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G aphical abs ac
pp xxx–xxxSyn hesis o a a ic acid analogues o FR258900 and hei e alua ion as glycogen phospho ylase inhibi o s
Ge gely Va ga, Tibo Docsa, Pál Ge gely, László Juhász
*
, László Somsák
*
HOOC
(S)
(R)
COOH
O
O
(E)
O
(E)
OH
HO
O
FR258900
co e uni
HOOC
(S)
(S)
COOH
OH
HO
HOOC
(R)
(R)
COOH
OH
HO
HOOC
(R)
(S)
COOH
OH
HO
D
- a a ic acid
L
- a a ic acid meso- a a ic acid
o o
(E)
COOH
R
2
R
1
R
1
=R
2
= H: cinnamic acid
R
1
=H;R
2
=OH:p-couma ic acid
R
1
=OCH
3
;R
2
=OH: e ulicacid
K
i
=5.47µM (agains G1P)
K
i
=0.2-0.46µM (agains AMP)
co e uni
eplaced by
a a ic acids
es e i ied by
K
i
=3.36-109µM(agains G1P)
K
i
=2.0-26.4µM(agains AMP)
BMCL 20030 No. o Pages 1, Model 5G
28 Janua y 2013
1
Syn hesis o a a ic acid analogues o FR258900 and hei e alua ion
as glycogen phospho ylase inhibi o s
Ge gely Va ga
a
,Tibo Docsa
b
,Pál Ge gely
b
,László Juhász
a,
⇑
,László Somsák
a,
⇑
a
Depa men o O ganic Chemis y, Facul y o Science and Technology, Uni e si y o Deb ecen, Egye em é 1, PO Box 10, H-4010 Deb ecen, Hunga y
b
Depa men o Medical Chemis y, Medical and Heal h Science Cen e, Uni e si y o Deb ecen, Egye em é 1, H-4032 Deb ecen, Hunga y
a icle in o
A icle his o y:
Recei ed 4 Decembe 2012
Re ised 10 Janua y 2013
Accep ed 12 Janua y 2013
A ailable online xxxx
Keywo ds:
20 FR258900
Ta a ic acid de i a i es
Diabe es
Glycogen phospho ylase
Inhibi o
abs ac
Di-O-cinnamoyla ed, -p-couma oyla ed, and - e uloyla ed D-, L-and meso- a a ic acids we e syn hesized
as analogues o he na u al p oduc FR258900, a glycogen phospho ylase (GP) inhibi o wi h in i o an i-
hype glycaemic ac i i y. The new compounds inhibi ed abbi muscle GP in he low mic omola ange,
and bound o he allos e ic si e o he enzyme. The bes inhibi o was 2,3-di-O- e uloyl meso- a a ic acid
and had K
i
alues o 2.0
l
M agains AMP (compe i i e) and 3.36
l
M agains glucose-1-phospha e
(non-compe i i e).
Ó2013 Published by Else ie L d.
The numbe o pa ien s su e ing om diabe es melli us (DM) is
d ama ically inc easing. In 2011 he in e na ional diabe es ede a-
ion p ojec (IDF) indica ed ha he numbe o diabe ic pa ien s
was mo e han 360 million wo ldwide.
1
In 2001 his numbe was
40
p edic ed o be eached in 2030 only.
2
Mo e han 90% o he diag-
nosed cases belong o ype 2 o non-insulin dependen diabe es
melli us (T2DM o NIDDM) cha ac e ized by pe iphe al insulin
esis ance, ele a ed hepa ic glucose p oduc ion, and de ec s in
panc ea ic insulin sec e ion.
3
Al hough se e al d ugs a e in clinical
use o symp oma ic ea men o T2DM,
4,5
hese he apies a e
inadequa e o 30–40% o he pa ien s.
6
Among se e al in es iga ional fields o diminish hepa ic
glucose ou pu in T2DM, glycogen phospho ylase (GP) as a main
egula o y enzyme o glycogen me abolism has become a alida ed
50
a ge .
2
P o ein c ys allog aphic s udies ha e shown ha endogenous
and syn he ic modula o s can bind o six majo si es in GP: he
ca aly ic, he inhibi o , he allos e ic (o AMP-binding), he glyco-
gen s o age, and he new allos e ic si es,
7
as well as he newly
disco e ed benzimidazole si e.
