TWI794575B - 化合物用於預防及/或治療高血脂症之用途 - Google Patents
化合物用於預防及/或治療高血脂症之用途 Download PDFInfo
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- TWI794575B TWI794575B TW108148432A TW108148432A TWI794575B TW I794575 B TWI794575 B TW I794575B TW 108148432 A TW108148432 A TW 108148432A TW 108148432 A TW108148432 A TW 108148432A TW I794575 B TWI794575 B TW I794575B
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Abstract
本發明提供一種化合物用於預防及/或治療肥胖之用途，其中該化合物是選自於由下列所組成之群組：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、及其任意組合，該化合物能有效促進脂肪分解及/或減少細胞脂肪含量，能有效減少細胞中脂肪的含量，以達到預防及/或治療肥胖之目的。
Description
本發明係關於一種化合物用於預防及/或治療肥胖的用途，其中該化合物是選自於由下列所組成之群組：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、及其任意組合。
近年來全球肥胖的發病率已經逐漸的增加，世界衛生組織(World Health Organization,WHO)更以「傳染病」形容快速蔓延的肥胖，並稱其為「全球肥胖症」(Globesity)，根據2014年世界衛生組織的估計，全球約有39%的人口超重(約19億人)，更有13%的人口肥胖(約6億人)。而隨著飲食習慣改變及生活品質改善，台灣的肥胖盛行率亦逐年上升，依據衛生福利部國民健康署所公布之國民營養健康狀況變遷調查，其中成人過重或肥胖盛行率高達百分之四十三左右，而男性與女性比率分別為百分之四十九及百分之四十，換句話說台灣人中平均每兩個男性就有一個過重或肥胖，平均女性則兩至三個就有一個過重或肥胖，且其中就有20萬人以上已達病態型肥胖的標準，而須以手術進行治療。
肥胖的個體會使多種健康問題的風險增加，並可能導致多種併發症的發生，包括高血壓、高血脂、心血管疾病、睡眠呼吸中止、狹心症、退化性關節炎、尿酸過高骨關節炎、第二型糖尿病、及癌症等疾病；其中，由於體
內脂肪細胞過多，會分泌阻礙胰島素作用的有害物質，使得胰島素功能受阻，便無法有效控制上升的血糖，因而導致高血糖的症狀，若身體長期處於高血糖的情況，將使胰臟疲於分泌更多的胰島素來降低血糖，一旦胰臟超過負荷便會發展成第二型糖尿病。另外，血脂係指血液中的脂肪，主要包括膽固醇及三酸甘油酯，當血液中流通之膽固醇或三酸甘油酯之濃度高於正常值時，稱為高血脂症；而膽固醇或三酸甘油酯值過高，或高密度脂蛋白濃度過低時，又稱為血脂異常。高血脂症除會導致心臟疾病之外，也與腦中風、高血壓、糖尿病、腎病等慢性疾病息息相關。
因此，肥胖會降低生活質量並可能導致過早的死亡，因此病態性肥胖病患的平均壽命比起正常體重者少了許多。雖然，基因可能參與肥胖的發展，但肥胖流行病主要歸因於高熱量飲食和久坐的生活方式。因此，生活方式的改變可以預防肥胖及其並發症。
雖然低卡路里飲食和定期運動能夠用於減輕體重和治療肥胖，但這些方法難以實施且其功效受到限制，主要是因為維持體內能量儲存的適應性生理機制導致。另外，有部分藥物已被批准用於長期肥胖症治療(例如奧利司他、芬特明、或托吡酯)，然而該些藥物常造成嚴重的副作用，因而限制了治療功效及患者依從性；再者，減肥手術能夠大幅的造成體重減輕，但這種干預式的手術並不適合所有超重的人；基於以上該些原因，研究安全且有效的方式減少體重及脂肪積累確實有其需求性。
綜上所述，因應現代人因生活及飲食習慣改變所面臨的肥胖及因肥胖造成之整體健康問題，且基於現代人生活水平提高且對於保健概念提高，研發一種能有效地促進脂肪分解，以減少脂肪的形成且減少肥胖機會之有效成分組成的組成物，著實有其必要性。
緣此，本發明之一目的在提供一種組成物用於製備預防及/或治療肥胖之藥物的用途，其中該組成物包含一有效濃度之選自於由下列所組成之
