Communications tothe Editor Bull. Korean Chem. Soc. 2009, Vol. 30, No. 12 2881 DOI 10.5012/bkcs.2009.30.12.2881
Methyl Aryloxy Gallates as Regulators of Vascular Smooth Muscle Cell Proliferation
Jae-HwanKwak, Jin-Kyung In, Mi-SungLee,Ji-Yeon Yu, Yeo-Pyo Yun,Jin Tae Hong, Soo Jae Lee, Seung-Yong Seo： Soon KilAhn,* Young-Ger Suh,§ Bang-YeonHwang,Heesoon Lee, Kyung Hoon Min,#,* and Jae-KyungJung*
College of Pharmacy, Chungbuk National University, Cheongju361-763,Korea. *E-mail:[email protected]
‘College of Pharmacy, Woosuk University, Wanju 565-701, Korea
*Equispharm Co.Ltd., Gyeonggi-Do 443-766,Korea
§College of Pharmacy, SeoulNational University, Seoul 151-742, Korea
규 College of Pharmacy, Chung-Ang University,Seoul 156-756,Korea. *E-mail: [email protected] Received November 6, 2009, Accepted November13, 2009
KeyWords: Atherosclerosis, Vascular smooth musclecell, Obovatol, Methyl gallate,PDGF
Abnormal proliferation and migration of vascularsmooth musclecell(VSMC) have been shown to beimportant events in pathogenesis ofatherosclerosis. Platelet-derived growth factor (PDGF) plays a keyrole inthe VSMC proliferationandpheno typic transform among manyfactorscontributing to VSMC activation.1 AmongPDGFfamily (PDGF-AA, AB, BB, CC, DD) PDGF-BBcan bindtoall PDGF receptors withhigh affi
nity and strongly stimulates VSMC proliferation.Thus,regula tion of PDGF -BB-induced VSMC proliferation is considered to be a promising therapeutic target to preventprogression of atherosclerosis.
Withrespectto the development of small moleculeregulator with antiproliferativeeffect on VSMC,wehavereported that
mCPBA CH2CI2
Pd/C, H2
MeOH
Scheme 1. Obovatol and synthesis of its derivatives
obovatol, isolated from Magnolia obovata, potentlyinhibitthe growth of rat aorticVSMCs and DNA synthesis induced by platelet-derived growthfactor (PDGF)-BB.2 Basedon ourpre
vious results, combinedwith ourcontinuing efforts toward diaryl ether compounds,3 we have made efforts to developmore potentmolecules through studieson structureactivity relation ship. Herein we report synthesis of obovatolderivatives and theiranti-proliferative effects on rataortic VSMC,acellular model for SMCproliferation.
The synthetic route for the obovatol derivatives is illustrated in Scheme1 and 2. Most compounds were obtainedaccording tothe procedure in our previous report.4 In brief, with methyl gallateinhand, selective dimethylationand Cu(OAc)2 catalyzed etherification provided the desired diarylethers. Cleavage of methyletherswith BBr3 furnished catechol derivatives. Syn thesis of derivativesbearing alkoxy group inB ring was accom plished via mono TBS-protected intermediate, which was obtainedby reacting methylgallatewithTBSCl only under K2CO3 in DMF. Otherconditions using tert-amine suchas E3N and Hunigbasegavethe productinapoor yield dueto many undesired sidereactions.
