百兩金皂苷類似物的化學與藥理學研究進展

蔡佳仲，胡英杰

廣州中醫(yī)藥大學熱帶醫(yī)學研究所，廣州510405

百兩金皂苷屬于齊墩果烷型五環(huán)三萜類，代表化合物是百兩金皂苷A 和B(ardisiacrispin A/B)，苷元均為西克拉明皂苷元A(cyclamiretin A)。百兩金皂苷結構類似物主要來自紫金?？?Myrsinaceae)紫金牛屬(Ardisia)、鐵仔屬(Myrsine)，報春花科(Primulaceae)報春花屬(Primula)、珍珠菜屬(Lysimachia)、仙客來屬(Cyclamen)和點地梅屬(Androsace)植物［1-4］。已有報道，百兩金皂苷A 和B(ardisiacrispin A/B)對白血病細胞HL-60、肝癌細胞Bel-7402、口腔上皮癌細胞KB、宮頸癌細胞HeLa、卵巢癌細胞SKOV-3、胃癌細胞BGC-823、乳腺癌細胞MCF-7 等均具有較強的細胞毒作用，機理與誘導細胞凋亡、抑制增殖有關［5，6］。不僅如此，結構類似西克拉明皂苷元A 的一些化合物也表現出一定的細胞毒活性，如Ardipusilloside III 在體外能濃度依賴性地抑制非小細胞肺癌NCI-H460 和膠質瘤細胞U251MG 的生長而誘導其凋亡［7，8］;而Saxifragifolin A、C 和D 體外對卵巢癌細胞SKOV-3、肺腺癌細胞A549、黑色素瘤細胞SK-MEL-2、平滑肌瘤細胞MESSA、結直腸腺癌細胞HCT-15 均顯示了較強的細胞毒，其IC50在0.19～2.37 μM 之間［9］。顯示這類化合物具有潛在的抗腫瘤藥物研究開發(fā)價值。迄今發(fā)現的百兩金皂苷類似物約有56 個，對該類化合物的研究似乎成為植物藥研究的一個熱點，因此我們將百兩金皂苷類似物的化學和藥理學研究情況作一綜述。

1 化學結構

百兩金皂苷三萜母核結構的重要特征有:(1)共有取代基13β，28-環(huán)氧醚，(2)共有取代基30-氧化甲基，(3)共有取代基3β-OH 或3β-O-糖鏈(由β-D-吡喃葡萄糖(β-D-glucopyranose)，α-L-吡喃鼠李糖(α-L-rhamnopyranose)，β-D-吡喃木糖(β-D-xylopyranose)，α-L-吡喃阿拉伯糖(α-L-arabinopyranose)和β-D-吡喃葡萄糖醛酸(β-D-glucopyranuronic acid)等構成)［1-11］，以及(4)16α-羥基等。根據30-氧化甲基氧化程度的不同，結構涉及醛/縮醛、醇、羧酸等。

1.1 30-醛/縮醛

這類化合物30 位是一個醛基，具有西克拉明皂苷元A 的基本結構(圖1)。根據苷元16 位或30 位取代基氧化情況可再劃分成:(I)16α-羥基-30-醛;(II)16-羰基-30-醛;(III)30-縮醛等(表1)。

圖1 具有30-醛/縮醛結構的西克拉明皂苷元A 類似物Fig.1 Structures of cyclamiretin A analogues with 30-aldehyde

表1 具有30-醛/縮醛結構的西克拉明皂苷元A 類似物Table 1 Derivatives of cyclamiretin A with 30-aldehyde structure

