TWI492765B - Glucose transferase inhibitor with epigallocatechin gallate polymer as an active ingredient - Google Patents
Glucose transferase inhibitor with epigallocatechin gallate polymer as an active ingredient Download PDFInfo
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- TWI492765B TWI492765B TW098128375A TW98128375A TWI492765B TW I492765 B TWI492765 B TW I492765B TW 098128375 A TW098128375 A TW 098128375A TW 98128375 A TW98128375 A TW 98128375A TW I492765 B TWI492765 B TW I492765B
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- polymer
- egcg
- glucose transferase
- oolong
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- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
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Description
本發明係有關以表沒食子兒茶素沒食子酸酯聚合物做為有效成分之葡萄糖轉移酶抑制劑,及添加其之飲食品。
過去對於齲蝕提出過各種假說,但目前根據米勒(Miller)的化學細菌說,認為是一種細菌感染症。根據該學說齲蝕的發生機轉係如下所述。亦即,由口腔鏈球菌特別是轉糖鏈球菌(Streptococcus mutans
,以下簡稱作「S. mutans」)所產生之葡萄糖轉移酶(糖轉移酵素,GTF),以口中的蔗糖為基質,生成具黏著性的不溶性多醣(葡聚醣)。而S. mutans的菌體就利用生成的葡聚醣附著於牙齒表面而形成牙菌斑(plaque)。有以S. mutans為首的各種微生物共生‧繁殖於牙菌斑中,由於這些微生物進行代謝產生有機酸,而因該有機酸的作用使牙菌斑內部的pH值下降,牙齒的琺瑯質表面產生脫鈣化而使齲蝕發生、進行。另外,齒垢形成係除齲蝕外,亦是形成牙周病及口臭的原因。
由此可知,由於以S. mutans為中心的口腔鏈球菌所形成的齒垢是造成齲蝕的原因,故抑制齒垢的形成,應可做為預防齲蝕發生的有效方法。
近年來植物等所含之兒茶素類作為具有抗齲蝕作用之物質受到注目。於專利文件1中報告有藉由將類黃酮(兒茶素類的一種)以過氧化酶進行處理,而製造之具有分子量為800~5000之類黃酮聚合物,與進行處理前相比,葡萄糖轉移酶的抑制作用被增強。
另外在非專利文件1中報告有類黃酮聚合物於濃度為2.5μg/mL時,可對來自邊緣鏈球菌(Streptococcus sobrinus
)之葡萄糖轉移酶的活性,產生50%的抑制作用。
而於專利文件2中,報告有於藉由將黃烷酮類/黃烷醇類之還原物或無色花青素類與兒茶素類進行縮合而製造重量分子量為1000~10000之類黃酮聚合物,發現有葡萄糖轉移酶的抑制作用。
然而該等類黃酮聚合物係類黃酮的3~5聚物或2~3聚物之混合物,並未對混合物中所含之各種化合物進行分離,因而完全無法得知與各個化合物單體有關的葡萄糖轉移酶抑制活性。
在日常飲用的茶當中,來自非發酵茶之綠茶的兒茶素類混合物,已被報告為具有葡萄糖轉移酶抑制作用。然而於使用小鼠的試驗中,被報告為未獲得充分的抗齲蝕作用。
另外於半發酵茶之烏龍茶及其純化物中,被報告發現有葡萄糖轉移酶抑制活性(專利文件3、非專利文件3、非專利文件4及非專利文件5)。且已知將綠茶、烏龍茶及紅茶藉由進行加熱處理,可增強葡萄糖轉移酶抑制活性(專利文件4),以及藉由對兒茶素類進行加熱處理,可增強葡萄糖轉移酶抑制活性(專利文件5)。
但上述任一種情況均未針對來自茶的混合物中,指明究竟是何種化合物具有活性。
專利文件1:特開平6-247959號公報
專利文件2:特開平7-242556號公報
專利文件3:特開平6-279302號公報
專利文件4:特開平3-284625號公報
專利文件5:特開平3-284671號公報
非專利文件1:FEMS Microbiology Letters 143(1996)35-40,Hamada S. et al.
非專利文件2:Caries Res. 25(1991)438-443,Otake S. et al.
非專利文件3:Applied and Environmental Microbiology,59,No.4(1993)968-973,Nakahara K. et al.
非專利文件4:The Nippon Dental review No.622(August 1994)179-189,Ooshima T. and Hamada S.
非專利文件5:FEMS Microbiology Letters 228(2003)73-80,Matsumoto M. et al.
