Synthesis, chiral resolution, and determination of novel furan lignan derivatives with potent anti-tumor activity

Article abstract of DOI:10.1016/j.bmcl.2010.01.122

A kind of racemic furan lignans were synthesized via a novel route, and two optical isomers were obtained through a selective hydrolization. The absolute configurations were determined by circular dichroism spectroscopy after separated through a preparati

Full text of DOI:10.1016/j.bmcl.2010.01.122

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1961–1964
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, chiral resolution, and determination of novel furan lignan
derivatives with potent anti-tumor activity
a,
Hai Ling Sun a, Tian Tian Wang a, Zhi Liang Lv a, Ji Lu Feng a, Dong Ping Geng a, Yong Mei Li b, , Ke Li
*
*
a Department of Medicinal Chemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People’s Republic of China
b Department of Oncology Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A kind of racemic furan lignans were synthesized via a novel route, and two optical isomers were
obtained through a selective hydrolization. The absolute configurations were determined by circular
dichroism spectroscopy after separated through a preparative column. The different activities of isomers
and the racemates were evaluated on QGY-7701 and HeLa cell lines, and compound 2c showed the best
Received 10 December 2009
Revised 18 January 2010
Accepted 22 January 2010
Available online 1 February 2010
activity on QGY-7701 and HeLa cell lines with IC50 12 lM and 13 lM, respectively.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Furan lignan
Selectively hydrolization
Circular dichroism spectra
Absolute configuration
Anticancer
QGY-7701
HeLa cell
The development of efficient and mild methods for heterocyclic
compound synthesis represents a broad area of organic chemistry
because of the existence in numerous natural products.1 Molecules
containing such structure unit often play an essential role in their
biological activity, particularly in cancer and virus researches.2 This
important class of heterocyclic products has therefore stimulated
the development of popular synthetic five-membered oxygen het-
erocycles. Moreover, some derivatives of furan lignans which have
been synthesized showed wide range of biological activities and
could be used as versatile intermediates.3–9 However, enough
attention has not been paid to the chirality of this kind of hetero-
cyclic compounds; especially the chiral center is locating on carbon
atom of furan ring. Herein, we reported the synthesis, chiral sepa-
ration and determination of two racemoid furan lignans, and the
anti-cancer activity was evaluated on QGY-7701 and HeLa cell
lines. The two pairs of chiral enantiomers are shown in Figure 1.
The preparation of target compound 2 was listed in Scheme
1. Compound 5 was synthesized through a conventional Knoeve-
THF. Then a Heck reaction was employed to synthesize the key
intermediate compound
7 from compound 6 and 1-iodo-4-
methoxybenzene.12 Compound 1 was prepared through a hydro-
lysis decarboxylation reaction in 20% of KOH aqueous solution in
ethanol (v/v = 1:1) at room temperature with an excellent yield.
In the end, compound 1 was reduced under LiAlH4 to form com-
pound 2 in THF with good yield.14,23 Compounds 1, 2, and 6–8
were characterized by NMR spectra.24
nagel Condensation between compound
3 and compound 4
refluxing in toluene with the catalytic piperidine and HOAc.10
Compound 5 reacted with prop-2-yn-1-ol via a coupling reaction
under nitrogen atmosphere to form compound 6, which was cat-
alyzed by PdCl2(Ph3P)2 and n-BuLi at room temperature11 in dry
* Corresponding authors. Tel.: +86 21 81871237 (K.L.).
E-mail addresses: liyongmei1976@sina.com (Y.M. Li), proflike@sina.com (K. Li).
Figure 1. Four chiral target compounds.
0960-894X/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.122

1962
H. L. Sun et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1961–1964
Scheme 1. Reagents and conditions: (a) piperidine, CH3COOH, toluene, reflux, 6 h, 85%; (b) prop-2-yn-1-ol, NaH, n-BuLi, Pd(Ph3P)2Cl2, THF, rt, 4 h, 90%; (c) 1-iodo-4-
methoxybenzene, Pd(OAc)2, PPh3, TEA, DMF–DMSO, 8 h, 70%; (d) KOH 20%, EtOH, rt, 5 h, 90%; (e) LiAlH4, THF, rt, 9 h, 80%.
Figure 2. HPLC assay of compound 1c (1a/1b = 50.3:49.7 m/m).
Figure 3. ORTEP drawing of compound 1c.
As shown in Scheme 1, compound 6 was formed through a cou-
pling reaction without orientation selectivity and two isomers should
be obtained because of the existence of chiral center on carbon 2.
Without changes, the chirality maintained after heck reaction, and
cis-configuration was the only configuration due to the existence of
stereospecific blockade. Then, compound 7 was hydrolyzed and one

