Synthesis and biological evaluation of 12 allenic aromatic ethers

Article abstract of DOI:10.1016/j.bmcl.2007.02.084

Twelve allenic aromatic ethers, some of them are natural products isolated from the mangrove fungus Xylaria sp. 2508 in the South China Sea, were synthesized. Their antitumor activities against KB and KBv200 cells were determined. All these compounds demonstrated cytotoxic potential, ranging from weak to strong activity. The analysis of structure-activity relationships suggested that the introduction of allenic moiety could generate or enhance cytotoxicity of these phenol compounds.

Full text of DOI:10.1016/j.bmcl.2007.02.084

Bioorganic & Medicinal Chemistry Letters 17 (2007) 2785–2788
Synthesis and biological evaluation of 12 allenic aromatic ethers
San-yong Wang,a Wei-wei Mao,b Zhi-gang She,a,* Chun-rong Li,c Ding-qiao Yang,b
Yong-cheng Lina,* and Li-wu Fua
aSchool of Chemistry and Chemical Engineering, Sun Yat-Sen(Zhongshan) University, Guangzhou 510275, China
bSchool of Chemistry and Environment, South China Normal University, Guangzhou 510006, China
cGuangdong Food Industry Institute, Guangzhou 510308, China
Received 20 November 2006; revised 24 January 2007; accepted 26 February 2007
Available online 12 March 2007
Abstract—Twelve allenic aromatic ethers, some of them are natural products isolated from the mangrove fungus Xylaria sp. 2508 in
the South China Sea, were synthesized. Their antitumor activities against KB and KBv200 cells were determined. All these com-
pounds demonstrated cytotoxic potential, ranging from weak to strong activity. The analysis of structure–activity relationships sug-
gested that the introduction of allenic moiety could generate or enhance cytotoxicity of these phenol compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
About 150 natural products with an allenic or cumulenic
structure moiety are known today.1 Inspired by the
intriguing biological activities of many allenic natural
products, allenic moieties are now introduced in the
compounds which have the pharmacologically activity.
The many functionalized allenes thus obtained exhibit
impressive activities, such as enzyme inhibitor activities,
cytotoxic or antiviral activities, etc.1
In the synthesis of these allenic aromatic ethers, one key
step was the preparation of 2,3-butadiene-1-ol (6). There
were two methods to synthesize 6 (Scheme 1). The first
method used 2-butyne-1,4-diol (4) as the starting mate-
rial. Chlorination of 4 with thionyl chloride gave the
monochloroalkyne (5), which was reduced with lithium
aluminum hydride to give compound 6,6 but in our
work, the yield of 6 was very low (15%), it was difficult
to separate the monochloroalkyne (5) from the dic-
hloroalkyne, and compound 5 was a severe skin irritant.
We tried another method that Baeckstrom et al.
reported,7 which started through a Mannich reaction
with diethylamine, formaldehyde, and 2-propynol. The
resulting 4-diethylamine-2-butyn-1-ol (7) was methyl-
ated with dimethyl sulfate, then reduced with lithium
hydride to afford 6 with a high yield of 71%. So the latter
method was used to synthesize a series of compound 2,
and 3.
Naturally occurring allenic compounds can be found in
microorganisms, fungi, higher plants, and insects. So
far, only several allenic aromatic ethers, for example,
chestersiene from the Hypoxylon chestersii,2 2b from the
Clitocybe eucalyptorum,3 xyloallenoide A and 2f from
the mangrove fungus Xylaria sp. 25084 were isolated. Re-
cently, we isolated four new allenic aromatic ethers (2c,
3a–c) from the Xylaria sp. 2508 again.5 In the preliminary
bioassay, some natural allenic aromatic ethers showed
antitumor activities against KB and KBv200 cells. The
limited amounts of isolated materials prevented the study
on their biological activities. Therefore, we synthesized 12
allenic aromatic ether analogs (see Fig. 1) to further
explore the effect of allenic groups bioactivities of com-
pounds. These compounds are the derivatives of allenic
group linking to compounds 1. Compound 2j is analo-
gous to the natural product xyloallenoide A.
Because 1a–h were commercially available and 6 was
also prepared, thus the series of compound 2 could be
synthesized readily. Scheme 2 shows the synthesis of
the compounds 2a–j. 4-Bromo-1,2-butadiene (8) was
prepared by bromination of 6 with phosphorus tribro-
mide and trace amount of pyridine at 0 °C.8
Then, treatment of compound 8 with 1a–d and 1g–j in
the presence of potassium carbonate gave 2a–d and
2g–j, respectively. Hydrolysis of compounds 2a and 2b
with LiOH in THF–H2O provided the corresponding
acids 2e and 2f.
Keywords: Allenic aromatic ethers; Synthesis; Antitumor agent;
KB cell; KBv200 cell.
*
Corresponding authors. Tel./fax: +86 20 84039623 (Y.L.); e-mail:
ceslyc@ mail.sysu.edu.cn
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.084