如上所述,目前已進行有關具有葡萄糖轉移酶抑制活性之植物萃取物等之報告,但均僅為報告來自植物萃取物之混合物具有活性,具體的活性成分(化合物)尚未釐清,同時也期望可鑑定出活性成分。而利用偏好性低之來自植物成分做為飲食品時,因可預期會損及飲食品的香味及安全性,希望探索風味性佳之來自植物之活性成分。
本發明之發明者們,考慮到利用為飲食品,著眼於日常飲用茶類中所含成分進行專心檢討後,發現將烏龍茶等所含的屬於兒茶素一種之(-)-表沒食子兒茶素-3-O-沒食子酸酯(以下亦稱做EGCG)進行聚合所得之EGCG聚合物中,其中特別以EGCG 3聚物具有很強的葡萄糖轉移酶抑制活性,本發明遂至完成。
亦即本發明係如下所述。
1.一種葡萄糖轉移酶抑制劑,其係以表沒食子兒茶素沒食子酸酯三聚物或其鹽為有效成分。
2.如1之葡萄糖轉移酶抑制劑,其中該表沒食子兒茶素沒食子酸酯三聚物係於色滿環之第6及/或第8位置,介由亞甲基所結合之化合物。
3.如2之葡萄糖轉移酶抑制劑,其中該表沒食子兒茶素沒食子酸酯三聚物係選自具有下述式(I):
之化合物,及具有下述式(II):
之化合物,以及具有下述式(III):
之化合物(式(I)~(III)中,R係下述式(A):
所示之沒食子醯基)所成群之化合物。
4.一種葡萄糖轉移酶抑制劑,其係以下述式(IV):
所示之化合物為有效成分。
5.一種抗齲蝕劑,其係以表沒食子兒茶素沒食子酸酯三聚物或其鹽為有效成分。
6.如5之抗齲蝕劑,其中該表沒食子兒茶素沒食子酸酯三聚物係於色滿環之第6及/或第8位置,介由亞甲基所結合之化合物。
7.如6之抗齲蝕劑,其中該表沒食子兒茶素沒食子酸酯三聚物係選自具有上述式(I)之化合物,及具有上述式(II)之化合物,以及具有上述式(III)之化合物(式(I)~(III)中,R係上述式(A)所示之沒食子醯基)所成群之化合物。
8.一種抗齲蝕劑,其係以上述式(IV)所示之化合物為有效成分。
9.一種飲食品,其係經添加如1~8中任一項之葡萄糖轉移酶抑制劑或抗齲蝕劑。
10.如9之飲食品,其中該飲食品係茶飲料。
11.一種口腔衛生劑,其係經添加如1~8中任一項之葡萄糖轉移酶抑制劑或抗齲蝕劑。
本發明之發明者們,發現了(-)-表沒食子兒茶素-3-O-沒食子酸酯(EGCG)聚合物,特別是特定的EGCG 2聚物及3聚物,具有極高的葡萄糖轉移酶抑制作用。如前所述,由於葡萄糖轉移酶(以下亦稱做GTF)會在口中生成造成齒垢原因的葡聚醣,藉由抑制GTF的活性可預防齲蝕。因此可將本發明之GTF抑制劑使用為抗齲蝕劑。而由於本發明之GTF抑制劑可抑制造成齒垢原因之葡聚醣的生成,亦可期待抑制口臭的效果。進而由於本發明之GTF抑制劑係來自日常飲用的烏龍茶等飲食品中所含之EGCG,具高偏好性,且對人體具有高安全性。另外,藉由使飲食品中含有一定量之該GTF抑制劑,可提供不會過度損害飲食品香味,且偏好性高、安全,具有抗齲蝕作用之飲食品。
(-)-表沒食子兒茶素-3-O-沒食子酸酯(EGCG)係綠茶等茶類中所含之兒茶素類中的主要成分之一,係具有以下述式
所示構造之化合物。
本發明之GTF抑制劑中所含之有效成分即為上述之EGCG之聚合物。於本發明中,所使用之EGCG特別以於其色滿環之第6及/或第8位置,介由亞甲基而具有2或3個結合構造之EGCG聚合物為佳。如此之EGCG聚合物之具體例可舉出以下述式(I)、式(II)及式(III):
所示之EGCG 3聚物(式(I)~(III)中,R係沒食子醯基),以及以下述式(IV):
所示之EGCG 2聚物等。
式(I)之化合物係以EGCG的結合樣式為基礎,可記為EGCG8:8EGCG6:8EGCG(以下於本說明書中,亦稱其為類烏龍雙黃烷-3聚物-1,OHBF-Tri-1,或Tri-1)。同樣的,式(II)之化合物可記為EGCG6:8EGCG6:8EGCG(以下於本說明書中,亦稱其為類烏龍雙黃烷-3聚物-2,OHBF-Tri-2,或Tri-2)。另外,式(III)之化合物可記為EGCG8:8EGCG6:6EGCG(以下於本說明書中,亦稱其為類烏龍雙黃烷-3聚物-4,OHBF-Tri-4,或Tri-4)。式(IV)之化合物可記為EGCG6:8EGCG。已知式(IV)之化合物被報告為含於烏龍茶等之化合物,為類烏龍雙黃烷-B(OHBF-B)。另外式(II)及式(III)之化合物係新穎的化合物。
