoate (13c)
Yellow powder, isolated yield: 43%; m.p. 142e144 ꢀC;
[a]2D0 ¼ ꢁ94ꢀ (c ¼ 0.5, DMF); IR (KBr, cmꢁ1): 3434 (NH),
1750 (NHCO), 3060, 1617, 1561 (ArH), 1663 (C]O), 1130,
1159, 1231 (CeO), 1354 (NOꢂ); ESR: g0 ¼ 2.0055,
AN ¼ 14.62 Gs (triplet peak in 1 ꢃ 10ꢁ4 M, DMF); HRMS:
m/z calcd for C38H37N4O7: 622.2735 [M þ H]þ, Found:
622.2736 [M þ H]þ.
Melting points were taken on a Kofler melting point
apparatus and are uncorrected; IR spectra were obtained on
NIC-5DX spectrophotometer; mass spectral analysis was
performed on a ZAB-HS and Bruker Daltonics APEXII49e in-
strument. Optical rotations were determined on PerkineElmer
Model 341 spectropolarimeter. ESR spectra were obtained
with a Bruker ER-200D-SRC X-band spectrometer. The start-
ing camptothecin was isolated from a Chinese medicinal plant
C. acuminata and was purified before being used. The N-(1-
oxyl-3-carbonyl-2,2,5,5-tetramethylpyrroline) amino acids
12ae12e used for the experiments were prepared by following
a modified previous procedure [35e40].
5.1.4. Camptothecin-20-O-[N-(10-oxyl-30-carbonyl-
20,20,50,50-tetramethylpyrroline)]-methioninoate (13d)
Yellow powder, isolated yield: 47%; m.p. 140e142 ꢀC;
[a]2D0 ¼ ꢁ86ꢀ (c ¼ 0.5, DMF); IR (KBr, cmꢁ1): 3481 (NH),
1749 (NHCO), 3060, 1616, 1560 (ArH), 1663 (C]O), 1131,
1157, 1230 (CeO), 1354 (NOꢂ); ESR: g0 ¼ 2.0055,
AN ¼ 14.62 Gs (triplet peak in 1 ꢃ 10ꢁ4 M, DMF); HRMS:
m/z calcd for C34H37N4O7S: 646.2456 [M þ H]þ, Found:
646.2454 [M þ H]þ.
5.1. General procedure for synthesis of target
compounds (13ae13e)
A suspension of camptothecin (0.1 g, 0.288 mmol), scandium
triflate (0.085 g, 0.173 mmol), N-(1-oxyl-3-carbonyl-2,2,5,5-
tetramethylpyrroline) amino acids 12ae12e (0.864 mmol) and
4-dimethylaminopyridine (0.11 g, 0.864 mmol) in anhydrous
methylene chloride (10 mL) under an atmosphere of nitrogen
was cooled to ꢁ20 ꢀC in an ice-salt bath for 30 min, and
DIPC (0.142 mL, 0.907 mmol) was added and the reaction
mixture stirred at ꢁ10 ꢀC for 30 min and allowed to warm
to room temperature over 10 h. The reaction mixture was fil-
tered and the filtrate was washed with 20 mL of 0.1 N HCl,
20 mL of 0.1 M NaHCO3, and 20 mL of distilled water, and
then dried over anhydrous MgSO4. Evaporation of solvent
left the crude product. The residue was chromatographically
5.1.5. Camptothecin-20-O-[N-(10-oxyl-30-carbonyl-
20,20,50,50-tetramethylpyrroline)]-leucinoate (13e)
Yellow powder, isolated yield: 25%; m.p. 145e147 ꢀC;
[a]2D0 ¼ ꢁ82ꢀ (c ¼ 0.5, DMF); IR (KBr, cmꢁ1): 33,679 (NH),
1749 (NHCO), 3061, 1617, 1559 (ArH), 1663 (C]O), 1127,
1155, 1233 (CeO), 1354 (NOꢂ); ESR: g0 ¼ 2.0055,
AN ¼ 14.62 Gs (triplet peak in 1 ꢃ 10ꢁ4 M, DMF); HRMS:
m/z calcd for C35H39N4O7: 650.2711 [M þ Na]þ, Found:
650.2714 [M þ Na]þ.

