TW201509928A - 化合物、醫藥品、抗炎劑、化妝品、飲食品及化合物之製造方法 - Google Patents
化合物、醫藥品、抗炎劑、化妝品、飲食品及化合物之製造方法 Download PDFInfo
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Abstract
本發明提供一種具有優良抗發炎作用之化合物、醫藥品、抗炎劑、化妝品及飲食品,以及該化合物的製造方法。
解決上述問題的手段為以下述式(I)或式(Ⅱ)表示之化合物。醫藥品係以下述式(I)、式(Ⅱ)或式(Ⅲ)表示之化合物作為有效成分。
Description
本發明是關於化合物、醫藥品、抗炎劑、化妝品、飲食品以及化合物的製造方法。
近年,異位性皮膚炎、接觸性皮膚炎、花粉症等過敏性疾病的患者正在增加當中。其治療方法大多依賴症狀治療法,以抑制過敏引起的發炎為目的,一般而言,係使用抗炎藥等。
紫蘇(Perilla frutescens Britton)為屬於紫蘇科之一年生草本植物,原產於中國南部,廣泛栽植於東洋的溫帶地區。在東洋,自古以來用於民間療法,亦調製作為漢藥。在日本,亦從平安時代左右開始供應於食用中作為調味料。
報告指出紫蘇科植物或來自紫蘇科植物的成分具有抑制過敏或發炎的作用。
專利文獻1揭示一種含有油脂與紫蘇葉萃取物作為有效成分之抗過敏食品。此外,專利文獻2揭示一種調配有紫蘇科植物的莖葉萃取物之抗過敏化妝原料組成物。此外,專利文獻3揭示一種含有多元不飽和脂肪酸與紫蘇葉萃取物作為有效成分之發炎性腸疾病患者用食品。此外,專利文獻4揭示一種具有抑制TNF產生的作用、有效改善過敏的紫蘇萃取液。此外,非專利文獻1記載萃取紫蘇葉獲得之迷迭香酸、葉黃酮、芹黃素(apigenin)對紫蘇葉萃取物的抗發炎作用提供貢獻。此外,非專利文獻2及非專利文獻3揭示來自綠紫蘇萃取物的迷迭香酸甲酯及7-甲氧基黃芩素(Negletein)具有抑制NO產生的作用。
(專利文獻1)日本特開平6-62795號公報
(專利文獻2)日本特開平6-293652號公報
(專利文獻3)日本特開平9-201號公報
(專利文獻4)日本特開平7-215884號公報
(非專利文獻1)三浦 健人、北館 健太郎;AROMA RESEARCH No.42(Vol.11/No.2 2010)p28-31
(非專利文獻2)池谷 幸信等、綠紫蘇中含有多量抑制一氧化氮誘導的成分;第20回統合醫療機能性食品國際會議(ICNIM2012)(2012年7月舉行)摘要集
(非專利文獻3)芳中 奈生等、關於綠紫蘇中的NO產生
抑制活性成分之研究;日本生藥學會第59回年會(2012年9月舉行)摘要集
現狀為正在等待紫蘇科植物中具有更強效抗發炎作用之新穎成分的鑑定。
本案發明者等發現紫蘇科植物中的新穎化合物具有抗發炎作用,遂完成本發明。本發明的目的為提供一種具有優良抗發炎作用之化合物、醫藥品、抗炎劑、化妝品及及飲食品,以及該化合物的製造方法。
為了達成上述目的,本發明第1觀點之化合物為下述式(I)或式(Ⅱ)所示。
本發明第2觀點之醫藥品係以下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物作為有效成分。
本發明第3觀點之抗炎劑係以下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物作為有效成分。
本發明第4觀點之化妝品含有下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物。
本發明第5觀點之飲食品含有下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物。
本發明第6觀點之下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物係由萃取處理紫蘇科植物所製得。
本發明第7觀點之下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物的製造方法,包含萃取處理紫蘇科植物之步驟。
依照本發明可提供一種具有優良抗發炎作用之化合物、醫藥品、抗炎劑、化妝品及飲食品,以及該化合物的製造方法。
圖1係表示NO產生量的測定結果。
圖2係表示IC50值的測定結果。
圖3係表示LDH活性的測定結果。
圖4係表示細胞素(cytokine)/趨化素(chemokine)陣列(生物體外,in vitro)的結果。
圖5係表示NO產生量的測定結果。
圖6係表示IC50值的測定結果。
以下,詳細說明關於本發明的實施形態。
本說明書中之結構式,若無特別標示立體構造等,本說明書中結構式所示之化合物包含互變異構物、幾何異構物、光學異構物等各種立體異構物、及此等之混合物(包含消旋體)。
首先,說明有關本發明之化合物。
本發明之新穎化合物為類黃酮(flavonoid)化合物,係由下述式(I)或式(Ⅱ)所示。
式(I)所示之化合物為8-羥基-6,7-二甲氧基黃烷酮,係新穎的類黃酮化合物。本說明書中,式(I)所示化合物亦稱為Pa5。
式(Ⅱ)所示化合物為5,8-二羥基-7-甲氧基黃烷酮,係新穎的類黃酮化合物。本說明書中,式(Ⅱ)所示化合物亦稱為Pa5’。