可使上述之EGCG聚合物與表沒食子兒茶素沒食子酸酯,於溶媒中在酸存在下,與甲醛進行反應而製造。
可使用於反應之溶媒可舉出例如甲醇、乙醇、正丙醇及異丙醇等醇類。對於溶媒使用量無特別限制,例如相對於1質量份之表沒食子兒茶素沒食子酸酯,可使用20~200質量份之溶媒。
可使用之酸可舉出如鹽酸、硫酸及硝酸等無機酸,還可使用蟻酸及醋酸等有機酸。針對酸的使用量無特別限制,例如相對於1莫耳之表沒食子兒茶素沒食子酸酯,可使用0.01~2莫耳之酸。
甲醛則為例如相對於1莫耳之EGCG,可使用1~100莫耳。
反應溫度及時間依所使用的溶媒量而定,例如反應溫度為-10~50℃,反應時間為10分鐘~12小時,典型反應溫度為室溫(25℃左右)。
藉由EGCG與甲醛之反應所得之生成物,一般為含有至少二種因亞甲基而與色滿環鍵結形式相異之化合物的混合物。而可藉由例如HP-20(三菱化學股份有限公司製)等苯乙烯系吸附樹脂,及藉由如Shephadex LH-20般之聚葡萄糖系樹脂之開放式管柱層析儀,及高速液相層析儀(HPLC)等周知之生成方法,由該等混合物中,分離出式(I)~(IV)之各化合物。
式(I)之化合物(OHBF-Tri-1)之調製方法係專利文件中(WO2005/116005)所載之「3聚物(4)」之合成及純化方法。式(IV)之化合物(OHBF-B)之調製方法,係記載於文獻(Chem.Pharm.Bull 37(12),3255-3563(1989))。
使用於本發明之葡萄糖轉移酶抑制劑之EGCG聚合物,亦可為鹽之型態。該等鹽若為醫藥或食品許可之鹽則無特別限制,可舉出例如鋰鹽、鈉鹽、鉀鹽、鈣鹽及鎂鹽等週期表IA族或IIA族之金屬元素的鹽。該等金屬鹽可形成於例如EGCG酚性羥基上。
例如EGCG 3聚物之鈉鹽,係將EGCG 3聚物與金屬鈉或氫化鈉,使其於非質子性溶媒中進行反應,藉由使EGCG 3聚物中所含羥基(-OH)轉變為鈉醇基(-ONa)而製造。此時,藉由調節金屬鈉或氫化鈉的使用量,可使EGCG 3聚物中所含羥基全部轉變為鈉醇基,另外,亦可僅將一部分的羥基轉變為鈉醇基。
該等EGCG聚合物係可藉由合成而得,但如後述實施例5所述,已證實亦存在於烏龍茶中。因此,為本發明GTF抑制劑之有效成分之EGCG聚合物,係可將Camellia sinensis[A1]的葉子為原料之茶類,其中以烏龍茶、紅茶等發酵茶及焙茶為佳,自該等茶類藉由萃取或純化而進行分離。
根據本發明之發明者們,發現了EGCG聚合物,特別係上述式(I)之化合物之類烏龍雙黃烷-3聚物-1,式(II)之化合物之類烏龍雙黃烷-3聚物-2,式(III)之化合物之類烏龍雙黃烷-3聚物-4,以及式(IV)之化合物之類烏龍雙黃烷-B,具有很強的葡萄糖轉移酶抑制作用。
葡萄糖轉移酶抑制作用之測定,可使用示於先前文獻等所記載的任一種評價法而進行。例如將由Streptococcus mutans
等所調製之葡萄糖轉移酶添加於含有蔗糖的水溶液中,於口腔內相同程度的溫度(約37℃)下,進行未達24小時,以16~20小時左右為佳之孵育,藉由酵素反應由蔗糖生成葡聚醣。而由於葡聚醣不溶於水,藉由測定所得之反應液之濁度(例如於波長550nm時之濁度),可評價葡聚醣之生成量。將生成較少葡聚醣(亦即濁度較低)時與生成較多葡聚醣(亦即濁度較高)時相比,可說前者之葡萄糖轉移酶之活性較被抑制。
本發明之葡萄糖轉移酶抑制劑,由於係藉由抑制葡萄糖轉移酶(GTF)之活性,而可抑制形成口中齒垢成因之葡聚醣之生成,進而可使用為抗齲蝕劑。
本發明之葡萄糖轉移酶抑制劑或抗齲蝕劑,由於係來自烏龍茶等日常飲用之飲食品中所含之EGCG,偏好性高且對人體具高安全性。
本發明之葡萄糖轉移酶抑制劑或抗齲蝕劑,係可將其添加於各種以預防齲齒等抗齲蝕為目的之飲食品中。添加本發明之葡萄糖轉移酶抑制劑或抗齲蝕劑之飲食品可例舉出清涼飲料、茶飲料、液狀強壯劑、健康飲料、營養補給飲料、運動飲料、碳酸飲料(包含該等飲料之濃縮原液及調製用粉末)等飲料,以及口香糖、糖果、果凍、錠型糖果、健康食品、營養補給食品、營養補充品等食品。