群組中的化合物：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)((E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoic acid)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮(7-[[2-O-(6-Deoxy-α-L-mannopyranosyl)-β-D-gluco-pyranosyl]]oxy]-2,3-dihydro-5-hydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one)、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮(5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one)、及其任意組合，以及一醫藥上可接受之載體。
本發明之又一目的在提供一種組成物用於製備促進脂肪分解之藥物的用途，其中該組成物包含一有效濃度之選自於由下列所組成之群組中的化合物：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、及其任意組合，以及一醫藥上可接受之載體。
本發明之另一目的在提供一種7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮用於製備預防及/或治療肥胖之藥物的用途。
在本發明之一實施例中，該化合物的有效濃度為至少10μg/mL。
在本發明之又一實施例中，該醫藥組成物係促進脂肪的分解；且該醫藥組成物係促進脂肪細胞中脂肪的分解。
在本發明之又一實施例中，該7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮的有效濃度為至少10μg/mL。
在本發明之另一實施例中，該7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮係促進脂肪的分解。
本發明之化合物4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、5-羥基-2-(3-羥基-4-甲氧基苯基)-4-氧代-3,4-二氫-2h-鉻-7-基-2-鄰-(6-脫氧己吡喃糖基)己吡喃糖苷、及(S)-2,3-二氫-5,7-二羥基-2-(3-羥基-4-甲氧基苯基)-4H-1-苯並吡喃-4-酮中，該4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、該7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、及該5,7-二羥基-2-(4-羥基苯基)苯並-4-酮能有效促進脂肪分解，以減少細胞中脂肪的含量。因此，自本發明之4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、及5,7-二羥基-2-(4-羥基苯基)苯並-4-酮可用於製備促進脂肪分解及/或減少細胞脂肪含量之組成物的用途，且該組成物是一醫藥品、一保養品、或一食品，可藉由口服、塗抹等方式給予一個體。
以下將配合圖式進一步說明本發明的實施方式，下述所列舉的實施例係用以闡明本發明，並非用以限定本發明之範圍，任何熟習此技藝者，在不脫離本發明之精神和範圍內，當可做些許更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
圖1係為本發明之一實施例的代代花萃取物的HPLC指紋分析圖譜。
圖2係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-01之氫光譜圖。
圖3係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-01之質譜圖。
圖4係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-02之氫光譜圖。
圖5係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-02之質譜圖。
圖6係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-03之氫光譜圖。
圖7係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-03之質譜圖。
圖8係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-04之氫光譜圖。
