蔡佳仲，胡英杰

廣州中醫(yī)藥大學(xué)熱帶醫(yī)學(xué)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(jié)構(gòu)類似物主要來自紫金牛科(Myrsinaceae)紫金牛屬(Ardisia)、鐵仔屬(Myrsine)，報(bào)春花科(Primulaceae)報(bào)春花屬(Primula)、珍珠菜屬(Lysimachia)、仙客來屬(Cyclamen)和點(diǎn)地梅屬(Androsace)植物［1-4］。已有報(bào)道，百兩金皂苷A 和B(ardisiacrispin A/B)對(duì)白血病細(xì)胞HL-60、肝癌細(xì)胞Bel-7402、口腔上皮癌細(xì)胞KB、宮頸癌細(xì)胞HeLa、卵巢癌細(xì)胞SKOV-3、胃癌細(xì)胞BGC-823、乳腺癌細(xì)胞MCF-7 等均具有較強(qiáng)的細(xì)胞毒作用，機(jī)理與誘導(dǎo)細(xì)胞凋亡、抑制增殖有關(guān)［5，6］。不僅如此，結(jié)構(gòu)類似西克拉明皂苷元A 的一些化合物也表現(xiàn)出一定的細(xì)胞毒活性，如Ardipusilloside III 在體外能濃度依賴性地抑制非小細(xì)胞肺癌NCI-H460 和膠質(zhì)瘤細(xì)胞U251MG 的生長而誘導(dǎo)其凋亡［7，8］;而Saxifragifolin A、C 和D 體外對(duì)卵巢癌細(xì)胞SKOV-3、肺腺癌細(xì)胞A549、黑色素瘤細(xì)胞SK-MEL-2、平滑肌瘤細(xì)胞MESSA、結(jié)直腸腺癌細(xì)胞HCT-15 均顯示了較強(qiáng)的細(xì)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(jià)值。迄今發(fā)現(xiàn)的百兩金皂苷類似物約有56 個(gè)，對(duì)該類化合物的研究似乎成為植物藥研究的一個(gè)熱點(diǎn)，因此我們將百兩金皂苷類似物的化學(xué)和藥理學(xué)研究情況作一綜述。

1 化學(xué)結(jié)構(gòu)

百兩金皂苷三萜母核結(jié)構(gòu)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(gòu)成)［1-11］，以及(4)16α-羥基等。根據(jù)30-氧化甲基氧化程度的不同，結(jié)構(gòu)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(gè)醛基，具有西克拉明皂苷元A 的基本結(jié)構(gòu)(圖1)。根據(jù)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(jié)構(gòu)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(jié)構(gòu)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?bào)春花科植物的天然產(chǎn)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?yàn)轸然?30/29-羧酸)(圖2)(表2)。

圖2 具有30/29-醇或羧酸結(jié)構(gòu)的西克拉明皂苷元A 類似物結(jié)構(gòu)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(jié)構(gòu)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(gè)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(jié)構(gòu)和30 位含氧基團(tuán)的核磁共振波譜數(shù)據(jù)是鑒定其苷元母核結(jié)構(gòu)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(yīng)特征［10，49］:往往出現(xiàn)化學(xué)位移值為86.6 的13 位連氧季碳信號(hào)和化學(xué)位移值為77.5 的28 位連氧亞甲基碳信號(hào);如果28 位碳再有一個(gè)羥基取代的話，28 位不再出現(xiàn)亞甲基信號(hào)，而是在低場(chǎng)形成一個(gè)連氧次甲基碳信號(hào)，其化學(xué)位移值為99.0;苷元結(jié)構(gòu)中30位如果是醛基，其碳-13 譜化學(xué)位移值為207 左右。