對飲食品之添加量,若於獲得所期望效果之範圍內則無特別限制,可考慮飲食品之味、色、香等而適宜地加以決定。例如調製抗齲蝕為目的之飲料時,可於飲料中以0.01~1000ppm左右之濃度範圍而添加EGCG聚合物。另外添加EGCG聚合物於固體食品中時,相對於固體食品的重量可添加0.01~5000μg/g左右之EGCG聚合物。
本發明之葡萄糖轉移酶抑制劑或抗齲蝕劑,由於係藉由抑制葡萄糖轉移酶(GTF)之活性,而可抑制形成口中齒垢成因之葡聚醣之生成,而可使用於預防齲齒及預防口臭等之口腔衛生劑。本發明中口腔衛生劑可舉出之例為牙膏、漱口藥水、口含錠等。該等口腔衛生劑可使用相關業界慣用之載體,以慣用之方法進行製造。載體之例可使用慣用為製劑素材之各種有機或無機載體物質。另外可因應需要而混合防腐劑、抗氧化劑、著色料、甜味劑等製劑添加物。本發明之GTF抑制劑或抗齲蝕劑對口腔衛生劑之添加量可因應口腔衛生劑之型態等而適當地決定,不過可使口腔衛生劑中含有0.0001~10重量%左右之濃度之EGCG聚合物。
本發明藉由以下實施例更詳細地進行說明,但本發明並未被限定於該等實施例。
將6g之(-)-表沒食子兒茶素-3-O-沒食子酸酯(EGCG)(Roche公司,Teavigo(登記商標)),溶解於含0.02N HCl之120ml之乙醇中,再加入180ml之4%甲醛之乙醇溶液,於室溫下進行4小時攪拌。停止反應後以純水進行10倍稀釋,再使其通過吸附樹脂CHP-20P管柱(600ml、37-75μm、三菱化學股份有限公司)。以1200ml之水進行洗淨後,依序使用900ml之25%CH3
CN,1200ml之30%CH3
CN進行溶出,將25%CH3
CN溶出劃分以每300ml分做3個劃分(fr.1至fr.3),30%CH3
CN溶出劃分以每300ml分做4個劃分(fr.4至fr.7)。
將CHP-20P管柱純化所得之劃分物再以逆相製備型HPLC進行純化。
管柱:Develosil ODS-HG-5(5cmΦ×50cm,野村化學股份有限公司)
移動相:A:0.05%TFA/H2
O,B:90%CH3
CN/0.05%TFA/H2
O
流速:32ml/min
梯度程式:以A80%/B20%進行等位流析(30min),梯度自A80%/B20%至A60%/B40%(100min),再以A60%/B40%進行等位流析(20min)
檢出:A280nm
檢體:將CHP-20P管柱純化所得之fr.2至fr.7分別以20%CH3
CN溶解,再分做數次將其全量通過管柱。
於上述製備條件下,收集相當於滯留時間113分鐘(化合物1)、120分鐘(化合物2)、130分鐘(化合物3)及滯留時間85分鐘(化合物4)、滯留時間106分鐘(化合物5)、滯留時間104分鐘(化合物6)之各波峰。
對以製備型HPLC分離之化合物進行MS及NMR測定。其中,化合物4~6進行MS測定時係藉由Q-TOF Premier(Micromass公司製,UK),以negative、v mode測定後,發現分別為m/z927.160、927.163、1397.248「M-H」-
離子波峰。另外,化合物4之NMR光譜數據係與文獻(Chem. Pharm. Bull 37(12),3255-3563(1989))所載之類烏龍雙黃烷-A之NMR光譜數據一致。化合物5之NMR光譜數據係與文獻(Chem. Pharm. Bull 37(12),3255-3563(1989))所載之類烏龍雙黃烷-B之NMR光譜數據一致。另外,由化合物6之NMR光譜數據,可得知化合物6係前述式(I)之化合物,亦即為類烏龍雙黃烷-3聚物-1。而由該等結果,可確認化合物4係具有EGCG8:8EGCG鍵結樣式之EGCG2聚物之類烏龍雙黃烷-A(OHBF-A),化合物5係具有EGCG6:8EGCG鍵結樣式之EGCG 2聚物之類烏龍雙黃烷-B(OHBF-B),化合物6係具有EGCG8:8EGCG6:8EGCG鍵結樣式之EGCG 3聚物之類烏龍雙黃烷-3聚物-1(於本申請案中亦稱作OHBF-Tri-1或Tri-1)。前述EGCG間之記做6:8或8:8之鍵結係表示EGCG的A環的第6或第8位置的碳原子間介由亞甲基之交聯狀態。前述之各化合物的構造式下如下所示。