圖9係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-04之質譜圖。
圖10係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-05之氫光譜圖。
圖11係為本發明之一實施例的代代花萃取物中所純化出的化合物TCI-CA-05之質譜圖。
圖12係為本發明之一實施例的代代花萃取物中純化出的化合物TCI-CA-01、化合物TCI-CA-02、化合物TCI-CA-03、化合物TCI-CA-04、及化合物TCI-CA-05促進脂肪分解之功效的長條圖。*** p<0.001。
本文中所使用數值為近似值，所有實驗數據皆表示在20%的範圍內，較佳為在10%的範圍內，最佳為在5%的範圍內。
使用Excel軟體進行統計分析。數據以平均值±標準差(SD)表示，各組之間的差異以學生t檢驗(student's t-test)分析。
依據本發明，醫藥品可利用熟習此技藝者所詳知的技術而被製造成一適合於非經腸道地(parenterally)或口服地(orally)投藥的劑型(dosage form)，這包括，但不限於：注射品(injection)[例如，無菌的水性溶液(sterile aqueous solution)或分散液(dispersion)]、無菌的粉末(sterile powder)、錠劑(tablet)、片劑(troche)、口含錠(lozenge)、丸劑(pill)、膠囊(capsule)、分散性粉末(dispersible powder)或細顆粒(granule)、溶液、懸浮液(suspension)、乳劑(emulsion)、糖漿(syrup)、酏劑(elixir)、濃漿(slurry)以及類似之物。
依據本發明的醫藥品可以一選自於由下列所構成的群組中的非經腸道途徑(parenteral routes)來投藥：腹膜內注射(intraperitoneal injection)、皮下注射(subcutaneous injection)、肌肉內注射(intramuscular injection)以及靜脈內注射(intravenous injection)。
依據本發明的醫藥品可包含有一被廣泛地使用於藥物製造技術之醫藥上可接受之載體。例如，該醫藥上可接受之載體可包含一或多種選自於由下列所構成之群組中的試劑：溶劑(solvent)、乳化劑(emulsifier)、懸浮劑(suspending agent)、分解劑(decomposer)、黏結劑(binding agent)、賦形劑(excipient)、安定劑(stabilizing agent)、螯合劑(chelating agent)、稀釋劑(diluent)、膠凝劑(gelling agent)、防腐劑(preservative)、潤滑劑(lubricant)、吸收延遲劑(absorption delaying agent)、脂質體(liposome)以及類似之物。有關這些試劑的選用與數量是落在熟習此項技術之人士的專業素養與例行技術範疇內。
依據本發明，該醫藥上可接受的載劑包含有一選自於由下列所構成之群組中的溶劑：水、生理鹽水(normal saline)、磷酸鹽緩衝生理鹽水(phosphate buffered saline,PBS)、含有醇的水性溶液(aqueous solution containing alcohol)以及它們的組合。
依據本發明，該醫藥品可以一選自於由下列所構成之群組中的非經腸道途徑(parenteral routes)來投藥：皮下注射(subcutaneous injection)、表皮內注射(intraepidermal injection)、皮內注射(intradermal injection)以及病灶內注射(intralesional injection)。
依據本發明，食品產品可被當作食品添加物(food additive)，藉由習知方法於原料製備時添加，或是於食品的製作過程中添加，而與任一種可食性材料配製成供人類與非人類動物攝食的食品產品。
依據本發明，食品產品的種類包括但不限於：飲料(beverages)、發酵食品(fermented foods)、烘培產品(bakery products)、健康食品(health foods)以及膳食補充品(dietary supplements)。