11 Lysichriside A H H OH CH3 β-D-xylopyranosyl-(1 →2)-β-D-glucopyranosyl-(1→4)-［β-D-6-acetyl-glucopyranosyl- (1→2)］-α-L-arabinopyranosyl-CHO 12 ［13］12 Paridiformoside H H OH CH3 α-L-rhamnopyranosyl-(1 →2)-β-D-glucopyranosyl-(1 →2)-［β-D-glucopyranosyl-(1→3)］-β-D-glucopyranosyl-CHO 15 ［36］13 Ardicrenin H H OH CH3 α-L-rhamnopyranosyl-(1 →4)-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranosyl-CHO 2，13 ［21，33］14 Cyclacoumin H H OH CH2OH β-D-xylopyranosyl-(1→2)-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranosyl-CHO 18，19 ［23，24］15 Cyclamin H H OH CH3 β-D-glucopyranosyl-(1 →3)-［β-D-xylopyranosyl-(1 →2)］-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranosyl-CHO 6，19，20 ［24，25，32，37］16 Isocyclamin H H OH CH3 β-D-glucopyranosyl -(1 →6)-［β-D-xylopyranosyl-(1 →2)］-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranosyl-CHO 19 ［24，37］17 Saxifragifolin D H H OH CH3 β-D-xylopyranosyl -(1 →2)-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl -(1 →4)-β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranosyl-CHO 22，23 ［26，29］18 Cyclamiretin A-3β-O-α-L- rhamnopyranosyl-(1 →4)-β -Dglucopyranosyl-(1→2)H H OH CH3 α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl- (1 →2)-［β-D-glucopyranosyl-CHO 6 ［38，39］-［β-D-glucopyranosyl-(1 →4)］-α-L-arabinopyranoside (1→4)］-α-L-arabinopyranosyl-19 Cyclamiretin A-3β-O-β-D- xylopyranosyl-(1 →2)-β-D- glucopyranosyl-(1 →2)-［β-D-glucopyranosyl-(1→4)］-α-L-arabinopyranoside H H OH CH3 β-D-xylopyranosyl -(1 →2)-β-D-glucopyranosyl-(1 →2)-［β-D-glucopyranosyl -(1 →4)］-α-L-arabinopyranosyl-CHO 16 ［40］20 Cyclamiretin A-3β-O-β-D- glucopyranosyl uronic acid-(1 →2)-β-D-xylopyranoside H H OH CH3 β -D-glucopyranosyl uronic acid-(1→2)-β-D-xylopyranosyl- CHO 14 ［34］21 Cyclamiretin A-3β-O-β-D-glucopyranosyl-(1→2)-{β-D-xylopyranosyl-(1→2)-［β-D-glucopyranosyl-(1 →3)-β-D-glucopyranosyl-(1→3)］-β-D-glucopyranosyl-(1→4)}-α-L-arabinopyranoside H H OH CH3 β-D-glucopyranosyl- (1 →2)-{β-D-xylopyranosyl- (1 →2)-［β-D-glucopyranosyl-(1 →3)-β-D-glucopyranosyl-(1 →3)］-β-D-glucopyranosyl-(1 →4)}-α-L-arabinopyranosyl-CHO 4 ［16］22 Cyclamiretin A-3β-O-α-L- rhamnopyranosyl-(1 →3)［β-Dxylopyranosyl-(1 →2)］ -β-Dglucopyranosyl-(1→4)-［β-Dglucopyranosyl-(1 →2)］-α-Larabinopyranoside H H OH CH3 α-L-rhamnopyranosyl-(1 →3)［β-D-xylopyranosyl-(1→2)］-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranosyl-CHO 3 ［15］