H. L. Sun et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1961–1964
1963
carboxyl group was cut off during the hydrolysis. Therefore, four iso-
mers should be generated theoretically. However, the substituted
benzene ring locating on position 2 had a steric hindrance effect on
the hydrolysis procedure; only two dominant configurations were
generated. And the optical mixture was analyzed on high perfor-
mance liquid chromatography (HPLC) equipped with a chiral column,
onlytwo isomerpeaks (peakpurity >99%)werefound(Fig. 2). Besides,
in the crystal cell13 of single crystal of compound 1, only two centro-
symmetric enantiomers15,16 could be observed (Fig. 3) and named as
(2S,3S,Z)-2-(3,5-dimethoxyphenyl)-4-(4-methoxybenzylidene)tetra
hydrofuran-3-carboxylic acid and (2R,3R,Z)-2-(3,5-dimethoxyphen
yl)-4-(4-methoxybenzylidene)tetrahydrofuran-3-carboxylic
acid,
respectively. Consequently, the two isomers were isolated by a pre-
parative Chiralpak IC column and specific rotations were determined.
The specific rotation of compound 1a, retention time was 5.345 min,
Figure 5. QGY and HeLa cell survival assessed by MTT.
was evaluated to be ½a D20
= ꢁ30 (c, methanol), while compound 1b,
ꢀ
retention time was 7.286 min, was evaluated to be ½a D20
ꢀ
= +31.4 (c,
used to evaluate the anti-tumor activity. For HeLa cell line, com-
pound 1a, 1b, and 1c (the racemate of 1a and 1b) showed no effec-
methanol). In order to determine the absolute configuration of 1a
and 1b, circular dichroism (CD) spectra of the two compounds were
detected (Fig. 4). The CD spectra were recorded in ethanol showed a
quasi-mirror image pattern. In case of compound 1b, the CD consists
of a strong positive band at 258 nm, followed by another smaller neg-
ative band at 216 nm; for compound 1a, the sequence of bands was
similar but their signs were inverted. The CD of compound 1a and
1b were mainly allied to the transitions of carboxyl group and benzyl
groupperturbedbyvariouschiralelementsattachedonthetwochiral
centers. In particular, the two bands in the CD spectra of 1a and 1b
tiveness (IC50 >100
and 2b), 2a, and 2b displayed higher inhibition, 5.35, 2.79, and
1.83 folds, than 5-Fu (IC50 = 64.2 M). For QGY-7701, compound
2c displayed the best inhibition (IC50 = 13 M), 5.17 folds more
effective than 5-Fu (IC50 = 67.2 M); followed by 2a, 1a, and 1c
(IC50 = 28, 28, and 33 M). Though compounds 1a, 1b, and 1c
lM), while compound 2c (the racemate of 2a
l
l
l
l
showed low cytotoxicity to HeLa, compound 1a displayed good
activity to QGY. For compounds 2a, 2b, and 2c, moderate to good
activity could be seen for both QGY and HeLa; especially 2c per-
formed the best activity among the six compounds.
We are satisfied with the different cytotoxicity between optical
monomers and their racemate. Compound 1c, the racemate of 1a
and 1b, shows a little weaker active than compound 1a because
of the comparative lower concentration and silence of compound
1b to QGY. Thanks to the moderate activity of 2a and 2b, com-
pound 2c emerged the highest cytotoxicity to both QGY-7701
and HeLa cancer cells.
1
*
could be assigned, from right to left, to the n–
p
and the Lb-type
p–
*
p
p
transition of chromophore.19 For the two major CD bands, the n–
*
transitionat 258 nm showeda positive Cotton effectforthe 3S con-
figuration as in 1b, and negative for the 3R configuration as in 1a;17–20
*
while the
p–p
transition at 216 nm showed a negative Cotton effect
for the 2S configuration as in 1b, and positive for the 2R configuration
as in 1a.20 So, the absolute stereochemistry of compound 1a and 1b
was established as (2R,3R,Z)-1a and (2S,3S,Z)-1b.21
The four optical monomers and two racemic compounds re-
ported herein were evaluated, in vitro, cytotoxicity to HeLa (cervi-
cal adenocarcinoma) and QGY-7701 (human hepatoma cell) using
the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide] assay.22 5-Fluorouracil (5-Fu) used in clinical trials was
included as the positive control substance. Results of this biological
activity study were summarized as Figure 5. IC50 (values concen-
tration of the drug required to reduce cell viability by 50%) was
In summary, we have found a novel route to synthesize racemic
furan lignan from substituted benzaldehyde and diethyl malonate.
The two ethyl ester was selectively hydrolyzed to form two optical
isomers, which were separated by preparative Chiralpak IC column
and their absolute configuration were established by the CD spec-
tra. We have evaluated and compared the anti-cancer activity of
optical monomer and racemate. The results revealed that enough
attention should be paid to the isomers and their racemate of this
Figure 4. Circular dichroism spectra of compounds 1a and 1b.

