胡祥正，臧臻臻

(1.天津科技大學(xué) 食品工程與生物技術(shù)學(xué)院，天津 300457；2.天津科技大學(xué) 化工與材料學(xué)院，天津 300457)

熊去氧膽酸衍生物及其生物活性研究進展

胡祥正1,2Δ，臧臻臻1

(1.天津科技大學(xué) 食品工程與生物技術(shù)學(xué)院，天津 300457；2.天津科技大學(xué) 化工與材料學(xué)院，天津 300457)

熊去氧膽酸是熊體內(nèi)產(chǎn)生的一種天然甾類物質(zhì)，具有重要的藥用價值。在臨床上用于治療肝膽疾病。熊去氧膽酸衍生物大多具有生物活性，具有潛在的藥用價值。本文從熊去氧膽酸衍生物的合成與生物活性方面概述其研究進展，并對熊去氧膽酸衍生物的應(yīng)用前景做了展望。

熊去氧膽酸衍生物；合成；應(yīng)用；生物活性

熊去氧膽酸(UDCA, 3α,7β-二羥基-5β-膽甾烷-24-酸，1)(見圖1)是熊膽汁中的一種甾類化合物，是治療膽結(jié)石和肝臟疾病的藥物[1-4]。熊去氧膽酸分子中羥基、羧基和甾環(huán)上的多個位置可以進行化學(xué)修飾，合成具有不同生物活性的衍生物。本文根據(jù)化學(xué)修飾不同位置所得產(chǎn)物，概述熊去氧膽酸衍生物及其生物活性。許多熊去氧膽酸衍生物具有抗菌、抗病毒、抗寄生蟲和抗變態(tài)反應(yīng)以及良好的抗腫瘤活性[5-8]。

圖1 熊去氧膽酸的分子結(jié)構(gòu)Fig.1 Molecule structure of ursodeoxycholic acid

1 不同位置修飾所得的UDCA衍生物及其生物活性

1.1 3位修飾所得的熊去氧膽酸衍生物及其生物活性 3位修飾所得的熊去氧膽酸衍生物數(shù)量眾多，許多具有生物活性。其中熊去氧膽酸3-硫酸酯(UDCA 3-Suls)是口服UDCA的主要尿代謝物[9-10]。健康男性尿液中1d排泄量相當(dāng)于(131.0±61.2)μg未氨基化UDCA 3-Suls當(dāng)量[11]。在臨床上UDCA 3-Suls被用作UDCA的應(yīng)變標(biāo)志物[12]。UDCA的谷胱甘肽聚合物的C-3硫酸酯在臨床上用于治療膽汁淤積疾病[13]。

UDCA 3α-氨基衍生物 (見圖2)對轉(zhuǎn)運蛋白具有高度識別力，科學(xué)家們應(yīng)用這個性質(zhì)研究細(xì)胞的相互作用和分布，以及膽汁酸生物學(xué)相關(guān)問題[14]。

圖2 UDCA 3-NBD 的分子結(jié)構(gòu)Fig.2 Molecule structure of UDCA 3-NBD

UDCA的3位-葡萄糖基衍生物 (見圖3)，具有較強的水溶性，被用于手術(shù)后患者及不能口服藥物的患者注射[15]。

圖3 3-GLG-UDCA 的分子結(jié)構(gòu)Fig.3 Molecule structure of 3-GLG-UDCA

UDCA、牛磺熊去氧膽酸(tauroursodeoxycholic acid，TUDCA)和甘氨熊去氧膽酸(glycoursodeoxycholic acid，GUDCA)的3α-乙酰葡萄糖胺羧酸酯，有希望應(yīng)用于治療人體代謝紊亂[16]。分子中同時含有乙酰葡萄糖胺基和磺酸基的UDCA衍生物 (見圖4)，與C1型尼曼-匹克病(Niemann-Pick type C1，NP-C1)有關(guān)[17]。