2614
Y.-Q. Liu et al. / European Journal of Medicinal Chemistry 43 (2008) 2610e2614
[5] D. Ormrod, C.M. Spencer, Drugs 58 (1999) 533e551.
[6] C. Kollmannsberger, K. Mross, A. Jakob, L. Kanz, C. Bokemeyer, Oncol-
ogy 56 (1999) 1e12.
5.2. In vitro determination of lactone levels in human
and mouse plasma for 1 and 13a
[7] M.L. Rothenberg, Oncologist 6 (2001) 66e80.
[8] W. Du, Tetrahedron 59 (2003) 8649e8687.
[9] D.J. Adams, Curr. Med. Chem. Anticancer Agents 5 (2005) 1e13.
[10] R.W. Driver, L.X. Yang, Mini Rev. Med. Chem. 5 (2005) 425e439.
[11] Q.Y. Li, Y.G. Zu, R.Z. Shi, L.P. Yao, Curr. Med. Chem. 13 (2006) 2021e
2039.
To 0.8 mL pre-incubated human and mouse plasma were
added, respectively, the test compounds (0.2 mL, 100 mg/mL)
in acetonitrile. The mixture was incubated at 37 ꢀC and
100 mL aliquots were taken at 2, 4, 6, 8 and 24 h. To precipi-
tate plasma protein, 400 mL acetonitrile (ꢁ20 ꢀC) was added,
vortexed for 20 s, and centrifuged at 10,000 rpm for 5 min. Su-
pernatant was transferred to a glass vial and stored at ꢁ20 ꢀC
immediately until HPLC analysis. HPLC (HP1100) analysis:
20 mL of solution obtained above was injected onto a C-18
column (Zobax SB, 4.6 ꢃ 150 mm) and chromatographed
with methanol/water/0.1% acetic acid as mobile phase. Com-
pounds camptothecin and 13a were detected (detector: DAB)
at 254 nm. The percent of lactone was determined by the ratio
of lactone levels measured at different time points to the lac-
tone levels measured at starting point (t ¼ 0 h).
[12] L.P. Rivory, J. Robert, Pharmacol. Ther. 68 (1995) 269e296.
[13] T.W. Moody, J. Fuselier, D.H. Coy, S. Mantey, T. Pradhan, T. Nakagawa,
R.T. Jensen, Peptides 26 (2005) 1560e1566.
[14] X.L. Liu, B.C. Lynn, J.H. Zhang, L. Song, D. Bom, W. Du, D.P. Curran,
T.G.A. Burke, J. Am. Chem. Soc. 124 (2002) 7650e7651.
[15] D.Z. Yang, J.T. Strode, H.P. Spielmann, A.H.J. Wang, T.G. Burke, J. Am.
Chem. Soc. 120 (1998) 2979e2980.
[16] R. Bhatt, P. de Vries, J. Tulinsky, G. Bellamy, B. Baker, J.W. Singer,
P. Klein, J. Med. Chem. 46 (2003) 190e193.
[17] Z.S. Cao, N. Harris, A. Kozielski, D. Vardeman, J.S. Stehlin,
B. Giovanella, J. Med. Chem. 41 (1998) 31e37.
[18] G. Sosnovsky, S.W. Li, Life Sci. 36 (1985) 1479e1483.
[19] E.G. Ankel, C.S. Lai, L.E. Hopwood, Z. Zivkovic, Life Sci. 40 (1987)
495e498.
5.3. Cytotoxicity assays
[20] Y. Jin, S.W. Chen, X. Tian, Bioorg. Med. Chem. 14 (2006) 3062e3068.
[21] A.M. Zheleva, V.G. Gadjeva, Int. J. Pharm. 212 (2001) 257e266.
[22] W.G. Li, X.Y. Zhang, Y.J. Wu, X. Tian, Acta Pharm. Sin. 23 (2002) 727e
732.