針對化合物1至化合物3,以下以MS、NMR進行構造分析。MS係使用離子光源附有電噴灑離子源之ESI之Q-TOF Premier(Micromass公司製,UK),以negative、V mode測定。Cone volt:45V,Capillary voltage:3KV,Desolvation Temp:180℃,進行藉由lock spray之質量補正,使用Leucine enkepharine作為對照(m/z554.2615「M-H」)。
其結果計算出化合物2係m/z1397.2479「M-H」-
,分子式為C68
H54
O33
(err.:0.7ppm),化合物3係m/z 1397.2509「M-H」-
,分子式為C68
H54
O33
(err.:2.9ppm),推測EGCG3分子係藉由2個亞甲基而交聯之物質。計算出化合物1係m/z 1867.3100「M-H」-
之分子及2價之933.1151「M-2H」2-
分子式為C91
H72
O44
(err.:-11.7ppm),推測EGCG4分子係藉由3個亞甲基而交聯之物質。
NMR之測定係將化合物2溶解於CD3
OH,化合物3溶解於DMSO-d6((CD3
)2
SO)後進行測定。化合物2係使用CD3
OH之質子及13
C之殘留波峰之δ3.30及δ48.97作為內標準,化合物3係使用DMSO-d6之1
H之2.50ppm與13
C之殘留波峰之δ39.43作為內標準。測定項目係藉由1
HNMR、13
CNMR、1
H{13
C}-HSQC、1
H{13
C}-HMBC、以及將TOCSY及DQF-COSY以DMX-750分光光度計(BRUKER BIOSPIN,Germany)進行測定。由NMR的結果可明確得知化合物2係具有EGCG6:8EGCG6:8EGCG之鍵結形式之上述式(II)之化合物(亦即為類烏龍雙黃烷-3聚物-2,於本說明書中亦稱其為OHBF-Tri-2或Tri-2),化合物3有EGCG8:8EGCG6:6EGCG鍵結形式之上述式(III)之化合物(亦即為類烏龍雙黃烷-3聚物-4於本說明書中亦稱其為OHBF-Tri-4或Tri-4)。化合物2及化合物3之1
HNMR、13
CNMR光譜圖示於圖1~4。
類烏龍雙黃烷-3聚物-2(CD3
OH中)之1
HNMR係可見δ6.95,6.92,6.90,6.60,6.54,6.44,6.08,6.02,5.57,5.55,5.49,5.18,5.12,4.91,3.86,3.83,3.81,3.76,3.03,3.01,2.94,2.89,2.89,2.82之訊號,13
CNMR則可見δ167.72,167.46,167.37,156.29,155.25,155.08,154.79,154.43,153.64,152.91,151.64,151.20,147.00,146.93,146.38,146.38,146.34,146.29,140.03,139.89,139.89,134.65,134.48,133.85,130.64,129.29,129.10,121.33,121.14,121.14,110.31,110.24,110.24,109.19,108.07,107.42,107.05,107.02,106.79,106.10,101.59,101.00,100.45,97.23,96.71,80.07,79.94,78.45,70.00,69.32,69.28,27.21,27.21,26.81,17.91,17.91之訊號。
類烏龍雙黃烷-3聚物-4(DMSO-d6中)之1
HNMR係可見δ10.46,9.18,9.16,9.16,9.12,9.06,9.05,8.90,8.88,8.84,8.72,8.69,8.69,8.46,8.34,8.05,8.02,8.00,6.81,6.78,6.78,6.52,6.47,6.35,6.03,5.93,5.48,5.46,5.39,5.04,4.95,4.89,4.05,3.95,3.56,3.56,3.06,3.00,2.98,2.76,2.71,2.67之訊號,13