Pa5及Pa5’如以下實施例所述般具有優良的抗發炎作用。因此,如下述般,作為抗炎劑,可用於治療異位性皮膚炎、接觸性皮膚炎、花粉症、風溼免疫疾病(Rheumatism)、發炎性腸疾病等發炎性疾病外,亦可作為化妝品及飲食品使用。
接著,根據本發明,說明關於將紫蘇科植物萃取處理所得之化合物。
根據本發明,將紫蘇科植物萃取處理所得之化合物係以下述式(I)、式(Ⅱ)或式(Ⅲ)表示。
關於紫蘇科植物的萃取處理的詳細情況如下述。
式(I)及式(Ⅱ)所示之化合物(Pa5及Pa5’)如前所述。本案發明者等首次發現將紫蘇科植物萃取處理可獲得Pa5及Pa5’。
式(Ⅲ)所示化合物為七葉樹苷(Esculetin),本案發明者等首次發現七葉樹苷可由紫蘇科植物萃取處理而獲得以及具有抗發炎作用。本說明書中,式(Ⅲ)所示化合物亦稱為Pa9。
推測Pa5、Pa5’及Pa9係以稱為葡萄糖苷(glucoside)或葡萄糖醛酸苷(glucuronide)之配糖體(glycoside)存在紫蘇科植物中。推測Pa5、Pa5’及Pa9的配糖體經口攝取時,藉由酵素(β-葡萄糖苷酵素(β-glucosidase)、葡萄糖醛酸苷酵素(glucuronidase)等)切斷糖成分,Pa5、Pa5’及Pa9以配質(aglycone)的狀態進入血液中,在體內產生作用。
Pa5、Pa5’及Pa9如以下實施例所述般,具有優良的抗發炎作用。因此,如下述般,作為抗炎劑,可用於治療異位性皮膚炎、接觸性皮膚炎、花粉症、風溼免疫疾病、發
炎性腸疾病等發炎症性疾病外,亦可作為化妝品及飲食品使用。
接著,說明關於本發明之化合物Pa5、Pa5’及Pa9的製造方法。
本發明之化合物Pa5、Pa5’及Pa9的製造方法,其特徵係包含將紫蘇科植物萃取處理之步驟。
可使用的紫蘇科植物之學名為紫蘇(Perilla flutescens Britton var.crispa及var.acta Kuto),亦可為其近緣植物(Labiatae)。例如,栽種於日本的綠紫蘇、縮緬青紫蘇、紅紫蘇、縮緬紫蘇、片面紫蘇等亦適用。只要是能夠達到本發明功效的紫蘇科植物皆適合選用。並且,並無特別限定紫蘇科植物的使用部位,全草、葉、葉柄、花、果實、枝根、種子等皆可利用。可將其直接或乾燥後使用,亦可將其粉碎、進一步將其作成萃取物使用。
萃取處理係指將紫蘇科植物作為原料,進行以溶劑萃取、濃縮、分餾、精製等一般化學分離精製手段。
作為萃取方法,可列舉例如將植物之部分或全部的粉碎物,通常在3至121℃,以水或有機溶劑萃取的方法。本文中,萃取所使用的有機溶劑並無特別限定,可列舉例
如石油醚、環己烷、甲苯、苯等烴類;四氯化碳、二氯甲烷、三氯甲烷等鹵化烴;乙醚類、乙酸乙酯等酯類;丙酮等酮類;甲醇、乙醇、丙醇、丁醇、聚乙二醇、丙二醇、丁二醇等醇類;吡啶等。萃取溶劑可單獨使用,亦可混合2種以上使用。以使用含水乙醇、含水甲醇等含水醇為佳。從對人體的安全性之觀點,更佳的方法可列舉如將紫蘇科植物的乾燥粉碎物,使用10至20倍量的水或10至20倍量的60%乙醇,在室温至121℃,攪拌萃取2至24小時之方法,更佳的方法可列舉如熱水萃取(例如:30分鐘至10小時的加熱回流萃取)。又,所得之萃取物雖然可直接使用,但必要時,亦可經濃縮、過濾、冷凍乾燥等處理後使用。又,萃取物或紫蘇科植物可單獨使用,亦可組合2種以上使用。只要可達到本發明的功效之萃取方法皆適合選用。
用以獲得Pa5及Pa5’之分餾方法如以下所例示。將紫蘇科植物的溶劑萃取液減壓濃縮,使所得之殘留物懸浮於水中,使用乙酸乙酯進行分層萃取,並將乙酸乙酯萃取液減壓濃縮。將所得之乙酸乙酯可溶部分進行矽膠管柱層析(Silica Gel Column Chromatography),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分再度進行矽膠管柱層析,以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=98:2的混合溶劑所溶出的部分進行製備型薄層層析(Preparative Thin-Layer
Chromatography),以三氯甲烷:甲醇=24:1的混合溶劑展開。在此,取Rf=0.82的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將所得之萃取液減壓濃縮,進行製備型薄層層析,以正己烷:丙酮=1:1的混合溶劑進行展開。在此,若欲獲得Pa5取Rf=0.44的部分,若欲Pa5’則取Rf=0.70的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。只要可達到本發明的功效之Pa5及Pa5’的分餾方法皆適合選用。
用以獲得Pa9的分餾方法如以下所例示。將紫蘇科植物的溶劑萃取液減壓濃縮,所得之殘留物懸浮水中,使用乙酸乙酯進行分層萃取,並將乙酸乙酯萃取液減壓濃縮。將所得之乙酸乙酯可溶部分進行矽膠管柱層析,以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分再度進行矽膠管柱層析,以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=96:4的混合溶劑所溶出之部分進行十八基矽膠的管柱層析,以水與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以水:甲醇=70:30的混合溶劑所溶出之部分進行製備型薄層層析,以三氯甲烷:甲醇=10:1的混合溶劑進行展開。取Rf=0.70的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。只要可達到本發明的功效之Pa9的分餾方法皆適合選用。