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S. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2785–2788
Figure 1. Structures of compounds 1a–j, 2a–j, and 3a–c.
Scheme 1. Two methods to synthesize 6.
Scheme 2. Synthesis of 2a–j.
In an attempt to study compound 2 analogs with two
allenic moieties, we used an excess amount of compound
8 to react with caffeic acid methyl ester (1d) or chloro-
genic acid (1g). Because the molecules of 1d and 1g con-
tain two phenol hydroxyl groups, it was anticipated that
they would form two allenic ethers in the excess amount
of 8 (mole ratio 2.5:1 or 3.5:1). However, it was unex-
pected that only one OH formed allenic ether, the OH
of R1 did not react with 8 in the two compounds. More-
over, the carboxyl group of 1g reacted with one allenic
moiety formed the ester. The structures of these com-
pounds were determined by the spectral data. Further-
more, the single crystals of 2g were obtained by
crystallization in EtOAc and PE.9 The structure of 2g
was finally confirmed by X-ray diffractive technique.
1-amino-cyclopropanecarboxylic (9) in the presence of
thionyl chloride in methanol. Compound 10 then cou-
pled with compound 1f in the presence of BOP and
DIEA in DMF to afford 1j.
The synthesis of the compounds 3a–c is presented in
Scheme 4. Several methods for preparation of halide of
2h were examined. When 2h was treated with phosphorus
tribromide or thionyl chloride, only a small amount of the
corresponding halide was obtained. We tried to use the
Ph3P/I2 reagent.10 The iodide compound 11 was success-
fully synthesized with a good yield of 82%. Treatment of
11 with 1a–c in the presence of potassium carbonate final-
ly gave compounds 3a–c, respectively.
The 12 allenic aromatic ethers, together with 1a–j, 6, 8,
and 10, were evaluated in vitro for their ability to inhibit
the growth of short-term cultured tongue cancer KB and
KBv200 cell lines by a modified MTT (3-(4,5-dimethyl-
The method described in Scheme 3 allowed for the prep-
aration of 1j. The intermediate 1-amino-cyclo-propane-
carboxylic acid methyl ester (10) was synthesized via

S. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2785–2788
2787
Scheme 3. Synthesis of 1j.
Scheme 4. Synthesis of 3a–c.
Table 1. Inhibitory activities of phenols and allenic aromatic ethers against tongue cancer KB and KBv200 cells in vitro
a
a
a
No.
IC50 (lM)
KBv200
>200
101.2
No.
IC50 (lM)
No.
IC50 (lM)
KB
KB
KBv200
KB
KBv200
1a
1b
1c
1d
1e
1f
>200
2a
2b
2c
2d
2e
2f
22.52
27.64
17.36
29.36
40.58
71.5
20.86
18.96
18.27
23.38
49.56
52.42
35.68
76.58
77.03
3a
3b
3c
6
75.40
48.76
34.55
>200
>200
135.2
52.92
55.47
30.27
>200
>200
>200
123.1
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
8
10
1g
1h
1j
2g
2h
2j
53.10
74.45
48.06
a Each experiment was independently performed three times and expressed as means. In addition, variation between the replicates was not greater
than 4% of any given value.
thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) as-
say.11,12 The IC50 values were also determined (Table 1).
the introduction of this moiety into 2b to form com-
pound 2j did not obtain the desired activity. It was also
observed that simple allenic compounds 6 and 8 had no
inhibitory activities against KB or KBv200 cells,
whereas the allenic aromatic ethers 2 or 3 showed good
inhibitory activities. Interestingly, when 2 and 3 have the
same R1, R2 group, 2 showed better inhibitory activities
than 3. The structurally difference between them was
that the latter has one more benzyloxy fragment.
As shown in Table 1, phenols, such as 1a and 1c–j, have
no inhibitory activities against KB or KBv200 cells,
while the corresponding allenic compounds 2a and 2c–
j exhibited inhibitory activities against these two cells.
Compound 1b itself has weak inhibitory activity, with
the IC50 values for KB/KBv200 of 123.1/101.2 lM, but
the corresponding allenic compound 2b has stronger
activity, with IC50 values for KB/KBv200 of 27.64/
18.96 lM. In fact, all the 12 allenic aromatic ethers
exhibited cytotoxic potential, ranging from weak to
strong activity. These data indicated that the introduc-
tion of allenic moiety to the phenol hydroxyl group
could generate or enhance cytotoxicity of these phenols.
Although the experiments were preliminary, it suggests
that the allenic moiety is effective for the antitumor
activities of these compounds.
In summary, we have synthesised 12 allenic aromatic
ethers and identified their structures. Ten of them are
new compounds, including four new natural products.
Many of these allenic aromatic ethers showed potent
and efficacious antitumor activities against KB and
KBv200 cells. The analysis of structure–activity relation-
ships suggested that the introduction of allenic moiety
could generate or enhance cytotoxicity of these phenol
compounds.
Among the 12 allenic aromatic ethers, four compounds
2a–d have significant cytotoxicities (IC50 < 30 lM). The
introduction of OCH3 (2c) or OH (2d) groups on the
benzene ring of 2b showed no influence on the activity.
Compound 2g has two allenic moieties (one is linked
to the carboxyl group), but it did not exhibit better
activity. Although compound 10 has weak inhibitory
activity against KB cells with IC50 value of 135.2 lM,
Acknowledgments
This work was supported by the 863-Foundation of
China (2003AA624010), the National Natural Science
Foundation of China (29672053), and Guangdong
Provincial Public Laboratory of Food Industry,
China.

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S. Wang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2785–2788
4. Lin, Y. C.; Wu, X. Y.; Feng, S.; Jiang, G. C.; Zhou, S. N.;
Supplementary data
Vrijmoed, L. L. P.; Gareth Jones, E. B. Tetrahedron Lett.
2001, 42, 449.
5. This work will be published in Nature Product Research.
6. Adegoke, E. A.; Emokpae, T. A.; Ephraim-Bassey, H.
J. Heterocyl. Chem. 1986, 23, 1195.
Synthetic details and characterization associated with
this article are included in the Supporting Information.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.02.084.
7. Baeckstrom, P.; Stridh, K.; Li, L.; Norin, T. Acta Chem.
Scand. 1987, 41, 442.
8. Masaki, M.; Yoshinori, Y. J. Org. Chem. 1999, 64, 694.
9. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 627543.
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