23 Cyclamiretin A-3β-O-α-L- rhamnopyranosyl-(1 →3)［β-Dglucopyranosyl-(1→3)-β-D-xylopyranosyl-(1→2)］-β-D-glucopyranosyl-(1→4)-［β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranoside H H OH CH3 24 Cyclamiretin A-3β-O-α-L- rhamnopyranosyl-(1→3)-［β-Dxylopyranosyl-(1 →2)］ -β-Dglucopyranosyl-(1→4)-［β-D-6-O-acetyl- glucopyranosyl-(1→2)］-α-L-arabinopyranoside H H OH CH3 25 Cyclamiretin A-3β-O-β-D- xylopyranosyl-(1→4)-［α-L-rhamnopyranosyl-(1 →2)］-β-Dglucopyranosyl-(1→4)-［β-Dglucopyranosyl-(1 →2)］-α-Larabinopyranoside H H OH CH3 26 Cyclamiretin A-3β-O-4-O-［3-hydroxyl-3- methylglutaryl］-β-D-xylopyranosyl-(1 →2)-β-Dglucopyranosyl-(1 →4)-［β-Dglucopyranosyl-(1 →2)］-α-Larabinopyranoside H H OH CH3 27 Deglucocyclamin II H H OH CH3 28 Denticin H H OH CH3 29 Denticulation H H OH CH3 30 Saxifragifolin A H OAc OH CH3 α-L-rhamnopyranosyl-(1 →3)［β-D-glucopyranosyl-(1 →3)-β-D-xylopyranosyl-(1→2)］-β-D-glucopyranosyl-(1→4)-［β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranosyl-CHO 3 ［15］α-L-rhamnopyranosyl-(1→3)-［β-D-xylopyranosyl-(1→2)］-β-D-glucopyranosyl-(1 →4)-［β-D-6-O-acetyl- glucopyranosyl-(1 →2)］-α-L-arabinopyranosyl-CHO 3 ［15］β-D-xylopyranosyl-(1→4)-［α-L-rhamnopyranosyl-(1→2)］-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranosyl-CHO 6 ［32］4-O-［ 3-hydroxyl-3-methylglutaryl］-β-D-xylopyranosyl -(1 →2)-β-D-glucopyranosyl -(1 →4)-［β-D-glucopyranosyl -(1 →2)］-α-L-arabinopyranosyl-CHO 20 ［25］β-D-glucopyranosyl -(1 →3)-［β-D-xylopyranosyl -(1→2)］-β-D-glucopyranosyl -(1→4)-α-L-arabinopyranosyl-CHO 21 ［2］β-D-glucopyranosyl- (1 →4)-［β-D-xylopyranosyl-(1→2)］-β-D-glucopyranosyl- (1 →4)-［β-D-glucopyranosyl- (1 →2)］-β-D-arabinopyranosyl-CHO 10 ［19］β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1 →4)-［β-D-xylopyranosyl- (1 →2)］-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranosyl-CHO 10 ［19］β-D-xylopyranosyl-(1 →2)-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranosyl-CHO 22 ［27］31 Androsacenol H OAc OH CH3 H CHO — ［27］32 Androsacenol-3β-O-β-D- glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranoside H OAc OH CH3 33 Saxifragifolin C H OAc OH CH3 β-D-glucopyranosyl- (1 →4)-［β-D-glucopyranosyl- (1 →2)］-α-L-arabinopyranosyl-CHO — ［27］β-D-xylopyranosyl-(1 →2)-β-D-glucopyranosyl-(1 →4)-［β-D-glucopyranosyl-(1→4)β-Dglucopyranosyl-(1 →2)］-α-Larabinopyranosyl-CHO 23 ［29］

注:植物來源(Origin):1.Ardisia crispa 2. Ardisia crenata 3. Ardisia gigantifolia 4. Ardisia pusilla 5. Ardisia mamillata 6. Ardisia japonica 7. Ardisia punctate 8.Myrsine australis 9.Myrsine pellucida 10. Primula denticulate 11.Lysimachia thysiflora 12.Lysimachia christinae 13. Lysimachia patungensis 14.Lysimachia davurica 15.Lysimachia paridiformis 16. Lysimachia microcarpa 17. Cyclamen repandum 18. Cyclamen coum 19. Cyclamen mirabile 20.Cyclamen trocopteranthum 21.Cyclamen europaeum 22.Androsace saxifragaefolia 23.Androsace umbellate 24.Remusatia vivipara 25.Eupatorium chinense.