1964
H. L. Sun et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1961–1964
15. Wang, T.-T.; Lv, Z.-L.; Feng, J.-L.; Sun, H.-L.; Liu, J.; Li, K. X-ray Struct. Anal. Online
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17. M.A.E. Sallam, Taylor & Francis, 2002, 7, 283.
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ated due to the existence of chirality.
18. Johnson, W. C., Jr.; Horton, R. S. T. a. D. In Advances in Carbohydrate Chemistry
and Biochemistry; Academic Press, 1987; Vol. 45, p 73.
Acknowledgments
19. Sallam, M. A. E. Chirality 2006, 18, 790.
We thank the National Natural Science Foundation of China
(No. 30572238) for financial support.
20. Zhang, W.; Krohn, K.; Ullah, Z.; Florke, U.; Pescitelli, G.; Bari, L. D.; Antus, S.;
Kurtan, T.; Rheinheimer, J.; Draeger, S.; Schulz, B. Chem. Eur. J. 2008, 14, 4913.
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References and notes
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Lindsley, C. W. Bioorg. Med. Chem. Lett. 2009, 19, 2240.
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13. Crystallographic data for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 699734. These data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail:deposit@ccdc.cam.ac.uk].
23. Typical procedure:370 mg of compound1 (1 mmol) was dissolved in50 mL of dry
THF and 43 mg of LiAlH4 (1.1 mmol) was added. The mixture was stirred at room
temperature for 9 h, then 100 mL of 3 N HCl was added, and 100 mL of EtOAc was
added to extract the crude product. Then the oil layer was washed with saturated
NaCl solution and dried with MgSO4. The crude product was purified with silica
gel column. 289 mg of compound 2 was obtained, yield 81%.
24. Spectral data: Compound 6: Oil; 1H NMR (300 M, CDCl3). d 7.4–7.5 (M, 3H), 5.72
(s, 1H), 5.54 (s, 1H), 5.22 (S, 1H), 5.09 (dd, J = 13.7 and 2.2, 1H), 4.77 (dd, J = 13.7
and 2.7, 1H), 3.85–3.95 (m, 1H), 3.80 (S, 6H), 3.55–3.65 (m, 1H), 1.30 (t,
J = 7.5 Hz, 3H), 0.75 (t, J = 7.0 Hz, 3H). Compound 7: mp: 130 °C; IR (KBr, cmꢁ1):
1727 (C@O), 1614 (C@C), 1606 (Ar-H), 1486 (Ar-H); 1H NMR (CDCl3, 300 MHz):
d 7.15 (d, J = 9, 2H), 6.95 (d, J = 9, 2H), 6.79 (S, 1H), 6.65 (S, 1H), 6.40 (S, 1H),
5.20 (s, 1H), 5.09 (dd, J = 13.7 and 2.2, 1H), 4.77 (dd, J = 13.7 and 2.7, 1H), 4.36
(q, J = 7.1, 2H), 3.89 (dq, J = 10.7 and 7.1, 1H), 3.86 (s, 3H), 3.78 (s, 6H), 3.61 (dd,
J = 10.7 and 7.1, 1H), 1.30 (t, J = 7.0, 3H), 0.75 (t, J = 7.0, 3H). 13C NMR (CDCl3,
300 MHz): d 168.3, 168.0, 160.4, 159.0, 139.5, 135.6, 129.9, 129.2, 125.4, 114.0,
104.7, 100.7, 84.6, 70.3, 69.5, 61.9, 61.3, 55.3, 14.0, 13.4. EI-MS: 469 (MꢁH),
493 (M+Na). Compound 1: C21H22O6: mp: 167.3–168.2 °C; IR (KBr, cmꢁ1): 3450
(COOH), 1727 (C@O), 1614 (C@C), 1606 (Ar-H), 1464 (Ar -H); 1H NMR (DMSO,
300 MHz): d 12.86 (S,1H), 7.15 (d, J = 9 Hz, 2H), 6.94 (d, J = 9 Hz, 2H), d 6.41–
6.49 (m, 3H), 5.06 (d, J = 7.2 Hz, 1H), 4.83 (dd, J = 13.7 and 2.2 Hz, 1H), 4.75 (dd,
J = 13.7 and 2.2 Hz, 1H), d 3.76 (s, 3H), 3.72 (s, 6H), 3.61 (d, J = 7.2 Hz, 1H). 13C
NMR (DMSO, 300 MHz): d 172.2, 160.4, 158.3, 142.7, 137.0, 129.4, 128.8, 121.3,
114.0, 103.7, 99.4, 81.6, 69.6, 58.3, 55.1. EI-MS: 369 (MꢁH), 393 (M+Na).
Compound 2: Oil, 1H NMR (DMSO, 300 MHz), d 7.10 (d, J = 9Hz, 2H), 6.90 (d,
J = 9Hz, 2H), 6.57 (s, 2H), 6.30–6.41 (m, 2H), 5.67 (s, 1H), 4.88 (d, 1H), 4.75 (d,
1H), 3.78–3.96 (m, 11H), 2.97 (S, 1H, +D2O disappeared).
14. Bergner, E. J.; Helmchen, G. J. Org. Chem. 2000, 65, 5072.