CNMR則可見δ165.11,165.09,164.99,157.66,154.29,153.82,153.48,153.07,152.68,152.23,152.18,150.88,145.56,145.52,145.50,145.26,145.24,145.23,138.43,138.43,138.39,132.34,132.23,132.19,128.34,128.34,128.23,119.17,119.12,119.04,110.35,110.31,110.29,109.19,108.59,108.56,108.51,106.97,106.63,105.26,105.26,105.13,104.73,101.28,99.44,99.41,98.21,97.34,97.15,96.03,79.48,79.07,78.47,69.95,69.39,69.28,27.18,26.98,26.58,18.16,17.13之訊號。
將化合物1溶解於DMSO-d6,以1
H及13
C之殘留波峰之δ2.50及δ39.43作為內標準進行NMR測定。測定項目係藉由1
HNMR、13
CNMR、1
H{13
C}-HSQC、1
H{13
C}-HMBC、以及將TOCSY及DQF-COSY以DMX-750分光光度計(BRUKER BIOSPIN,Germany)進行測定。由NMR的結果可明確得知化合物1係具有EGCG8:6EGCG8:8EGCG6:8EGCG之鍵結形式之EGCG4聚物之化合物(類烏龍雙黃烷-4聚物-2,於本說明書中亦稱其為OHBF-Tet-2或Tet-2)。化合物1之1
HNMR、13
CNMR光譜圖示於圖5及圖6。
類烏龍雙黃烷-4聚物-2之1
HNMR(DMSO-d6中)係可見δ9.91,9.25,9.16,8.09,7.22,6.81,6.76,6.74,6.52,5.94,5.50,5.38,4.77,4.52,3.95,3.95,3.80,3.54,2.80,2.74,2.73,2.67之訊號,13
CNMR則可見δ165.08,165.01,154.06,152.83,152.35,151.45,150.78,150.26,145.52,145.52,145.24,145.18,138.49,138.44,132.21,132.10,128.42,127.63,119.05,118.95,108.58,108.46,108.46,106.95,105.74,104.92,104.06,98.32,97.81,76.59,75.94,66.69,66.35,26.33,25.26,16.72,15.99之訊號。
上述被鑑定出之化合物之構造式如下所述。
上述藉由合成及純化步驟所得之各化合物的產量分別為類烏龍雙黃烷-A(984mg),類烏龍雙黃烷-B(374mg),類烏龍雙黃烷-3聚物-1(468mg),類烏龍雙黃烷-3聚物-2(73mg),類烏龍雙黃烷-3聚物-4(12mg)及類烏龍雙黃烷-4聚物-2(44mg)。
以論文M.matsumoto et al,FEMS Microbiology Letters 228(2003)73-80所記載之方法為準調製rGTF。亦即將具有含編碼Streptococcus mutans
其葡萄糖轉移酶B(GTFB)之基因之載體pSK6的Escherichia coli
XL-2株,於含100μg/mL之安比西林及7.5μg/mL之四環黴素之Luria Bertani液體培養基中,於37℃下進行培養16個小時。將培養基以離心分離收集菌體,再將菌體懸濁於經冷卻後之10mM磷酸緩衝液(pH6.5)之後,以超音波產生器(UD201型,TOMYS,東京)於冰冷下使菌體破碎。進行破碎後,以12,000x g進行30分鐘離心分離而去除沉澱。將所得之上清液作為重組葡萄糖轉移酶B(rGTFB)用於後續實驗。
同樣的,使用具有含編碼Streptococcus mutans
其葡萄糖轉移酶C(GTFC)之基因之載體pSK6的Escherichia coli
XL-2株,調製重組葡萄糖轉移酶C(rGTFC)用於後續實驗。
rGTFB係使用比活性為503mU/mg protein者,而rGTFC則將比活性為6.3~22.3mU/mg protein者混合使用。於此活性1U係表示在1分鐘內,將來自蔗糖之1.0mM葡萄糖轉變為葡聚醣時之酵素活性。蛋白質定量係採用二辛可寧酸法(BCA法)(BCA蛋白質分析試劑組,PIERCE公司)而進行。