2 藥理活性

2.1 細(xì)胞毒作用

研究報(bào)道較多的是百兩金皂苷A 和B、九節(jié)龍?jiān)碥闸?、?和Ш 等少數(shù)幾個(gè)化合物。

其中，朱砂根皂苷A、B、I 和J、百兩金皂苷A 和B 對(duì)人乳腺癌細(xì)胞MCF-7、人非小細(xì)胞肺癌NCIH460 和人神經(jīng)膠質(zhì)瘤細(xì)胞SF-268 均有一定的細(xì)胞毒作用，半數(shù)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(qiáng)，而且百兩金皂苷A 體外對(duì)人腎胚正常細(xì)胞293 的毒性較弱［10］。有研究顯示，百兩金皂苷A 對(duì)肝癌細(xì)胞HepG 2 的細(xì)胞毒作用，是通過阻滯細(xì)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(xì)胞色素C，并使磷脂絲氨酸外化和PARP 降解機(jī)理誘導(dǎo)細(xì)胞凋亡［28］。有學(xué)者報(bào)道了百兩金皂苷A體外抗人黑色素瘤細(xì)胞HTB-140 和對(duì)人人正常皮膚成纖維細(xì)胞HSFs 的毒性實(shí)驗(yàn)研究。結(jié)果顯示百兩金皂苷A 能明顯影響HTB-140 細(xì)胞的活力、增殖、形態(tài)和細(xì)胞骨架，具有時(shí)間濃度依賴性地抑制腫瘤細(xì)胞的活力，通過使肌動(dòng)蛋白細(xì)胞空泡化并解聚而影響腫瘤細(xì)胞的轉(zhuǎn)移和增殖。但同時(shí)也能降低人正常皮膚成纖維細(xì)胞HSFs 的活力和生長［50］。由此可見，百兩金皂苷A 在體外對(duì)多種腫瘤細(xì)胞具有較強(qiáng)的細(xì)胞毒活性，但對(duì)一些正常人體細(xì)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(bào)道，但體內(nèi)抗腫瘤實(shí)驗(yàn)結(jié)果仍未見報(bào)道。

對(duì)九節(jié)龍?jiān)碥闸?、?和Ш 的體內(nèi)外藥理研究也有一些報(bào)道。Zhang 等研究報(bào)道了九節(jié)龍?jiān)碥誌 體外對(duì)人非小細(xì)胞肺癌NCI-H460 具有明顯的抑制作用，藥物作用細(xì)胞后，使細(xì)胞阻滯于亞G1 期，并使核固縮，染色質(zhì)濃集而形成凋亡小體，結(jié)果表明能時(shí)間、濃度依賴性地抑制腫瘤細(xì)胞的生長，從而誘導(dǎo)其凋亡［7］。林洪等也發(fā)現(xiàn)了九節(jié)龍?jiān)碥乍?能通過阻滯人膠質(zhì)瘤細(xì)胞U251MG 于G2/M 期，引起時(shí)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(xì)胞增殖［8］。對(duì)于體內(nèi)抗腫瘤研究，李偉芳等報(bào)道了九節(jié)龍?jiān)碥闸窈艇?經(jīng)腹腔注射，對(duì)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?jiān)碥闸駥?duì)小鼠黑色素瘤抑瘤率為27.3%，九節(jié)龍?jiān)碥乍?對(duì)小鼠肝癌的抑制率為23.3%［51］。

也有學(xué)者研究了davuricoside C(苷元結(jié)構(gòu)中有16α-OH)體外對(duì)人卵巢癌細(xì)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(qiáng)的細(xì)胞毒作用［34］;劉岱琳等也通過對(duì)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(duì)多種腫瘤細(xì)胞和人腎胚正常細(xì)胞293 的細(xì)胞毒作用，探討了結(jié)構(gòu)與細(xì)胞毒活性之間的關(guān)系，得出一些見解:①16 位α-羥基和13β，28-環(huán)氧醚結(jié)構(gòu)對(duì)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(qiáng);③苷元中碳30 的取代基對(duì)活性影響也很大，其對(duì)活性影響順序?yàn)?-CHO ＞ -CH(OCH3)2＞-CH2OH ＞-COOH［10］。

2.2 抗炎

有實(shí)驗(yàn)顯示，用100 μM 百兩金皂苷A 作用于人巨噬細(xì)胞THP-1 能明顯抑制脂多糖誘導(dǎo)的IL-8和TNF-α 的釋放，并降低mRNA 轉(zhuǎn)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(bào)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(dāng)于0.2 μg/mL 乙酰膽堿所起的作用［14］。在此基礎(chǔ)上，Calis 等也對(duì)百兩金皂苷A、primulanin A、cyclamin 和cyclacoumin 進(jìn)行了體外小鼠子宮收縮反應(yīng)試驗(yàn)，結(jié)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(shí)，作用效果分別相當(dāng)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(jī)理目前尚不明確。

2.4 抗真菌

據(jù)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(gè)化合物的最小抑菌濃度MIC 在80-160 μg/mL 之間，作用要強(qiáng)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(jié)語

百兩金皂苷類似物的結(jié)構(gòu)和數(shù)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(xiàn)一些有意義的苗頭。因此，進(jìn)一步從中篩選具有抗腫瘤活性且對(duì)人體毒性較小的活性類似物并作為結(jié)構(gòu)優(yōu)化的基礎(chǔ)，對(duì)發(fā)現(xiàn)抗腫瘤藥物先導(dǎo)化合物具有重要意義。

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