接著,說明關於本發明之醫藥品。
關於本發明之醫藥品係含有本發明之化合物Pa5、Pa5’或Pa9作為有效成分。
本發明之醫藥品係Pa5、Pa5’或Pa9以其自體或與1種以上藥學可容許之賦形劑或載體組合之型態使用者。又,本發明之醫藥品中,可適當含有通常可使用之結合劑、崩解劑、增黏劑、分散劑、再吸收促進劑、矯味劑、緩衝劑、界面活性劑、溶解輔助劑、保存劑、乳化劑、等張化劑、安定化劑、pH調製劑等。又,本發明之醫藥品中亦可適當含有其他活性成分。
作為本發明之醫藥品的劑型,可依疾病的種類或程度等選定,例如可列舉適合經口、非經口或經鼻內投予者、錠劑或糖衣錠、舌下錠、明膠膠囊劑、片劑、塞劑、乳劑、軟膏劑、皮膚用凝膠劑等。
本發明之醫藥品的投藥量雖然依患者的年齢及體重、疾病的種類及嚴重程度以及投藥的路徑而變化,然而,例如成人經口投藥時,Pa5、Pa5’或Pa9以1次0.1至500mg,1日1至3次投藥。
接著,說明關於本發明之抗炎劑。
本發明之抗炎劑含有本發明之化合物Pa5、Pa5’或Pa9作為有效成分。
Pa5、Pa5’及Pa9如以下實施例所述般,具有優良的抗發炎作用。因此,可作為抗炎劑用於治療異位性皮膚炎、接觸性皮膚炎、花粉症、風溼免疫疾病、發炎性腸疾病等發炎性疾病。
關於本發明之抗炎劑的劑型、投藥量等係如上述。
接著,說明關於本發明之化妝品及飲食品。
本發明之化妝品及飲食品含有本發明之化合物Pa5、Pa5’或Pa9。
本發明之化妝品以緩和或預防異位性皮膚炎或接觸性皮膚炎等症狀的目的,可於護膚製品、粉底或化妝製品等添加Pa5、Pa5’或Pa9外,亦可添加上述紫蘇科植物的乾燥粉末或萃取物。
本發明之飲食品可用於緩和或預防異位性皮膚炎、接觸性皮膚炎、花粉症等症狀的目的,為了充分活用此種作為食品的機能,可於一般食品、補充品、特定保健用食品、
特殊營養食品、營養補助食品、健康食品等調配Pa5、Pa5’或Pa9。不僅是添加Pa5、Pa5’或Pa9,亦可使用上述紫蘇科植物的乾燥粉末或萃取物。可於各種食品中添加此等。飲料可列舉如作為特定保健用食品、特殊營養食品、營養補助食品的飲料或其他營養飲料、健康飲料、各種健康茶等。其他食品可列舉如點心類、麵包、麵類、練製品、油脂、調味料等。
關於本發明之化妝品及飲食品,Pa5、Pa5’或Pa9的調配量並無特別限定,然而,一般以乾燥固形分換算為0.001至100重量%,特別是0.01至50重量%為佳。
以下,列舉實施例以具體說明本發明。然而,本發明並不限定於此等實施例。
萃取來自紫蘇葉片之8-羥基-6,7-二甲氧基黃烷酮(Pa5),加以精製。
使用綠紫蘇(Perilla frutescens f.viridis)之葉片4.40kg,以甲醇44.3L進行2次回流萃取(1小時)。將2次回流萃取所得之甲醇萃取液減壓濃縮,得到甲醇萃取物
772g(17.5%)。將甲醇萃取物772g懸浮於水3.9L中,使用乙酸乙酯3.9L進行3次分層萃取。將3次分層萃取所得之乙酸乙酯萃取液合併,進行減壓濃縮,獲得乙酸乙酯可溶部分254.7g。
將所得之乙酸乙酯可溶部分87.7g進行矽膠管柱層析(7.5cm i.d.×49cm),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分4.24g再度進行矽膠管柱層析(3.0cm i.d.×25cm),以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=98:2的混合溶劑所溶出之部分383.2mg進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以三氯甲烷:甲醇=24:1的混合溶劑進行展開。取Rf=0.82的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將所得之萃取液減壓濃縮,獲得淡褐色殘留物195.7mg。將此等再度進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以正己烷:丙酮=1:1的混合溶劑進行展開。將Rf=0.44的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將此萃取液減壓濃縮,所得之白色粉末以三氯甲烷及甲醇的混合溶劑進行結晶化,獲得無色稜柱結晶82.3mg。
上述所得之無色稜柱結晶的分析數據如以下所示。
mp 166-168℃
[α]23 D0(c1.03,MeOH)
IR ν(KBr)cm-1:3290(OH),1672(C=O),1605(芳香環)
UV λmax(MeOH)nm(ε):201(27074),244(11253),288(13489),349(5085)