這些化合物中除了cyclamiretin A、androsacenol、androsacenol-3β-O-β-D-glucopyranosyl -(1 →4)-［β-D-glucopyranosyl-(1→2)］-α-L-arabinopyranoside 和cyclamigenin B 等苷元和次生苷外，都是來源于紫金?？坪蛨蟠夯浦参锏奶烊划a物。上述苷元和次生苷可以通過酸水解或高碘酸鈉水解或酶解法獲得［12，27，42］。其中，cyclamiretin A 是ardisiacrispin A的原生苷元，而cyclamiretin A 繼續(xù)酸水解縮合則生成次生苷元cyclamiretin D。Androsacenol 和androsacenol-3β-O-β-D-glucopyranosyl-(1→4)-［β-D-glucopyranosyl-(1 →2)］-α-L-arabinopyranoside 是saxifragifolin A 的原生苷元和次生皂苷。而cyclamigenin B則是第二亞類化合物的原生苷元。

1.2 30/29-醇，以及30/29-羧酸

這兩類化合物，29 或30 位碳為羥甲基(30/29-醇)，或為羧基(30/29-羧酸)(圖2)(表2)。

圖2 具有30/29-醇或羧酸結構的西克拉明皂苷元A 類似物結構Fig.2 Structures of cyclamiretin A analogues with 30/29-alcohol，or with 30/29-carboxylic acid

表2 具有13β，28-環(huán)醚-30/29-醇結構的西克拉明皂苷元A 類似物Table 2 Derivatives of cyclamiretin A with 13β，28-epoxy-30/29-alcohol structure

注:植物來源(Origin):1.Ardisia crenata 2. Ardisia japonica 3.Ardisia mamillata 4.Lysimachia christinae 5.Lysimachia davurica 6. Ardisia gigantifolia.

劉岱琳等［10，48］還從朱砂根(Ardisia crenata)中分得一個30 位甲基缺失的罕見三萜類似物朱砂根皂苷L。

百兩金皂苷類似物中的13β，28-環(huán)氧醚結構和30 位含氧基團的核磁共振波譜數據是鑒定其苷元母核結構的重要特征。由于13β，28-環(huán)醚的存在，百兩金皂苷類似物的核磁共振波譜具有相應特征［10，49］:往往出現化學位移值為86.6 的13 位連氧季碳信號和化學位移值為77.5 的28 位連氧亞甲基碳信號;如果28 位碳再有一個羥基取代的話，28 位不再出現亞甲基信號，而是在低場形成一個連氧次甲基碳信號，其化學位移值為99.0;苷元結構中30位如果是醛基，其碳-13 譜化學位移值為207 左右。

2 藥理活性

2.1 細胞毒作用

研究報道較多的是百兩金皂苷A 和B、九節(jié)龍皂苷Ⅰ、П 和Ш 等少數幾個化合物。

其中，朱砂根皂苷A、B、I 和J、百兩金皂苷A 和B 對人乳腺癌細胞MCF-7、人非小細胞肺癌NCIH460 和人神經膠質瘤細胞SF-268 均有一定的細胞毒作用，半數抑制濃度IC50在2.0～13.0 μM 之間，其中以百兩金皂苷A 和B 的作用較強，而且百兩金皂苷A 體外對人腎胚正常細胞293 的毒性較弱［10］。有研究顯示，百兩金皂苷A 對肝癌細胞HepG 2 的細胞毒作用，是通過阻滯細胞于亞G1 期，從而激活caspase-8 和caspase-9，使線粒體膜電位下降，釋放細胞色素C，并使磷脂絲氨酸外化和PARP 降解機理誘導細胞凋亡［28］。有學者報道了百兩金皂苷A體外抗人黑色素瘤細胞HTB-140 和對人人正常皮膚成纖維細胞HSFs 的毒性實驗研究。結果顯示百兩金皂苷A 能明顯影響HTB-140 細胞的活力、增殖、形態(tài)和細胞骨架，具有時間濃度依賴性地抑制腫瘤細胞的活力，通過使肌動蛋白細胞空泡化并解聚而影響腫瘤細胞的轉移和增殖。但同時也能降低人正常皮膚成纖維細胞HSFs 的活力和生長［50］。由此可見，百兩金皂苷A 在體外對多種腫瘤細胞具有較強的細胞毒活性，但對一些正常人體細胞也具有一定程度的毒性。雖然百兩金皂苷A、B 的體外抗腫瘤研究有較多報道，但體內抗腫瘤實驗結果仍未見報道。

