Bioorganic & Medicinal Chemistry Letters
Synthesis and biological activity of 5-(4-methoxyphenyl)-oxazole
derivatives
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Daisuke Yamamuro , Ryuji Uchida , Masaki Ohtawa , Shiho Arima , Yushi Futamura , Masumi Katane ,
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Hiroshi Homma , Tohru Nagamitsu , Hiroyuki Osada , Hiroshi Tomoda
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Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
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a r t i c l e i n f o
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Article history:
5-(4 -Methoxyphenyl)-oxazole (MPO), originally reported as a synthetic compound, was isolated from
fungal culture broth as an inhibitor of hatch and growth of Caenorhabditis elegans. Nineteen MPO deriv-
atives were chemically synthesized, but showed no effect on C. elegans hatch and growth. These findings
strongly suggested that the whole structure of MPO is essential for anti-C. elegans activity.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 24 October 2014
Revised 12 November 2014
Accepted 14 November 2014
Available online xxxx
Keywords:
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5
-(4 -Methoxyphenyl)-oxazole
Caenorhabditis elegans
Hatch inhibition
6
Small-molecule inhibitors of protein function are powerful tools
for biological analysis1 and can lead to the development of new
drugs. It is important in chemical biological study to characterize
the targets of small molecules with biological functions. Recently,
the nematode Caenorhabditis elegans has been established as a
useful model organism for studying developmental and metabolic
reported to be an octopamine receptor agonist. However, octopa-
mine (1.0 mM) had no effect on hatch and growth of C. elegans. In
this study, twenty MPO derivatives were synthesized and their bio-
logical activities including effect on phenotype of C. elegans were
investigated.
To investigate structure–activity relationships (SAR) of the MPO
derivatives, regioisomers 2–4, oxazole derivatives 5–15 with
chemical modifications at the 5-position, oxazole derivatives
16–18 with an aryl group at the 2-position, a thiazole 19 and an
imidazole 20 were synthesized according to the known proce-
dures. Most derivatives (except for 4, 16, 19 and 20 ) were
constructed by the coupling reaction of the corresponding
aldehydes with p-toluenesulfonylmethylisocyanide (TosMIC) as
shown in Scheme 1.
2
,3
processes. The whole genome sequence of C. elegans was com-
4
pleted; therefore we focused on the phenotypic abnormality of
C. elegans caused by a small molecule, and started forward genomic
screening for microbial metabolites which caused the phenotypic
abnormality of C. elegans to obtain small molecules with a new
mechanism of action. In our previous study, we screened a library
of 315 known microbial compounds and 9,156 culture broths for
small molecules that induced phenotypic abnormality of wild-type
7
,8
9
10
11
12
5
C. elegans and identified 7 active compounds. Among them, we
The effect of the synthetic MPO derivatives (1–20) on pheno-
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5,13
focused on 5-(4 -methoxyphenyl)-oxazole (MPO; 1) for two rea-
type of C. elegans was tested
(see Supplementary data). As
sons; (1) compound 1 was isolated from fungal metabolites for
the first time, and (2) 1 showed unique activity in our screening
assay using C. elegans. Namely, 1 caused abnormal arrangement
of germ cells and inhibited the hatch of eggs newly spawned by
shown in Figure 1a and b, germ cells were orderly arranged and
normal eggs were spawned in control C. elegans, respectively. How-
ever, synthetic 1 was found to cause a growth inhibition at 17–
100
lM (data not shown) and abnormal arrangement of germ cells
adult C. elegans (100% hatch inhibition) at 17
over, the growth of C. elegans stopped at the L1 stage (egg to Larvae
stage; it takes 8 hours from the laying of egg) on day 3 after incu-
bation in the presence of 1 at 17–100 M without growth inhibi-
tion of Escherichia coli. There are few information about 1. It was
l
M on day 3. More-
of C. elegans at 17 l
M (Fig. 1c). And newly spawned eggs appeared
labile and the contents seep out (Fig. 1d). These abnormality
(growth inhibition and hatch inhibition) caused by synthetic 1
was the same as those caused by natural 1. Among the derivatives,
1
l
only 12 showed moderate hatch inhibition of C. elegans at 100 lM.
However, the other derivatives lost the growth inhibition and the
hatch inhibition of C. elegans (Table 1). For example, derivative 6
⇑
(
3
OCH moiety in 1 was replaced with OH in 6) showed no growth
960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
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