將各個針對由實施例1所得之類烏龍雙黃烷-A(OHBF-A),類烏龍雙黃烷-B(OHBF-B),及類烏龍雙黃烷-3聚物-1(Tri-1),以及以論文(Hashimoto,F. Nonaka,G. Nishioka,I. Chem. Pharm. Bull. 36(5),1676-1684(1988)為準而調製之Thea Sinensin A(TSN-A)之葡萄糖轉移酶(GTF)抑制作用,根據下述順序進行評價。另外,此處用於進行比較之茶雙沒食子兒茶素A(TSN-A),於EGCG之B環上2'位彼此間係以對稱的方式而結合之物質,具有下述構造:
於含有含1%蔗糖之0.1%葡萄聚糖T10之2mL的0.1M KPB(pH6.0)中,與實施例2所得之rGTFB或rGTFC(相當於15mU(平均值)者),及上述各檢體(0.1mg/mL最終濃度)進行混合,於37℃下進行培育1晚。藉由測定所得反應液的濃度(550nm)而測定非水溶性之葡聚醣生成量。非水溶性葡聚醣之生成量較少(亦即濁度較低)時,顯示葡萄糖轉移酶之活性較被抑制。結果示於圖7及圖8。而圖中控制組(cont)係表示未與上述檢體混合時之濁度。
如圖7及圖8所示可得知,OHBF-A雖可抑制GTFB之活性,但對GTFC卻反而稍稍增強其活性。而TSN-A雖幾乎不會對GTFB產生影響,但對GTFC卻反而劇烈地增
強其活性。另一方面,已知OHBF-B及OHBF-Tri-1,對GTFB與GTFC二者均抑制其活性。特別係已知3聚物之OHBF-Tri-1,與2聚物之其他化合物相比,可對GTFB與GTFC二者的活性有最強的抑制。
將各個針對由實施例1所得之類烏龍雙黃烷-3聚物-1(OHBF-Tri-1),類烏龍雙黃烷-3聚物-2(OHBF-Tri-2),及類烏龍雙黃烷-3聚物-4(OHBF-Tri-4),及類烏龍雙黃烷-4聚物-2(OHBF-Tet-2)之葡萄糖轉移酶(GTF)抑制作用,根據下述順序進行評價。
於含有含1%蔗糖之0.1%葡萄聚糖T10之2mL的0.1M KPB(pH6.0)中,與實施例2所得之rGTFB或rGTFC(相當於15mU(平均量)者),及上述各檢體(0.05mg/mL最終濃度)進行混合,於37℃下進行培育1晚。藉由測定所得反應液的濃度(550nm)而測定非水溶性之葡聚醣生成量。非水溶性葡聚醣之生成量較少(亦即濁度較低)時,顯示葡萄糖轉移酶之活性較被抑制。結果示於圖9及圖10。而圖中控制組(cont)係表示未與上述檢體混合時之濁度。
如圖9及圖10所示可得知,EGCG 4聚物之Tet-2雖可稍稍抑制GTFC之活性,但卻未發現對GTFB有意義的抑制效果。而分別發現EGCG 3聚物之Tri-1、Tri-2、Tri-4對GTFB與GTFC的抑制作用,比EGCG 4聚物之Tet-2
具有更高之GTFB抑制活性。
由上述結果,判斷EGCG 3聚物之Tri-1、Tri-2、Tri-4,及EGCG 2聚物之OHBF-B具有高GTF抑制作用。特別係EGCG 3聚物之Tri-1、Tri-2、Tri-4,與EGCG 2聚物之OHBF-A、OHBF-B、TSN-A,還有EGCG 4聚物之Tet-2相比,可知其具有高GTF抑制作用。
EGCG聚合物之LC-MS/MS測定係以4000 Q TRAP(Applied公司製),使用Turbo Ion Spray,根據以下條件進行測定。Collision energy:46eV(nega.),Ionspray voltage:4500V,Temp:450℃。
各化合物於MRM(multiple reaction monitoring)之測定頻道為類烏龍雙黃烷-3聚物類,以698.40/168.90(nega.2價),標準物質係使用類烏龍雙黃烷-3聚物-1。類烏龍雙黃烷-4聚物類,則以933.16/168.90(nega.2價),標準物質係使用類烏龍雙黃烷-4聚物-2。以下述測定條件進行。
管柱:Develosil C30-UG-3(野村化學,3mm×150mm)
流速:0.3ml/min
管柱溫度:40℃
移動相A:0.1%HCOOH/H2
O
移動相B:0.1%HCOOH/CH3
CN
梯度程式:A91%/B9%(0min)→A40%/B60%(17min)→A15%/B85%(17.1min),再以A15%/B85%進行等位流析(17.1~19min)
