Bioorganic & Medicinal Chemistry Letters
Synthesis and anti-tumor activity of glycosyl oxadiazoles derivatives
⇑
Kui Du, Xianting Cao, Pengfei Zhang, Hui Zheng
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310016, China
a r t i c l e i n f o
a b s t r a c t
A new series of glycosyl oxadiazoles compounds were synthesized and characterized through 1H NMR,
13C NMR, IR and HRMS. The anti-tumor activities for MDA-MB-231 of all these new compounds were
screened in vitro by MTT assay. Due to the modification of gastrodin analogues, the anti-tumor activities
of these 1,3,4-oxadiazoles derivatives were greatly improved. Six compounds (6c, 6d, 6i, 6j, 6k and 6l)
displayed relatively higher MDA-MB-231 potency with IC50 values (0.89, 0.26, 1.35, 3.60, 0.95 and
Article history:
Received 10 May 2014
Revised 27 August 2014
Accepted 16 September 2014
Available online xxxx
1.08
l
M) compared with the reference medicine Rosiglitazone (5.23
lM).
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Gastrodin analogues
Anti-tumor activities
Oxadiazoles derivatives
Heterocycles
Malignant breast cancer is still one of the most common malig-
nant tumors which threatening female health in the world.
Although in the past few years the great progress in breast cancer
research has been achieved, new therapies are still in desperate
need nowadays. So it becomes more and more important to iden-
tify new targets for the treatment of malignant breast cancer.
Gastrodin is the main effective component of Chinese traditional
medicine gastrodia elata, it has been widely used in the clinic for
the treatment of hypertension, headache and neuralgia in China.
Moreover, the gastrodin analogues have been proved be a novel
class of potential anti-influenza agents.1 In recent reports, gastrodin
also displayed anti-tumor activity and anticoagulant effects.2,3
There was also report about the acylation of gastrodin can increase
activity to various extent.4 As one important part of five-membered
heterocyclics, the 1,3,4-oxadiazoles play a particularly vital role in
medicinal chemistry due to their variety of biological activities such
as antitumor,5–7 antibacterial,8 antimicrobial.9–12
As depicted in Scheme 1, the first position of D-glucose pent ace-
tate was placed by bromine in acetic acid in the presence of phos-
phorus tribromide to give compound 1, which reacted with methyl
p-hydroxybenzoate in anhydrous acetonitrile to obtain compound
2 and then the compound 3 was got through deacetylation of com-
pound 2 in sodium methoxide. Treatments of compound 3 with
98% hydrazine hydrate in methanol under reflux to give compound
4. The syntheses of compounds 5a–5l were accomplished by
refluxing compound 4 with fatty aldehydes or aromatic aldehydes
in ethanol. The glycosyl oxadiazoles compounds 6a–6l were
obtained by refluxing compounds 5a–5l in acetic anhydride. All
compounds were structurally characterized by IR, NMR and HRMS.
The (M+H)+ molecular ion peak of the compounds 6a–6l confirmed
the respective molecular weights. IR spectroscopy of 6a–6l showed
a peak ranging between 1607 and 1617 cmÀ1 confirming the C@N
stretch of oxadiazole ring. In 13C NMR spectra, the C proton of oxa-
diazoles ring showed peak in the range of 164–166 ppm.
Based on the good anti-tumor activities of the 1,3,4-oxadiazoles
and potential antitumor activities of acetagastrodin analogues, we
intend to design the new chemical structures which contain the
acetylated gastrodin and oxadiazoles moieties, and wish it had
the better activities. So we synthesized a series of new glycosyl
oxadiazoles compounds containing acetagastrodin analogues and
1,3,4-oxadiazoles (Fig. 1) in this Letter. The preparation of glycosyl
oxadiazoles compounds were achieved over the following process
Twelve glycosyl oxadiazoles compounds 6a–6l and twelve gly-
cosyl acyl hydrazone compounds 5a–5l were evaluated for anti-
tumor effect of MDA-MB-231 in vitro. The IC50 value and percent
of inhibition of the compounds were summarized in Tables 1 and
2. Most of the compounds were effective against MDA-MB-231
OAc
N
N
showed in Scheme 1 using D-glucose pentaacetate as the starting
material. The synthesized compounds were evaluated with anti-
tumor activities.
O
R
AcO
AcO
O
O
OAc
Target compounds
⇑
Corresponding author.
Figure 1. Synthesis of target compounds.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.