依據本發明，以管柱層析法(Column chromatography)及薄層層析法(Thin layer chromatography,TLC)自本發明之代代花萃取物的乙酸乙酯層萃取物中，所純化出之五種化合物：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)((E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoic acid)，本文命名為TCI-CA-01；7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮(7-[[2-O-(6-Deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]]oxy]-2,3-dihydro-5-hydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one)，本文命名為TCI-CA-02；5,7-二羥基-2-(4-羥基苯基)苯並-4-酮(5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one)，本文命名為TCI-CA-03；5-羥基-2-(3-羥基-4-甲氧基苯基)-4-氧代-3,4-二氫-2h-鉻-7-基-2-鄰-(6-脫氧己吡喃糖基)己吡喃糖苷(5-hydroxy-2-(3-hydroxy-4-methoxy-phenyl)-4-oxo-3,4-dihydro-2h-chromen-7-yl 2-o-(6-deoxyhexopy-ranosyl)hexopyranoside)，本文命名為TCI-CA-04；及(S)-2,3-二氫-5,7-二羥基-2-(3-羥基-4-甲氧基苯基)-4H-1-苯並吡喃-4-酮((S)-2,3-Dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one)，本文命名為
TCI-CA-05。其中，用語「代代花萃取物」意為代代之花朵與溶劑經一特定時間與溫度萃取而得。
依據本發明，有關混合物之化學分離及化學結構分析的操作程序與參數條件等是落在熟習此項技術之人士的專業素養與例行技術範疇內。
本發明提供一種製備4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、及/或5,7-二羥基-2-(4-羥基苯基)苯並-4-酮用於促進脂肪分解及/或減少細胞脂肪含量之組成物的用途，能有效促進脂肪分解，以減少細胞中脂肪的含量。
同時，本發明用於促進脂肪分解及/或減少細胞脂肪含量之組成物，亦可包含一有效濃度之選自於由下列所組成之群組中的化合物：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮(5,7-Dihydroxy-2-(4-hydroxy-phenyl)chroman-4-one)、及其任意組合，及一醫藥上可接受之載體，且該組成物係一醫藥品、一保養品、一食品。
以下將詳細說明本發明之4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、5-羥基-2-(3-羥基-4-甲氧基苯基)-4-氧代-3,4-二氫-2h-鉻-7-基-2-鄰-(6-脫氧己吡喃糖基)己吡喃糖苷、及(S)-2,3-二氫-5,7-二羥基-2-(3-羥基-4-甲氧基苯基)-4H-1-苯並吡喃-4-酮之詳細萃取純化方法；以及該五種化合物分別於促進脂肪細胞中脂肪分解的測試實驗。
正己烷(n-hexane)、乙酸乙酯(ethyl acetate)、丙酮(acetone)、甲醇(methanol)、乙醇(ethanol)、正丁醇(n-butanol)、乙腈(acetonitrile)、氯仿-d1(氘化程度99.5%)、甲醇-d6(氘化程度99.5%)、重水(deuterium oxide，氘化程度大於99.8%)、及二甲基亞碸-d 6 (dimethyl sulfoxide-d 6 ，氘化程度>99.9%)購自台灣默克公司。