ESI-MS m/z:301[M+H]+,197
正型HR-ESI-MS m/z 301.1068[M+H]+,Calcd for C17H17O5:301.1076。
CD(c=0.00114,MeOH)△ε(nm):0(220-400)
1H-NMR δ in CDCl3:2.85(1H,dd,J=16.5,2.8Hz),3.08(1H,dd,J=16.5,12.8Hz),3.92(3H,s,OCH3),4.02(3H,s,OCH3),5.03(1H,s,隨D2O消失),5.46(1H,dd,J=12.8,2.8Hz),6.19(1H,s,H-5),7.41-7.49(5H,m)。
13C-NMR δ in CDCl3:45.8(C-3),56.2(OCH3),56.3(OCH3),80.0(C-2),89.6(C-5),105.7(C-4a),126.3(C-2’,C-5’),127.6(C-8a),128.85(C-3’,C-5’),128.89(C-4’),138.3(C-1’),149.4(C-8),152.5(C-7),155.0(C-6),189.4(C-4)。
由上可知,上述所得之無色稜柱結晶含有8-羥基-6,7-二甲氧基黃烷酮(Pa5)。
將綠紫蘇(Perilla frutescens f.viridis)的葉片0.6kg以水1L加熱回流萃取(1小時)。待冷卻後,將萃取液以濾紙(ADVANTEC定性濾紙No.2)過濾。藉此所得之熱水萃取液9.5L,使用乙酸乙酯9.5L,進行3次分層萃取。將3次分層萃取所得之乙酸乙酯萃取液合併,進行減壓濃縮,獲得乙酸乙酯可溶部分8.78g。
將所得之乙酸乙酯可溶部分8.78g進行矽膠管柱層析(3.0cm i.d.×30cm),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分0.425g再度進行矽膠管柱層析(3.0cm i.d.×25cm),以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=98:2的混合溶劑所溶出之部分39.1mg進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以三氯甲烷:甲醇=24:1
的混合溶劑進行展開。取Rf=0.82的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將所得之萃取液減壓濃縮,獲得淡褐色殘留物20.5mg。將其再度進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以正己烷:丙酮=1:1的混合溶劑進行展開。取Rf=0.44的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將此萃取液減壓濃縮,所得之白色粉末以三氯甲烷及甲醇的混合溶劑進行結晶化,獲得無色稜柱結晶9.1mg。由分析的結果可知,此無色稜柱結晶中含有與上述相同的8-羥基-6,7-二甲氧基黃烷酮(Pa5)。
萃取來自紫蘇葉片之5,8-二羥基-7-甲氧基黃烷酮(Pa5’),加以精製。
使用綠紫蘇(Perilla frutescens f.viridis)的葉片4.40kg,以甲醇44.3L進行2次回流萃取(1小時)。將2次回流萃取所得之甲醇萃取液減壓濃縮,獲得甲醇萃取物772g(17.5%)。將甲醇萃取物772g懸浮於水3.9L中,使用乙酸乙酯3.9L進行3次分層萃取。將3次分層萃取所得之乙酸乙酯萃取液合併,進行減壓濃縮,獲得乙酸乙酯可溶部分254.7g。
將所得之乙酸乙酯可溶部分87.7g進行矽膠管柱層析(7.5cm i.d.×49cm),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分4.24g再度進行矽膠管柱層析(3.0cm i.d.×25cm),以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=98:2的混合溶劑所溶出之部分383.2mg進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以三氯甲烷:甲醇=24:1的混合溶劑進行展開。取Rf=0.82的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將所得之萃取液減壓濃縮,獲得淡褐色殘留物195.7mg。將其再度進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以正己烷:丙酮=1:1的混合溶劑進行展開。將Rf=0.70的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將此萃取液減壓濃縮,所得之黄色粉末由甲醇進行結晶化,獲得結晶粉末14.4mg(收率0.00095%)。
上述所得之結晶粉末的分析數據如以下所示。
黃色針狀(from MeOH).mp 220-225℃。
UV λmax(MeOH)nm(log ε):246(3.97),292(4.16),364(3.62)nm。