Cytotoxicity assays are performed on human bladder can-
cer (T-24) cell line. One thousand two hundred cells per
well were plated in 96-well plates. After culturing for 24 h,
compounds 13ae13e were added onto triplicate wells with
different concentration, and 0.1% DMSO for control. After 4
days of incubation, 10 mL MTT (3-[4,5-dimethyl thiazol-2-
yl]-2,5-diphenyltetrazolium bromide) solution (5 mg/mL)
was added to each well, and after shaking for 1 min, the plate
was incubated further for 4 h. Formazan crystals were dis-
solved with 100 mL DMSO. The absorbance (OD) was quan-
titated with microplate spectrophotometer at 570 nm. Wells
containing no drugs were used as blanks for the spectropho-
tometer. The survival of cells was expressed as percentage
of untreated control wells. The prototypical inhibitors campto-
thecin and irinotecan were included as reference standards, the
results of these assays were used to obtain the corresponding
inhibition rates.
[23] X. Tian, F.M. Zhang, W.G. Li, Life Sci. 70 (2002) 2433e2443.
[24] V.G. Gadjeva, Int. J. Pharm. 247 (2002) 39e45.
[25] G. Sosnovsky, Pure Appl. Chem. 62 (1990) 289e294.
[26] Y.G. Wang, X. Tian, Y.Z. Chen, Acta Pharm. Sin. 23 (1988) 792e798.
[27] Y.Z. Chen, C.J. Zhang, X. Tian, Sci. Sin. B 30 (1987) 1070e1079.
[28] Y.Z. Chen, X. Tian, Y.G. Wang, Life Sci. 45 (1989) 2569e2571.
[29] J.Z. Wang, X. Tian, H. Tsumura, Anticancer Drug Des. 8 (1993) 193e
202.
[30] X. Tian, Z.Q. Yan, J.X. Li, Y.Z. Chen, Chem. Res. Chin. Univ. 11 (1995)
79e83.
[31] K.K. Lu, Y.G. Wang, Y.Z. Chen, Synth. Commun. 27 (1997) 1963e1968.
[32] Y.Q. Liu, X. Tian, Synth. Commun. 27 (2005) 1963e1968.
[33] X. Tian, Y.G. Wang, M.G. Yang, Y.Z. Chen, Life Sci. 60 (1997) 511e
517.
[34] Y.Q. Liu, L. Yang, X. Tian, Curr. Bioact. Compd 3 (2007) 37e66.
[35] H.O. Hankovszky, K. Hideg, J. Tigyi, Acta Chim. Acad. Sci. 98 (1978)
339e348.
[36] T.L. Wong, R. Schwenk, C.J. Hsia, Can. J. Chem. 52 (1974) 3381e3383.
[37] E.G. Rozantzev, L.A. Krinitzkaya, Tetrahedron 21 (1965) 491e499.
[38] W.R. Couet, R.C. Brasch, G. Sosnovsky, J. Lukszu, I. Prakash,
C.T. Gnewuch, T.N. Tozer, Tetrahedron 40 (1984) 1165e1172.
[39] N. Naik, R. Braslau, Tetrahedron 54 (1998) 667e696.
[40] K. Hideg, L. Lex, H.O. Hankovszky, J. Tigyi, Synthesis 7 (1978) 914e
916.
References
[1] S. Sirikantaramas, T. Asano, H. Sudo, M. Yamazaki, K. Saito, Curr.
Pharm. Biotechnol. 8 (2007) 196e202.
[41] R.B. Greenwald, A. Pendri, Z. Hong, Tetrahedron: Asymmetry 9 (1998)
915e918.
[2] G. Capranico, F. Ferri, M.V. Fogli, A. Russo, L. Lotito, L. Baranello, Bi-
ochimie 89 (2007) 482e489.
[42] X.G. He, W. Lu, X.Q. Jiang, J.C. Cai, X.W. Zhang, J. Ding, Bioorg. Med.
Chem. 12 (2004) 4003e4008.
[3] Y. Pommier, Nat. Rev. Cancer 6 (2006) 789e802.
[4] J.T. Hartmann, H.P. Lipp, Drug Saf. 29 (2006) 209e230.