化合物的分離係利用管柱層析法(Column chromatography)及薄層層析法(Thin layer chromatography,TLC)。具體而言，管柱層析之管住係選用自Sephadex LH-20(購自Amersham BioSciences，英國)、Diaion HP-20(購自Mitsubishi Chemical Co.，日本)、Merck Kieselgel 60(40-63μm，購自默克，德國，編號Art.9385)、Merck LiChroprep® RP-18(40-63um，購自默克，德國，編號Art.0250)。高效液相層析(High Performance Liquid Chromatography,HPLC)系統裝配Hitachi L-2310系列幫浦、Hitachi L-2420 UV-VIS偵測器(偵測波長為200nm至380nm)、及D-2000 Elite資料處理軟體；管柱係選用自分析級Discovery® HS C18(250×4.6mm,5μm；SUPELCO)管柱與Mightysil RP-18 GP 250(250×4.6mm,5μm；Kanto Chemical)管柱，以及半製備級Discovery® HS C18(250×10.0mm,5μm；SUPELCO)管柱與製備級Discovery® HS C18(250×21.0mm,5μm；SUPELCO)管柱。層析系統配備紫外燈UVP UVGL-25(波長為254nm及365nm)。薄層層析片係塗覆矽膠60 F254(0.25mm；購自默克，德國)或RP-18 F254S(0.25mm；購自默克，德國)之鋁片。
化合物的化學結構係以質譜法(Mass spectrometry,MS)及核磁共振光譜法(Nuclear magnetic resonance spectrometry,NMR)進行分析。具體而言，使用二維離子阱串聯傅立葉轉換質譜、電噴灑離子化串聯質譜(ESI-MS/MS,Thermo Scientific Orbitrap Elite system)、及Bruker amaZon SL系統及進行測定，單位為m/z；並使用400MHz Varian 400 FT-NMR取得一維與二維NMR光譜，
以δ表示化學位移(Chemical shift)，其中單位為ppm；以四甲基矽烷(Tetramethylsilane,TMS)作為內部標準品；偶合常數(J)以Hz為單位，並以s表單峰(Singlet)，d表二重峰(Doublet)，t表三重峰(Triplet)，q表四重峰(Quartet)，p表五重峰，m表多重峰(Multiplet)，brs則表寬峰。
本實施例所純化的化合物是得自於代代(Citrus aurantium)，其為芸香科(Rutaceae)柑橘屬(Citrus)之常綠灌木植物，又稱酸橙、青橙、苦橙。源於地中海，於古希臘時代，已被古希臘人用作芳香療法的殺菌劑，和植物療法的鎮靜劑。代代喜溫暖濕潤氣候且不耐寒，花白色或帶紫紅色。代代已知具有理氣解鬱、減緩腹脹痛及嘔吐、促進血液循環、破氣行痰等功效，也因代代的花香氣濃郁，聞之令人忘倦，而可用於鎮定心情、解除緊張不安。
首先，製備代代花萃取物，將代代花乾料與水、醇、或醇水混合物之萃取溶劑，以5-20：1-5之液固比混合，其中萃取溶劑較佳為水，均質後在溶劑中以50-100℃進行萃取0.5-3小時。萃取後冷卻至室溫，將該粗萃取物經由400 mesh之濾網過濾以獲得濾液。最後，將該濾液於45-70℃進行減壓濃縮，即得到本發明之代代花萃取物，其高效能液相層析(high performance liquid chromatography,HPLC)指紋圖譜顯示於圖1。
接著，取10公升本發明之代代花萃取物進行分離純化，將乙酸乙酯與水以比例1：1進行混合，並以液相分配萃取的方式對該代代花萃取物進行萃取三次後，合併該乙酸乙酯層的萃取液並經減壓濃縮乾燥，即得到本發明之代代花萃取物的乙酸乙酯層萃取物共4.4g。
接著，依據生物活性導引分離方法(Bioassay guided fractionation)，追蹤本發明之代代花萃取物的乙酸乙酯層萃取物中的活性成
分。首先，將4.4g的乙酸乙酯層萃取物以柱層析方法進行分離純化，其中係以矽膠分子篩管為層析材料，並以甲醇作為沖提液，經管柱層析後共分離得到7個劃分層(F1-F7)；接著，再將劃分層F1以中壓管柱層析儀進行進一步的分離純化，其中填充Merck LiChroprep® RP-18為層析材料，並以水與甲醇的混合液為沖提液且漸減極性，經管柱層析分離純化後再經薄層層析法進行點片後合併，最後共得到5個次劃分層(F1-1-F1-7)。
再將次劃分層F1-3以HPLC進行分離純化，其中係以4：1比例混合之水與乙腈的混合溶劑系統為移動相，並於分離純化後得到6.9mg之化合物TCI-CA-01、8.0mg之化合物TCI-CA-02、及12.7mg之化合物TCI-CA-03。
再將次劃分層F1-5以HPLC進行分離純化，其中係以3：1比例混合之水與乙腈的混合溶劑系統為移動相，並於分離純化後得到5.6mg之化合物TCI-CA-04、及9.2mg之化合物TCI-CA-05。