[α]23 D0(c0.253,MeOH)CD(c=0.00172,MeOH)△ε(nm):0(220-400)
正型MALDI-TOF-MS(基質:已二酸):m/z(%):287.30
([M+H]+,100),288.30(17),289.31(3)。
1H-NMR(DMSO-d6)δ2.78(1H,dd,J=16.9,3.2Hz),and 3.19(1H,dd,J=16.9,12.4Hz)(H-3),3.77(3H,s,OCH3),5.51(1H,dd,J=12.4,3.2Hz,H-2),6.15(1H,s,H-7),7.35(2H,m,H-3’,-5’),7.36(1H,m,H-4’),7.48(2H,m,H-2’,-6’),8.15(1H,s,OH),11.74(1H,s,OH)。
13C-NMR(DMSO-d6)δ42.7(C-3).56.4(OCH3),78.6(C-2),92.8(C-6),102.6(C-4),126.9(C-2’,6’),128.66(C-3’,-5’,128.72(C-4’),139.1(C-1’),148.3(C-8a),156.0(C-5),157.5(C-8),197.2(C-4)。
由上可知,上述所得之結晶粉末中含有8-二羥基-7-甲氧基黃烷酮(Pa5’)。
將綠紫蘇(Perilla frutescens f.viridis)的葉片0.6kg以水1L加熱回流萃取(1小時)。待冷卻後,將萃取液以濾紙(ADVANTEC定性濾紙No.2)過濾。藉此所得之熱水萃取液9.5L,使用乙酸乙酯9.5L,進行3次分層萃取。將3次分層萃取所得之乙酸乙酯萃取液合併,進行減壓濃縮,獲得乙酸乙酯可溶部分8.78g。
將所得之乙酸乙酯可溶部分8.78g進行矽膠管柱層析(3.0cm i.d.×30cm),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分0.425g再度進行矽膠管柱層析(3.0cm i.d.×25cm),以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=98:2的混合溶劑所溶出之部分39.1mg進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以三氯甲烷:甲醇=24:1的混合溶劑進行展開。取Rf=0.82的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將所得之萃取液減壓濃縮,獲得淡褐色殘留物20.5mg。將其再度進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以正己烷:丙酮=1:1的混合溶劑進行展開。將Rf=0.70的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將此萃取液減壓濃縮,所得之黄色粉末由甲醇進行結晶化,獲得結晶粉末2.0mg。由分析的結果可知,此結晶粉末中含有與
上述相同的8-二羥基-7-甲氧基黃烷酮(Pa5’)。
從紫蘇葉片萃取七葉樹苷(Pa9)並加以精製。
使用綠紫蘇(Perilla frutescens f.viridis)的葉片4.40kg,以甲醇44.3L進行2次回流萃取(1小時)。將2次回流萃取所得之甲醇萃取液減壓濃縮,獲得甲醇萃取物772g(17.5%)。將甲醇萃取物772g懸浮於水3.9L中,使用乙酸乙酯3.9L進行3次分層萃取。將3次分層萃取所得之乙酸乙酯萃取液合併,進行減壓濃縮,獲得乙酸乙酯可溶部分254.7g。
將所得之乙酸乙酯可溶部分87.7g進行矽膠管柱層析(7.5cm i.d.×49cm),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分4.24g再度進行矽膠管柱層析(3.0cm i.d.×25cm),以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=96:4的混合溶劑所溶出之部分1167mg進行十八基矽膠的管柱層析,以水與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以水:甲醇=70:30的混合溶劑所溶出之部分82mg進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),
以三氯甲烷:甲醇=10:1的混合溶劑進行展開。取Rf=0.70的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將此萃取液減壓濃縮,所得之殘留物由甲醇進行結晶化,獲得淡褐色針狀結晶9.7mg。
上述所得之淡褐色針狀結晶的分析數據如以下所示。
mp 255-258℃
UV λmax(MeOH)nm(log ε):228(4.00),259(3.61),299(3.65),347(3.81)
負型MALDI-TOF-MS m/z(%):177.24([M-H]-,100),178.24(15)。
1H-NMR δ in MeOH-d4:6.17(1H,d,J=9.6Hz),6.75(1H,s),6.93(1H,s),7.78(1H,d,J=9.6Hz)。
