Synthesis of tartaric acid analogues of FR258900 and their evaluation as glycogen phosphorylase inhibitors

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Please check his box i you ha e no co ec ions o make o he PDF ile 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. Re e ences and no es 1. 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