將化合物TCI-CA-01、TCI-CA-02、TCI-CA-03、TCI-CA-04、及TCI-CA-05經由核磁共振光譜儀與質譜儀分析後經文獻比對，確定該五個化合物之名稱及化學結構式如下表1所示，TCI-CA-01之氫光譜資料如圖2所示，TCI-CA-01之質譜圖資料如圖3所示；TCI-CA-02之氫光譜資料如圖4所示，TCI-CA-02之質譜圖資料如圖5所示；TCI-CA-03之氫光譜資料如圖6所示，TCI-CA-03之質譜圖資料如圖7所示；TCI-CA-04之氫光譜資料如圖8所示，TCI-CA-04之質譜圖資料如圖9所示；TCI-CA-05之氫光譜資料如圖10所示，TCI-CA-05之質譜圖資料如圖11所示；其中，化合物TCI-CA-01為4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)((E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoic acid)，該化合物俗稱為阿魏酸(Ferulic acid)其結構式為式(I)化合物；化合物TCI-CA-02為7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮(7-[[2-O-(6-Deoxy-α-L-mannopyranosyl)-β-D-
glucopyranosyl]]oxy]-2,3-dihydro-5-hydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one)，俗稱為柚皮苷(Naringin)其結構式為式(II)化合物；化合物TCI-CA-03為5,7-二羥基-2-(4-羥基苯基)苯並-4-酮(5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one)，俗稱為柚皮素(Naringenin)其結構式為式(III)化合物；化合物TCI-CA-04為5-羥基-2-(3-羥基-4-甲氧基苯基)-4-氧代-3,4-二氫-2h-鉻-7-基-2-鄰-(6-脫氧己吡喃糖基)己吡喃糖苷(5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxo-3,4-dihydro-2h-chromen-7-yl 2-o-(6-deoxyhexopy-ranosyl)hexopyranoside)，俗稱為新橙皮苷(Neohesperidin)其結構式為式(IV)化合物；及化合物TCI-CA-05為(S)-2,3-二氫-5,7-二羥基-2-(3-羥基-4-甲氧基苯基)-4H-1-苯並吡喃-4-酮((S)-2,3-Dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one)，俗稱為橙皮素(Hesperetin)其結構式為式(V)化合物。
本實施例以小鼠骨髓基質細胞(Bone marrow stromal cell)進行本發明之化合物TCI-CA-01、化合物TCI-CA-02、化合物TCI-CA-03、化合物TCI-CA-04、及化合物TCI-CA-05)於促進脂肪分解之功效測試。其中，該小鼠骨髓基質細胞係購自美國典型培養物保藏中心(美國ATCC®)，編號CRL-2749TM。該細胞於分化前係培養於前脂肪細胞擴增培養液(Pre-adipocyte Expansion Medium)，其中包含90%之α-MEM(Minimum Essential Medium Eagle -Alpha Modification，購自Gibco，美國)細胞培養液、10%之胎牛血清(Fetal Bovine Serum，購自Gibco，美國)，且加入1.0%之青黴素/鏈黴素
(Penicillin-streptomycin，購自Gibco，美國)；並使用分化培養液(Differentiation Medium)使小鼠骨髓基質細胞進行分化，其中包含90%之α-MEM細胞培養液、20%之胎牛血清，且加入1.0%之青黴素/鏈黴素。