由上可知,上述所得之淡褐色針狀結晶中含有七葉樹苷(Pa9)。
將綠紫蘇(Perilla frutescens f.viridis)的葉片0.66kg以水11L加熱回流萃取(1小時)。待冷卻後,將萃取液以濾紙(ADVANTEC定性濾紙No.2)過濾。藉此所得之熱水萃取液9.5L,使用乙酸乙酯9.5L,進行3次分層萃取。將3次分層萃取所得之乙酸乙酯萃取液合併,進行減壓濃縮,獲得乙酸乙酯可溶部分8.78g。
將所得之乙酸乙酯可溶部分8.78g進行矽膠管柱層析(3.0cm i.d.×30cm),以正己烷與丙酮的混合溶劑依序提高丙酮的比率進行溶出。將以正己烷:丙酮=60:40的混合溶劑所溶出之部分0.425g再度進行矽膠管柱層析(3.0cm i.d.×25cm),以三氯甲烷與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以三氯甲烷:甲醇=96:4的混合溶劑所溶出之部分117.7mg進行十八基矽膠的管柱層析,以水與甲醇的混合溶劑依序提高甲醇的比率進行溶出。將以水:甲醇=70:30所溶出之部分9.5mg進行製備型薄層層析(silica gel 70、Wako Pure Chemical Industries,Ltd.),以三氯甲烷:甲醇=10:1的混合溶劑進行展開。取Rf=0.70的部分,以三氯甲烷:甲醇=1:1的混合溶劑進行萃取。將此萃取液減壓濃縮,將所得之殘留物以甲醇進行結晶化,獲得淡褐色針狀結晶1.1mg。由分析的結果可知,此結晶粉末中含有與上述相同的七葉樹苷(Pa9)。
為了檢驗Pa5的抗發炎作用,調查抑制一氧化氮(NO)產生的作用。
已知一氧化氮(NO)為由間質素(interleukin,IL)-1β所誘發之發炎媒介之一,因此,NO產生之抑制作用可作為抗發炎作用的指標。本實施例藉由檢查Pa5的NO產生抑制作用驗證Pa5是否具有抗發炎作用。並且,作為比較例,使用報告指出存在於綠紫蘇中具有NO產生抑制作用之7-甲氧基黃芩素(negletein)。
從雄性威斯特(Wistar)系大鼠(200-250g、Charles River),以膠原蛋白酵素(collagenase)灌流法(膠原蛋白酵素:Wako Pure Chemicals)進行肝細胞分離。將分離之肝細胞以6×105cells/mL的濃度懸浮於培養皿中,播植於35mm塑膠培養皿(Falcon Plastic)中(2mL/皿),培養於37℃、5%CO2的培養箱。使用含有10%初生小牛血清(newborn calf serum)、HEPES(5mM)、青黴素(100U/mL)、鏈黴素(0.1mg/mL)、迪皮質醇(dexamethasone)(10nM)及胰島素(10nM)之威廉斯培養皿E(Williams’ Medium E,以下稱WE)作為培養皿。5小時後,以不含血清及荷爾蒙的新WE置換,在用於實驗前先培養一晚。
在培養開始後第1天,將細胞移入不含血清及荷爾蒙的新WE,於培養皿中,添加重組的大鼠IL-1β(純度為97%以上)(PeproTech公司、Rocky Hill、NJ、USA)及由實施例1以甲醇萃取之Pa5或比較例的7-甲氧基黃芩素。各個培養皿中濃度分別為IL-1β:1nM、Pa5:5、10及20mM、7-甲氧基黃芩素:10、20及40μM(圖1)。自添加IL-1β及Pa5或7-甲氧基黃芩素起8小時後,使用Griess法(Green LC et al,Anal Biochem 1982;126:131-138)測定各培養皿中NO的量。更具體而言,測定培養皿中亞硝酸鹽(NO的安定代謝物)的量。
又,為了檢驗Pa5的細胞傷害性,測定乳酸脫氫酵素(LDH)活性。使用LDH Cytotoxicity Detection Kits(Takara-bio公司),測定培養皿的乳酸脫氫酵素(LDH)活性。由於LDH為存在於細胞內的酵素,隨著細胞傷害,而釋放至培養皿中。自添加IL-1β及Pa5或7-甲氧基黃芩素起8小時後,取培養皿用於活性測定。實際上,各試樣(50μl的培養皿)與試劑套組中的溶液C(50μl)混合,在室温放置30分鐘,添加1M鹽酸(25μl)使反應停止,測定490nm的吸光度,與使用已知濃度的LDH之檢量線比較,求得LDH活性。並且,以1枚培養皿上全體細胞的LDH活性(亦即全細胞萃取液)當作正對照(圖3中的正對照),視為100%。從存在有肝細胞的培養皿將培養皿移除,將細胞以磷酸緩衝生理食鹽水(PBS)清洗3次並用
超音波破碎,取在10000×g離心3分鐘後的上清液作為全細胞萃取液使用,測定LDH活性。
圖1中大鼠肝細胞的NO產生量測定的結果,於圖2中表示IC50值(NO產生50%時的藥劑濃度)。圖1中,「(-)」表示無添加IL-1β,「(+)」表示添加IL-1β。雖然,Pa5、7-甲氧基黃芩素(比較例)皆依用量而抑制因IL-1β而起的NO產生,然而,當Pa5與7-甲氧基黃芩素(比較例)以相同添加濃度(10μM)進行比較時,Pa5相較於7-甲氧基黃芩素(比較例),NO產生抑制作用的程度高(圖1)。又,相對於Pa5的IC50值為9.0μM,7-甲氧基黃芩素(比較例)的IC50值為16.3μM(圖2),表示Pa5的NO產生抑制作用比7-甲氧基黃芩素(比較例)高。