8
A numbe o GP inhibi o s o he
di e en binding si es ha e been disclosed and se e al o hem
ha e conside able in i o e ec s owa ds no malizing blood
glucose and li e glycogen le els.
9,10
In ecen yea s, he in e ac ion o GP and glycogen a ge ing
60
subuni (G
L
) o p o ein phospha ase 1 (PP1) has been iden ified
as a no el molecula a ge o he ea men o T2DM.
11–13
I
was demons a ed in an in i o mouse model ha dis up ion o
G
L
–GP in e ac ion esul ed in an inc eased glycogen syn hase
ac i i y and he mice had imp o ed glucose ole ance.
14
X- ay
c ys allog aphy showed ha he G
L
–GP in e ac ion ook place by
binding he C- e minal egion o G
L
o he allos e ic si e o GP.
15
Thus, occupa ion o his si e may p e en G
L
–GP in e ac ion, he e-
by enhancing glycogen syn hesis which, on he o he hand, dimin-
ishes hepa ic glucose p oduc ion. This e ec could be achie ed by
70
modula o s ha bind o he allos e ic si e o GP.
Se e al molecules o high s uc u al di e si y we e epo ed o
bind o he allos e ic si e o GP, such as de i a i es o acyl u ea,
dihyd opy idine dica boxylic acid, pen anedioic acid, ph halic acid,
N,N
0
-dia yl-u ea, and pen acyclic i e penoids.
9,16
HOOC
COOH
O
O
OOH
HO
O
FR258900
1
co e uni
IC50 = 2.5 μM (human li e GP)17
Ki= 0.46 μM ( abbi muscle GP)18
0960-894X/$ - see on ma e Ó2013 Published by Else ie L d.
h p://dx.doi.o g/10.1016/j.bmcl.2013.01.042
⇑
Co esponding au ho s. Tel.: +36 52 512900x22474; ax: +36 52 512744 (L.J.),
el.: +36 52 512900x22348; ax: +36 52 512744 (L.S.).
E-mail add esses: [email p o ec ed] (L. Juhász), somsak.laszlo@
science.unideb.hu,[email p o ec ed] (L. Somsák).
Q2
Q1
Bioo ganic & Medicinal Chemis y Le e s xxx (2013) xxx–xxx
Con en s lis s a ailable a SciVe se ScienceDi ec
Bioo ganic & Medicinal Chemis y Le e s
jou nal homepage: www.else ie .com/loca e/bmcl
BMCL 20030 No. o Pages 5, Model 5G
29 Janua y 2013
Please ci e his a icle in p ess as: Va ga, G.; e al. Bioo g. Med. Chem. Le . (2013), h p://dx.doi.o g/10.1016/j.bmcl.2013.01.042
FR258900, a bis-O-(p-couma oyla ed)2,3-dihyd oxypen ane-
dioic acid de i a i e 1,was isola ed om he e men a ion b o h
o ungi No. 138354.
17
The compound was shown o inhibi glyco-
80
gen phospho ylases and o bind o he allos e ic si e o GP.
18
Com-
pound 1s imula ed glycogen syn hesis in p ima y a hepa ocy es,
and in es iga ions on glucagon-induced hype glycemia in C57BL/6
mice sugges ed ha 1could supp ess hepa ic glucose ou pu in
i o.
19
On he basis o he abo e in o ma ion and as a con inua ion o
ou esea ch on he design and syn hesis o small molecule inhib-
i o s o GP we en isaged he p epa a ion o s uc u al analogues o
1. Since he syn hesis o 2,3-dihyd oxy-pen anedioic acid is un-
known in he li e a u e, he co e uni was planned o be eplaced
90
by easily a ailable a a ic acid, also allowing o s udy he influ-
ence o configu a ional isome ism on he biological ac i i y. Fu -
he mo e, he subs i u ion pa e n o he a oma ic ings was also
modified.
A simila de i a i e o ou a ge compounds is chico ic acid
20
(2) wi h immunos imula o and HIV-1 in eg ase inhibi o ac i i-
ies.