為證實化合物TCI-CA-01、化合物TCI-CA-02、化合物TCI-CA-03、化合物TCI-CA-04、及化合物TCI-CA-05具有促進脂肪分解的功效，首先將小鼠骨髓基質細胞分化成脂肪細胞，將8x104個小鼠骨髓基質細胞培養於含有0.5mL上述前脂肪細胞擴增培養液之24孔培養盤中，於37℃下培養7天，且期間每3天更換一次新鮮之上述分化培養液，7天後以顯微鏡觀察脂滴的形成，確保細胞已完全分化，接著將細胞分成以下七組：(1)僅含細胞培養液之控制組(Mock)、(2)加入10μg/mL本發明之化合物TCI-CA-01之實驗組、(3)加入10μg/mL本發明之化合物TCI-CA-02之實驗組、(4)加入10μg/mL本發明之化合物TCI-CA-03之實驗組、(5)加入10μg/mL本發明之化合物TCI-CA-04之實驗組、(6)加入10μg/mL本發明之化合物TCI-CA-05之實驗組、及(7)加入10μg/mL本發明之化合物TCI-CA-02加上10μg/mL本發明之化合物TCI-CA-03之實驗組，並於37℃培養7-10天，且同樣每3天更換一次新鮮之分化培養液。
接著，使用甘油檢測試劑盒(購於Cayman Chemical，美國)檢測細胞外甘油之數值，其中儲存在細胞中之三酸甘油脂被分解之後，會產生游離之甘油及脂肪酸，因此藉由測量細胞外的甘油含量，可以推知細胞中脂肪分解之數值。本試劑盒係利用測量會產生明亮之紫色產物的偶聯酵素反應系統之產物含量，來定量細胞外甘油的數值，並以標準品建立標準曲線以推算出樣品之細胞外甘油的數值。其中收集每孔之細胞培養上清液，並將25μL之細胞培養上清液轉移到新的96孔培養盤中，再於每孔中加入100μL重構的游離甘油測定試劑(Free Glycerol Assay Reagent)在室溫下反應15分鐘，接著讀取OD540nm處之數值。並利用Excel軟體進行student t-test以決定兩個樣本群體之間是否在統計上具有顯著差異(*p值<0.05；**p值<0.01；***p值<0.001)。
本發明之化合物TCI-CA-01、化合物TCI-CA-02、化合物TCI-CA-03、化合物TCI-CA-04、及化合物TCI-CA-05促進脂肪分解之測試結果如圖12所示。由圖12可見，經本發明之化合物TCI-CA-01作用後，相較於控制組，能有效地促進脂肪的分解；而經本發明之化合物TCI-CA-02、及化合物TCI-CA-03作用後，相較於控制組，能分別顯著的促進8%及15%的脂肪分解；經本發明化合物TCI-CA-04、及化合物TCI-CA-05作用後，皆相似於控制組的數值。此結果顯示本發明之代代花萃取物中活性成分化合物TCI-CA-01、化合物TCI-CA-02、及化合物TCI-CA-03能有效促進脂肪分解，以減少細胞中脂肪的含量。然而，將具有優異的促進脂肪分解能力之化合物TCI-CA-02及化合物TCI-CA-03混合後，於脂肪細胞作用後，其促進脂肪分解的功效卻與控制組相似，此結果顯示並非任意具有促進脂肪分解的化合物進行組合後，皆能有效加成其於促進脂肪分解的功效。
綜上所述，本發明之化合物4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、5-羥基-2-(3-羥基-4-甲氧基苯基)-4-氧代-3,4-二氫-2h-鉻-7-基-2-鄰-(6-脫氧己吡喃糖基)己吡喃糖苷、及(S)-2,3-二氫-5,7-二羥基-2-(3-羥基-4-甲氧基苯基)-4H-1-苯並吡喃-4-酮中，該4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、該7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、及該5,7-二羥基-2-(4-羥基苯基)苯並-4-酮能有效促進脂肪分解，以減少細胞中脂肪的含量。因此，自本發明之4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、及5,7-二羥基-2-(4-羥基苯基)苯並-4-酮可用於製備促進脂肪分解及/或減少細胞脂肪含量之組成物的用途，
且該組成物是一醫藥品、一保養品、或一食品，可藉由口服、塗抹等方式給予一個體。
Claims (3)
- 一種組成物用於製備預防及/或治療高血脂症之藥物的用途，其中該組成物包含一有效濃度之選自於由下列所組成之群組中的化合物：4-羥-3-甲氧基肉桂酸亦可稱3-(4-羥基-3-甲氧苯基)-2-丙烯酸)、7-[[2-O-(6-脫氧-α-L-甘露吡喃糖基)-β-D-吡喃吡喃糖基]]氧基]-2,3-二氫-5-羥基-2-(4-羥基苯基)-4H-1-苯並吡喃-4-酮、5,7-二羥基-2-(4-羥基苯基)苯並-4-酮、及其任意組合，以及一醫藥上可接受之載體。
- 如請求項1所述之用途，其中該化合物的有效濃度為至少10μg/mL。
- 如請求項1所述之用途，其中該組成物係促進脂肪細胞中脂肪的分解。
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