圖3表示LDH活性的測定結果。圖3中,「(-)」表示無添加IL-1β,「(+)」表示添加IL-1β。添加Pa5時的LDH活性與添加IL-1 β時相同,顯示Pa5不具有細胞傷害性。
如上所示,Pa5具有高NO產生抑制作用。因此,可知Pa5具有優良的抗發炎作用。
關於Pa5及Pa5’對各種發炎性細胞素/趨化素產生之
影響,藉由細胞素/趨化素陣列(生物體外)進行驗證。
在發炎初期,由受到傷害的組織釋放數種白血球趨化因子,白血球滲入發炎部位。白血球趨化因子包含如白三烯(leukotriene)B4(LTB4)之類特異性低的因子以及特異性高的蛋白質性趨化因子之趨化素家族。趨化素分為2大類:4個保存的Cys殘基中前2個Cys殘基之間夾有1殘基之CXC趨化素,以及Cys殘基為連續之CC趨化素,前者主要具有嗜中性球的趨化活性,後者具有單核球的趨化活性。已知發炎性疾病患者表現過剩的特定趨化素,趨化素及其受體的訊息傳達之抑制,可期待成為抗炎藥的標的。
本實施例係以細胞素/趨化素陣列(生物體外)驗證Pa5及Pa5’對於添加IL-1β而引發之各種發炎性細胞素/趨化素之產生有何影響。
與實施例4同樣,以膠原蛋白酵素灌流法由雄性威斯特系大鼠分離肝細胞。將分離之肝細胞以1.2×106cells/mL的濃度懸浮培養皿(與實施例4相同),播植於35mm塑膠培養皿(與實施例4相同)(1mL/皿),培養於37℃、5%CO2的培養箱。5小時後,以不含血清及荷爾蒙之新的WE置換,在用於實驗前先培養一晚。
培養開始後第1天,將細胞移入不含血清及荷爾蒙的
新WE,於培養皿中添加IL-1β(與實施例4相同)及實施例1中以甲醇萃取之Pa5或實施例2中以甲醇萃取之Pa5’。各個培養皿中的濃度分別為IL-1β:1nM、Pa5:20μM、Pa5’:100μM(表1)。然後,培養於37℃,自培養開始3小時後將培養皿取出。取出的培養皿在5,000rpm離心1分鐘,去除細胞殘渣,將上清液用於分析。在進行分析前,上清液保存於-80℃。
關於各種炎症性細胞素/趨化素的產生量,使用Proteome Profiler(註冊商標)抗體陣列(Antibody Array)當中,可檢出29種細胞素/趨化素之大鼠細胞素抗體陣列(Rat Cytokine Antibody Array,R&D Systems公司)(http://www.rndsystems.com/product_detail_objectname_ratcytokinearray.aspx),遵照隨附的操作方式進行測定。此測定係使用1mL上述所得之培養皿的上清液。
上述方法可同時檢出29種細胞素/趨化素,各細胞素/趨化素量依比例在Proteome Profiler Antibody Array的過濾上的化學發光增加。在此,Proteome Profiler Antibody Array的過濾器之化學發光係以LAS3000mini(GE Healthcare)檢出,進行密度測定解析後,加以數值化。關於密度測定解析係使用ImageJ軟體,參照http://www.hm6.aitai.ne.jp/~maxcat/imageJ/technique.html#gels(「Analyzing Electrophoretic Gels~電氣泳動膠體的解
析」的項目)進行。
各種炎症性細胞素/趨化素詳述如下。
(1)CINC-2α/β及(2)CINC-3
CINC(cytokine-induced neutrophil chemoattractant)(細胞素誘導性嗜中性球趨化性因子)屬於趨化素的α(CXC)次家族。以CINC-1為首,3個大鼠CXC趨化素(CINC-2α、CINC-2β、CINC-3/MIP-2)已被鑑定。嗜中性球滲入為代表性的急性期發炎反應,嗜中性球受到CINCs的刺激而快速發生形態變化。在生物體外研究的結果,各CINC的趨化性活性本質並無差異,在生物體內(in vivo)顯示對嗜中性球特別強的趨化性活性。期待以抑制CINC的表現,使局部發炎中嗜中性球的滲入受到抑制,而緩和發炎症狀。
(3)分形素(Fractalkine)(CX3CL1)
表現於活性化血管內皮細胞、神經細胞、樹狀細胞及腸管上皮細胞。由發炎系細胞素之TNFα、IL-1或IFNγ等發炎性刺激,誘導CX3CL1之表現。在生物體內存在有膜結合型及分泌型兩種形態,不僅是作為趨化素,亦表現整合素(integrin)非依存的細胞接著能力,可作為細胞接著分子發揮功能。分泌型趨化素對於NK細胞、T細胞及單核球顯示細胞趨化活性。CX3CL1亦具有血管新生作用。已知分形素-CX3CR1的表現與關節風溼免疫疾病或動脈硬化等各種疾病相關。期待藉由阻礙CX3CL1,可抑制對滑
膜組織的發炎細胞之滲入,以抑制關節風溼免疫疾病等以關節炎為首之發炎。
(4)sICAM-1(CD54)
CD54(ICAM-1:Intercellular Adhesion Molecule 1)屬於免疫球蛋白超級家族之接著分子,為膜穿透型糖蛋白質,常見於許多細胞中。CD54與細胞接著分子LFA-1(淋巴球機能相關抗原1)結合,在發炎或免疫反應的細胞間相互作用擔任重要角色。已知ICAM當中,sICAM(soluble Intercellular Adhesion Molecule)經由ICAM控制免疫反應,在自體免疫疾病、內分泌疾病、胃癌、胰臟癌、乳癌等的表現上昇,推測因此抑制細胞傷害性T細胞、自然殺手細胞對癌細胞之攻擊,而促進癌轉移。