21
O
O
COOH
HOOC
O
O
HO
HO
OH
OH
2
C ucial poin s o bo h he syn heses o chico ic acid
20–23
and
100
he p epa a ion o ou a ge compounds a e he p o ec ions o
phenolic OH and COOH g oups. Acyla ion o unp o ec ed a a ic
acids wi h ca bonylca eoyl chlo ide is easible, bu his ca bona e
ype p o ec ion can be used only o ca eic acid.
20
Benzylic p o ec-
ion o bo h unc ionali ies seemed e y a ac i e, howe e , o
he emo al an equimola amoun o Pd(OAc)
2
o each p o ec i e
g oup was necessa y ende ing his me hod ex emely expen-
si e.
23
O hogonal es e ype p o ec ion (ace yl o OH and e -bu-
yl o COOH
22
o me hoxyca bonyl o OH and diphenylme hyl o
COOH
21
) we e also applied in he syn heses o 2and hei ana-
110
logues. Ou compa a i e p elimina y expe imen s showed ha
in oduc ion o he la e pai o p o ec ing g oups was mo e e fi-
cien and easie o ep oduce han ha o he benzylic p o ec ion.
Thus, he COOH g oups o
D
-,
L
-and meso- a a ic acids (3–5)
we e ans o med in o diphenylme hyl (DPM) es e s (7–9)by
diphenyldiazome hane (DPDAM) gene a ed in si u om benzophe-
none-hyd azone (6) by oxida ion wi h ac i a ed MnO
2
in CH
2
Cl
224
(Scheme 1). DPM es e s 7–9we e isola ed in excellen yields as
whi e c ys als and used u he wi hou any pu ifica ion.
Nex , acid-chlo ides 15–17 we e p epa ed om comme cially
120
a ailable cinnamic (10), p-couma ic (11), and e ulic acids (12),
espec i ely (Scheme 2), whe eby phenolic OH g oups o 11 and
12 we e p o ec ed as me hyl-ca bona es 13 and 14, espec i ely.
Thionyl-chlo ide ea men o ca boxylic acids 10,13, and 14 ga e
acid-chlo ides 15–17 which we e used o acyla ions wi hou u -
he pu ifica ion.
Acyla ions o 7–9 we e ca ied ou in d y oluene using
2.2 equi o acid-chlo ides 15–17 and 2.2 equi d y py idine as
base (Scheme 3). The ully p o ec ed 18–25 we e isola ed by col-
umn ch oma og aphy in accep able yields.
130
Subsequen dep o ec ions ollowing he sugges ed p o ocol
21
( emo al o me hoxyca bonyl g oups wi h Na
2
CO
3
/aq THF and
clea age o DPM es e s wi h 70% aq AcOH) caused in ou hands o-
al decomposi ion o he molecules, i espec i e o he o de o he
dep o ec ion s eps.
The e o e, a new p o ocol o he clea age o p o ec ing g oups
in 18–25 was de eloped. The DPM es e s could be clea ed by using
d y anisole–TFA eagen in d y CH
2
Cl
2
a oom empe a u e.
25
Pu i-
fica ion o he c ude p oduc s by column ch oma og aphy
(PhCH
3
:AcOH 3:1) ga e 26–33 in good o excellen yields (Scheme
140
4). Hyd olysis o he me hoxyca bonyl es e s was achie ed by
using an aq solu ion o NH
3
in MeOH and he p oduc s 34–39 we e
isola ed in good o excellen yields. Re e sing o he sequence e-
sul ed in decomposi ion o he molecules in he fi s s ep. The
s uc u e o he molecules was iden ified by NMR and MS
measu emen s.
The syn hesized de i a i es we e e alua ed as inhibi o s o ab-
bi muscle glycogen phospho ylase b ( mGPb), and he esul s a e
summa ized in Table 1. Fo compa ison FR258900 (1) was also
es ed unde ou condi ions. Compound 1p o ed a compe i i e
150
inhibi o agains AMP and he ob ained K
i
o 0.2
l
M showed a good
ag eemen wi h he li e a u e alue. When es ed agains G1P, 1
appea ed as a non-compe i i e inhibi o wi h a K
i
o 5.47
l
M
(please, see Fig. 1 in he Supplemen a y da a o de ails o he mea-
su emen s and plo s o he da a). Simila conclusions could be
d awn om he kine ic s udies o compounds 32–39, as well,
he eby indica ing ha in gene al he a a ic acid de i a i es
bound o he same si e as FR258900 (1).