對九節(jié)龍皂苷Ⅰ、П 和Ш 的體內外藥理研究也有一些報道。Zhang 等研究報道了九節(jié)龍皂苷I 體外對人非小細胞肺癌NCI-H460 具有明顯的抑制作用，藥物作用細胞后，使細胞阻滯于亞G1 期，并使核固縮，染色質濃集而形成凋亡小體，結果表明能時間、濃度依賴性地抑制腫瘤細胞的生長，從而誘導其凋亡［7］。林洪等也發(fā)現了九節(jié)龍皂苷Ш 能通過阻滯人膠質瘤細胞U251MG 于G2/M 期，引起時間濃度依賴性地使BAD 去磷酸化，并激活caspase-8 和caspase-3，從而抑制細胞增殖［8］。對于體內抗腫瘤研究，李偉芳等報道了九節(jié)龍皂苷Ⅰ和П 經腹腔注射，對小鼠肉瘤和艾氏腹水瘤的生長有一定的抑制作用，使瘤體生長緩慢，抑瘤率為16%～39%，而九節(jié)龍皂苷Ⅰ對小鼠黑色素瘤抑瘤率為27.3%，九節(jié)龍皂苷П 對小鼠肝癌的抑制率為23.3%［51］。

也有學者研究了davuricoside C(苷元結構中有16α-OH)體外對人卵巢癌細胞A2780 的增殖抑制作用，并提出16 位碳上有α-羥基比沒有α-羥基的顯示出更強的細胞毒作用［34］;劉岱琳等也通過對比百兩金皂苷A 和B、朱砂根皂苷I 和J 這四種皂苷體外對多種腫瘤細胞和人腎胚正常細胞293 的細胞毒作用，探討了結構與細胞毒活性之間的關系，得出一些見解:①16 位α-羥基和13β，28-環(huán)氧醚結構對活性起著決定性作用;②碳3-O-連接的糖鏈越長，其活性也越強;③苷元中碳30 的取代基對活性影響也很大，其對活性影響順序為:-CHO ＞ -CH(OCH3)2＞-CH2OH ＞-COOH［10］。

2.2 抗炎

有實驗顯示，用100 μM 百兩金皂苷A 作用于人巨噬細胞THP-1 能明顯抑制脂多糖誘導的IL-8和TNF-α 的釋放，并降低mRNA 轉錄水平，從而發(fā)揮其抗炎作用［22］。

2.3 收縮子宮

Chaweewan 等(1987)研究報道了百兩金皂苷A和B 具有收縮子宮的作用，在8 μg/mL 的皂苷溶液中小鼠子宮的收縮程度相當于0.2 μg/mL 乙酰膽堿所起的作用［14］。在此基礎上，Calis 等也對百兩金皂苷A、primulanin A、cyclamin 和cyclacoumin 進行了體外小鼠子宮收縮反應試驗，結果顯示，化合物的濃度分別為7.5 ×10-6、8.6 × 10-6、7.4 ×10-6和6.5 ×10-6μM 時，作用效果分別相當于10-5.2、10-4.9、10-5.2和10-4.9M 的乙酰膽堿的作用［24］。作用機理目前尚不明確。

2.4 抗真菌

據研究［24］，百兩金皂苷A、primulanin A、cyclamin、cyclacoumin 和isocyclamin 均具有一定的抗真菌作用，前三個化合物的最小抑菌濃度MIC 在80-160 μg/mL 之間，作用要強于后兩者。

2.5 其他藥理作用

百兩金皂苷類似物在其他方面的藥理活性，還包括抗cAMP 磷酸二酯酶作用等［52］。

3 結語

百兩金皂苷類似物的結構和數目具有一定的多樣性，其藥理作用特別是抗腫瘤活性研究也已發(fā)現一些有意義的苗頭。因此，進一步從中篩選具有抗腫瘤活性且對人體毒性較小的活性類似物并作為結構優(yōu)化的基礎，對發(fā)現抗腫瘤藥物先導化合物具有重要意義。

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