(5)MIG(CXCL9)
CXCL9為14kDa的趨化素,且是CXC趨化素家族的一員。CXCL9在巨噬細胞或單核球、嗜中性球、APC、B細胞或嗜酸性球中被特異的誘導,其誘導機制係經由IFNγ-JAK、STAT訊息傳達路徑。因此,被干擾素γ所誘導之單核球性細胞素,亦稱為干擾素γ誘導單核細胞因子(Monokine induced by gamma interferon,MIG)。又,在靜脈內皮細胞或皮膚纖維母細胞中,TNFα所引起之CXCL9的誘導被促進。CXCL9於腸管上皮亦進行構成性表現。若干研究報告指出此趨化素的主要機能為召集針對感染或發炎處的白血球,藉由格蘭氏陰性或陽性細菌的感染活化CXCL9。CXCL9與關節風溼免疫疾病等免疫反應
或慢性發炎有密切的相關。推測CXCL9的表現也作為T細胞的召集與活化之媒介,對乾癬或肺疾病亦可能具有作用。亦表現於皮膚移植數日後、排斥反應發生前。
(6)VEGF(VEGF-A/vasculotropin)
血管內皮生長因子(Vascular endothelial growth factor,VEGF)為與血管新生相關的因子之一,在固態癌的增殖中擔任重要角色。VEGF-A具有對於血管內皮細胞之增殖因子及血管穿透性的亢進因子等2種性質。VEGF-A的遺傳基因表現受到增殖因子或動情素、低氧等而被誘導。VEGF的阻礙為實質固態癌治療的正確戰略之事實,可由對VEGF特異結合,以阻礙其機能之抗體藥癌思停(Bevacizumab)顯示優良的延命效果獲得證明。再者,關節風溼免疫疾病的小鼠模型或動脈硬化模型等亦顯示與VEGF系相關。VEGFR經由發炎細胞的動員或機能活化而與發炎深切相關,可謂其表現之抑制與抗發炎作用連結。
(7)IL-17
IL-17(IL-17A)為從小鼠活性化T細胞cDNA庫被鑑定的細胞素CTLA-8。已知IL-17的作用為與IL-6、G-CSF、CXCL1、CXCL8(僅人類)等主要嗜中性球的活化、趨化相關的細胞素/趨化素及β-防禦素(β-Defensin)或S100家族等抗菌胜肽的表現誘導。對膠原蛋白誘導關節炎或自體免疫性腦脊髓炎等自體免疫疾病,相對於IFN-γ或IL-12缺陷小鼠並無抑制反而惡化,IL-17缺陷小鼠有更強的抑制,在使用抗IL-17抗體之人類臨床試驗中,顯示對
於關節風溼免疫疾病或乾癬之有效性,表示IL-17表現之抑制對於發炎性疾病的改善有效。
(8)胸腺趨化素(Thymus Chemokine)(CXCL7)
CXCL7主要伴隨著源自血小板之活化而產生,促進嗜中性球或嗜鹼性球、纖維母細胞、單核球的趨化,促進纖維母細胞的增殖或玻尿酸、葡萄胺聚醣、PGE2等的分泌。或促進來自嗜鹼性球的組織胺的釋放。CXCL7表現之抑制會抑制嗜中性球等的滲入,由於防止組織胺的釋放促進,表示抗發炎性的作用。
細胞素/趨化素陣列(生物體外)的結果表示於表1及圖4。表1及圖4中,「(-)」表示無添加IL-1β,「(+)」表示添加IL-1β。Pa5對各種細胞素/趨化素的誘導顯示強的抑制。又,Pa5’對分形素(CX3CL1)、IL-17及胸線趨化素(CXCL7)的誘導顯示強的抑制。
由上可知,Pa5及Pa5’可抑制許多發炎性趨化素/細胞素的誘導,具有優良的抗發炎作用。
為了檢驗Pa9的抗發炎作用,調查一氧化氮(NO)產生之抑制作用。
培養與實施例4相同的取自大鼠的肝細胞,培養開始後第1天,將細胞移入不含血清及荷爾蒙的新WE,於培養皿中添加重組的大鼠IL-1β(與實施例4相同)及實施例3中以甲醇萃取之Pa9。各個培養皿中的濃度分別為IL-1β:1nM、Pa9:10μM、50μM及100μM(圖5)。自添加IL-1β及Pa9起8小時後,與實施例4相同測定各培養皿中NO量。
圖5中大鼠肝細胞的NO產生量測定的結果,於圖6表示IC50值(NO產生50%時的藥劑濃度)。圖5中,「(-)」表示無添加IL-1β,「(+)」表示添加IL-1β。Pa9依用量會抑制因IL-1β所引起之NO產生(圖5)。又,Pa9的IC50值為32μM(圖6)。
如上所示,Pa9顯示具有高NO產生抑制作用。因此,可知Pa9具有優良的抗發炎作用。
Claims (7)
- 一種化合物,係以下述式(I)或式(Ⅱ)表示者,
- 一種醫藥品,係以下述式(I)、式(Ⅱ)或式(Ⅲ)表示之化合物作為有效成分者,
- 一種抗炎劑,係以下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物作為有效成分者,
- 一種化妝品,係含有下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物者,
- 一種飲食品,係含有下述式(I)、式(Ⅱ)或式(Ⅲ)表示之化合物者,
- 一種化合物,係由紫蘇科植物經由萃取處理製得,以下述式(I)、式(Ⅱ)或式(Ⅲ)表示者,
- 一種下述式(I)、式(Ⅱ)或式(Ⅲ)所示之化合物之製造方法,係包含將紫蘇科植物萃取處理之步驟者,
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