As non-compe i i e inhibi o s agains G1P, he cinnamoyl
de i a i es 32 and 33, lacking he 4-OH subs i uen s cha ac e is ic
160
o he na u al p oduc 1, p o ed p ac ically ine ficien . In he
p-couma oyl (34–36) and e uloyl (37–39) se ies he meso-config-
u ed compounds 36 and 39 p o ed mos e ficien . The la e dem-
ons a ed ha in oduc ion o an addi ional subs i uen in he
MnO2- MgSO4
d y CH2Cl2
.
Ph2CNNH2
6
Ph2CN2
d y CH2Cl2
.
3-5 7-9
DPMOOC
OH
COODPM
HO
COOH
HO
HOOC
OH
S a ing compound Con igu a ion P oduc Yield (%)
3
D
o (2S,3S) 7 85
4
L
o (2R,3R) 8 83
5 meso o (2R,3S) 9 82
Scheme 1. P epa a ion o DPM es e s 7–9.
a hen b
10 - 14 15 - 17
o b
R1
R2
COOH R1
R2
COOR3
a: ClCOOCH
3
in 50% aq. NaOH a 0 °C; b: SOCl
2
, e lux, 6 h.
R
1
R
2
R
3
Yield (%) Abb e ia ion
10 H H Cinn-OH
11 HOH Coum-OH
12 OCH
3
OH Fe u-OH
13 H OCOOCH
3
OH 84 4-MC-Coum-OH
14 OCH
3
OCOOCH
3
OH 88 4-MC-Fe u-OH
15 H H Cl 100* 4-MC-Cinn-Cl
16 H OCOOCH
3
Cl 100* 4-MC-Coum-Cl
17 OCH
3
OCOOCH
3
Cl 100* 4-MC-Fe u-Cl
* Con e sion o he s a ing ma e ial.
Scheme 2. P epa a ion o acid chlo ides 15–17.
2G. Va ga e al. / Bioo g. Med. Chem. Le . xxx (2013) xxx–xxx
BMCL 20030 No. o Pages 5, Model 5G
29 Janua y 2013
Please ci e his a icle in p ess as: Va ga, G.; e al. Bioo g. Med. Chem. Le . (2013), h p://dx.doi.o g/10.1016/j.bmcl.2013.01.042
a oma ic ings (3-CH
3
O) was e y ad an ageous and 39 p o ed
equipo en wi h 1.
As compe i i e inhibi o s agains AMP, beside he meso-config-
u ed 36 and 39, he
L
-configu ed 38 p o ed mos e ficien . Ne e -
heless, he e ficiency o he inhibi o s lagged behind ha o 1.
The p esence o he 3-CH
3
O moie ies in 39 ende ed his com-
170
pound he bes inhibi o unde hese es condi ions, as well.
In o de o de e mine he molecula basis o he e ficiency o
hese syn he ic compounds, p epa a ion o u he analogues as
well as molecula dockings and X- ay c ys allog aphic s udies a e
in p og ess, and will be epo ed in due cou se.
In conclusion, h ee se ies o
D
-,
L
-and meso- a a ic acids di-O-
acyla ed by cinnamic, p-couma ic, and e ulic acids we e p epa ed
as syn he ic analogues o FR258900, a na u al p oduc wi h
glycogen phospho ylase inhibi o y and in i o an ihype glycemic
ac i i ies. The syn heses we e cha ac e ized by using me hoxyca -
180
bonyl (MC) and diphenylme hyl (DPM) es e s o p o ec phenolic
OH and COOH g oups, espec i ely. New me hods we e applied
o he emo al o hese p o ec i e g oups (anisole–TFA o he
clea age o DPM, aq NH
3
–MeOH o hyd olyse MC). Some o he
new compounds p o ed inhibi o s o abbi muscle glycogen phos-
pho ylase b (compe i i e inhibi ion agains AMP, non-compe i i e
agains G1P) in he low mic omola ange. I was demons a ed by
his wo k ha simple syn he ic compounds can bind o mGPb
simila ly o he na u al p oduc , he eby opening up a new way
o u he s udies o allos e ic si e inhibi o s. The syn he ic a ail-
190
abili y o hese analogs o e s ob ious ad an ages o e FR258900.