由於黑烏龍茶中僅含有微量該等化合物而無法進行直接定量。因此將黑烏龍茶(殺菌前)以CHP-20P管柱(三菱化學股份有限)逐步進行劃分,而於將各劃分進行定量後,以各劃分中被檢出之濃度合算起來作為茶中濃度。黑烏龍茶中之濃度係將3聚物類被檢出的5個成分換算為類烏龍雙黃烷-3聚物-1再合算,為172ng/ml。將4聚物類被檢出的4個成分合算,換算為類烏龍雙黃烷-4聚物-2為55ng/ml。
[圖1]圖1係化合物2之1
HNMR光譜圖。
[圖2]圖2係化合物2之13
CNMR光譜圖。
[圖3]圖3係化合物3之1
HNMR光譜圖。
[圖4]圖4係化合物3之13
CNMR光譜圖。
[圖5]圖5係化合物1之1
HNMR光譜圖。
[圖6]圖6係化合物1之13
CNMR光譜圖。
[圖7]圖7係EGCG 2聚物及3聚物之各化合物,對葡萄糖轉移酶B之抑制作用之評價結果。
[圖8]圖8係EGCG 2聚物及3聚物之各化合物,對
[圖9]圖9係EGCG 3聚物及4聚物之各化合物,對葡萄糖轉移酶B抑制作用之評價結果。
[圖10]圖10係EGCG 3聚物及4聚物之各化合物,對葡萄糖轉移酶C抑制作用之評價結果。
Claims (5)
- 一種以作為表沒食子兒茶素沒食子酸酯三聚物或其鹽作為葡萄糖轉移酶之抑制劑之使用,該葡萄糖轉移酶係用以預防或治療齲蛀(齲齒)、齒垢形成或口臭產生,其特徵為,該表沒食子兒茶素沒食子酸酯三聚物係選自具有下述式(I):
- 一種以下述式(IV)所示之化合物作為葡萄糖轉移酶抑制劑之使用,該葡萄糖轉移酶係用以預防或治療齲蛀(齲齒)、齒垢形成或口臭產生,
- 如請求項1或2之使用,其中,用以預防或治療齲蛀(齲齒)、齒垢形成或口臭產生之葡萄糖轉移酶抑制劑為飲食品之形態。
- 如請求項3之使用,其中該飲食品係茶飲料。
- 如請求項1或2之使用,其中,用以預防或治療齲蛀(齲齒)、齒垢形成或口臭產生之葡萄糖轉移酶抑制劑為口腔衛生劑之形態。
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JP5539881B2 (ja) * | 2008-08-29 | 2014-07-02 | サントリーホールディングス株式会社 | 新規エピガロカテキンガレート4量体、およびそれらを含む血管内皮機能改善剤 |
CN105342863B (zh) * | 2015-12-11 | 2018-08-24 | 张凌 | 表没食子儿茶素没食子酸脂在提高牙科树脂粘接材料修复方面的应用 |
JP7345250B2 (ja) * | 2018-12-27 | 2023-09-15 | 太陽化学株式会社 | 歯垢形成予防剤 |
CN109879850B (zh) * | 2019-02-26 | 2021-01-05 | 中国农业科学院茶叶研究所 | 一种制备三种聚酯型儿茶素单体的方法 |
CN114763551B (zh) * | 2021-12-07 | 2023-09-15 | 西藏自治区农牧科学院农业研究所 | 一种青稞矢车菊素糖基转移酶基因及其用途 |
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TW201014837A (en) | 2010-04-16 |
JP2010053110A (ja) | 2010-03-11 |
ES2619525T3 (es) | 2017-06-26 |
US20110150790A1 (en) | 2011-06-23 |
WO2010024138A1 (ja) | 2010-03-04 |
EP2330104A4 (en) | 2011-09-21 |
EP2330104A1 (en) | 2011-06-08 |
CN102137853B (zh) | 2013-11-06 |
CN102137853A (zh) | 2011-07-27 |
US9237996B2 (en) | 2016-01-19 |
JP5563753B2 (ja) | 2014-07-30 |
EP2330104B1 (en) | 2017-03-01 |
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