Rat aorticvascular smoothmusclecells (RAVSMCs) were isolatedby enzymatic dispersion according to the modified method of Chamleyet al.2,5
The anti-proliferation activity of theobovatol derivatives at 10卩M is summarized inTable 1. Saturated obovatol analog 1 was equipotent to obovatol. Acetylatedanalog2 of obovatol
Methyl gallate
K2CO3, MeI
DMF
(HO)2B R
Cu(OAc)2, Et3N CH2Cl2
a: R =4-n-Pr b:R =4-n-Bu c:R= 4-t-Bu d: R =4-OH e: R = 4-OMe f: R= 4-OEt g: R =4-O-n-Pr h:R = 3,4-di-F i: R = 4-Cl j:R = 4-Br k:R= 4-Ac l: R = 4-CN TBSCl, K2CO3
DMF
(H이2B°R
Cu(OAc)2, Et3N CH2Cl2
Scheme 2. Synthesis of derivatives from methyl gallate
2882 Bull.KoreanChem. Soc. 2009, Vol. 30, No. 12 Communicationsto theEditor
Table 1. Anti-proliferation activity of obovatol derivatives at 10 卩M
compound obovatol 1 2 3 5l 5e 5i 5h 5c 5k 6a
% inhibition 100 100 100 0 0 12.3 100 0 0 0 100
compound 6b 6c 6d 6f 6g 6h 6i 6j 6k 8f 8g
% inhibition 100 100 0 0 0 8.5 5.5 100 22.3 9.8 100
Table 2. IC50 values of selected derivatives
compound 1 2 5i 6a 6b 6c 6j 8g obovatol
IC50 (卩M) 2.73 2.93 2.99 0.99 0.96 1.23 4.91 2.48 3.00
Figure 1. Effect of the representative compounds (6 a, 6b and 6 c) on PDGF-BB induced proliferation in RAVSMC.
still retained anti-proliferation activity. However,introduction of oxiranes (3)led to a completeloss of activity. Methyl ester functionality wasintroducedtoreplace the allygroup in Aring.
Theseanalogueswere foundtopossesssignificant anti-proli
ferativeactivity for VSMC. Compound 6b, methyl esterderiva tive of compound 1, was 3-fold more active than obovatol (Table 2).Wenextexplored modification of phenoxymoiety, Bring. Incorporation ofacetyl group (6k) or chloro (6i) orfluoro (6h) atom intoB ring resulted in a considerable loss of activity.
Derivatives possessing alkyl group such as n-propyl (6a), n- butyl (6b) or t-butyl (6c) exhibitedinhibitory effect about 3-fold better than obovatol. As shown in Figure 1,anti-proliferative activity of derivatives for smoothmuscle cells is clearly not driven from intrinsic cytotoxicity, but by inhibition ofPDGF-BB dependentsignaling events.Unlike chloro (6i)or fluoro (6h) compoundhaving high electron negativity, bromoanalog (6j) was exceptionally active,but weakerthan obovatol. In addition, strongelectrondonatinggroups (6d, 6f and 6g)ledtocomplete loss of activity aswell. It indicates that neither strong electron withdrawing or donatingsubstituentsat B ring are favorable toactivity.Unexpectedly, while TBS-protected8fshowedvery weak activity, 8g showed anti-proliferative activity slightly better than obovatol. However, removal of TBSgroup of 8g resulted inloss of activity. Hence,itmay not betrue that TBS group is expected tobe unstable and removed easily in physi ological condition in thiscase.It hasbeen reportedthat a TBS- protected compound showed excellentbiological activity.6 Di
rectcomparison of catechol 6c and dimethoxy5c revealed that catechol moiety isessential to exhibit anti-proliferative activity.
Only4-chloro analog 5iretained activity among dimethoxyderi
vatives,thus wehypothesize it couldhavedifferent binding mode.
In summary, we have discoveredpotentinhibitors for PDGF- BBinducedVSMCproliferation. Some methyl aryloxygallate compounds showed better inhibitoryactivity than obovatol.
We identified obovatol derivativesthat are potentially promising agentsfor targeting the progression of atherosclerosis and need attentionfor furtherinvestigation.
Acknowledgments.This study wassupportedby the Korea Research Foundation Grant funded bythe Korean Government (MOEHRD) (The RegionalResearchUniversities Program/
Chungbuk BITResearch-Oriented University Consortium)and bythe Korea Science and EngineeringFoundation(KOSEF) Grant funded by the Korea Government(MOST)(R13-2008- 001-00000-00).
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