Acknowledgmen s
This wo k was suppo ed by NKTH-OTKA (CK-77712), TÁMOP
4.2.1/B-09/1/KONV-2010-0007 and TÁMOP-4.2.2./B-10/1-2010-
0024 p ojec s co-financed by he Eu opean Union and he
Eu opean SocialFund, as well as János Bolyai Resea ch Schola ships
( o L.J. and T.D.) o he Hunga ian Academy o Sciences. As ellas
25% NH3solu ion
25 eq. CF3COOH
7 eq. d y anisole
d y CH2Cl2
O
HOOC
COOH
O
O
O
R2
R1
R2
R1
MeOH
32 - 39
18 - 25
26 - 31
P oduc s A
DPMOOC
O
COODPM
O R
R
HOOC
O
COOH
O R
R
o 32, 33
o 34-39
P oduc s B
RS a ing compound
(Con igu a ion) P oduc s A Yield (%) P oduc s B R
1
R
2
Yield (%)
Cinn 18 (
D
)--32 H H 83
19 (
L
)--33 H H 86
20 (
D
)26 88 34 H OH 85
4-MC-Coum 21 (
L
)27 82 35 HOH 89
22 (meso)28 82 36 HOH 30
23 (
D
)29 85 37 CH
3
OOH 81
4-MC-Fe u 24 (
L
)30 79 38 CH
3
OOH 69
25 (meso)31 92 39 CH
3
OOH 88
Scheme 4. Clea age o he p o ec i e g oups.
acid-chlo ide (15 - 17)
d y py idine
d y oluene, . .
7-9 18 - 25
DPMOOC
OH
COODPM
HO
DPMOOC
O
COODPM
O R
R
S a ing compound R P oduc (Con igu a ion) Yield (%)
7
8Cinn 18 (
D
)
19 (
L
)
63
52
7
8
9
4-MC-Coum
20 (
D
)
21 (
L
)
22 (meso)
54
48
83
7
8
9
4-MC-Fe u
23 (
D
)
24 (
L
)
25 (meso)
48
50
43
Scheme 3. Acyla ions wi h acid chlo ides 15–17.
Table 1
Inhibi ion (K
i
[
l
M]) o abbi muscle glycogen phospho ylase b by he syn he ic
compounds
Compound (configu a ion) G1P dependence AMP dependence
1(
L
a
) 5.47 0.20
0.46
18
32 (
D
) 800
b
—
33 (
L
) No inh. —
34 (
D
) 109 26.4
35 (
L
) 300
b
—
36 (meso) 71.4 5.68
37 (
D
) 29.1 19.0
38 (
L
) 28.5 2.68
39 (meso) 3.36 2.0
a
Configu a ion o he na u al p oduc co esponds o ha o
L
- a a ic acid.
b
Calcula ed om he IC
50
alue by using a web-based ool.
26
G. Va ga e al. / Bioo g. Med. Chem. Le . xxx (2013) xxx–xxx 3
BMCL 20030 No. o Pages 5, Model 5G
29 Janua y 2013
Please ci e his a icle in p ess as: Va ga, G.; e al. Bioo g. Med. Chem. Le . (2013), h p://dx.doi.o g/10.1016/j.bmcl.2013.01.042

Pha ma Inc., Japan is g a e ully hanked o kind p o ision o a
sample o FR258900.
Supplemen a y da a
200
Supplemen a y da a (kine ics o FR258900 inhibi ion o mGPb)
associa ed wi h his a icle can be ound, in he online e sion, a
h p://dx.doi.o g/10.1016/j.bmcl.2013.01.042.
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Please ci e his a icle in p ess as: Va ga, G.; e al. Bioo g. Med. Chem. Le . (2013), h p://dx.doi.o g/10.1016/j.bmcl.2013.01.042