圖4 UDCA-3α-N-乙酰氨基葡萄糖-7β-硫酸酯的分子結(jié)構(gòu) Fig.4 Molecule structure of UDCA-3α-N-acetylglucosamine-7β-sulphate

3-對叔丁基苯甲酰胺基熊去氧膽酸鈉鹽，在水溶液中呈管狀結(jié)構(gòu)，其疏水性對-叔丁基苯基具有增強表面活性劑性能，管狀結(jié)構(gòu)的壁為雙層結(jié)構(gòu)，內(nèi)外表面帶負(fù)電荷，有希望應(yīng)用于中等尺度主客體化學(xué)領(lǐng)域[18-19]。

1.2 6位修飾衍生物 UDCA的6位氟化物6-FUDCA (見圖5)，能夠治療和預(yù)防患者的癌前細(xì)胞的形成，防止結(jié)腸癌治愈患者病的復(fù)發(fā)，具有優(yōu)良的生物活性[20-23]。6位乙基取代的熊去氧膽酸衍生物 (見圖6)可作為法尼酯X受體(farnesoid X Receptor, FXR)誘導(dǎo)劑。在臨床上作保肝藥物，在預(yù)防和治療肝臟及膽汁淤積疾病方面有很好的療效[24]。

圖5 6α-F-UDCA的分子結(jié)構(gòu)Fig.5 Molecule structure of 6α-F-UDCA

圖6 6α-烷基-UDCA 的分子結(jié)構(gòu)Fig.6 Molecule structure of 6α-alkyl-UDCA

由6-乙基鵝去氧膽酸(也叫奧貝膽酸，6alpha-ethyl-chenodeoxycholic acid，6-ECDCA)為原料，合成的化合物6-E-23(S)Me-UDCA (見圖7)，能夠增加腸內(nèi)胰高血糖素樣肽1 (glucagon-like protein-1，GLP-1)的轉(zhuǎn)錄，增強GP-BAR1效能和專一性，為配體提供潛在的結(jié)合位點信息，預(yù)計可用于治療肥胖癥、Ⅱ型糖尿病等代謝紊亂引起的疾病[25]。

圖7 6α-乙基 -UDCA (7) and 6α-乙基-23(S)-甲基-UDCA(8)的分子結(jié)構(gòu)Fig.7 Molecule structure of 6α-ethyl -UDCA (7) and 6α-ethyl-23(S)-methyl-UDCA(8)

1.3 7位修飾衍生物 UDCA的7位或3、7位引入磺酸基的熊去氧膽酸7-硫酸酯(UDCA 7-Suls)和熊去氧膽酸3,7-二硫酸酯(UDCA 3,7-DSuls)，能夠防止膽汁淤積和限制肝細(xì)胞損害，可用于治療消化道、肝臟炎癥，也可用于改善肝臟疾病或肝功能引起的血清生化性質(zhì)，增加膽汁流量或降低磷脂或膽固醇的膽汁排泄[12]。在UDCA的7位引入?；玫幕衔飳δ懼Y(jié)石病、膽管肌能障礙、高甘油三酯血癥等疾病具有很好的療效[26]。UDCA、TUDCA和GUDCA的7位羥基上的氫原子被N-乙酰葡萄糖胺取代后所得的衍生物，具有酶吸附性能，可以利用其在尿液中的含量為診斷原發(fā)性肝硬化(Primary Biliary Cirrhosis, PBC)提供有用的信息，是臨床上判斷肝硬化的診斷指標(biāo)，期望用于治療PBC[27]。

UDCA的7位或3、7位引入葡萄糖基得到的UDCA衍生物7-GLG-UDCA和3,7-二GLG-UDCA (見圖8)，在水中的溶解度都較高，有希望作為利膽藥物，用于手術(shù)后或不能口服藥物的患者注射治療[15]。

圖8 7-GLG-UDCA(9) and 3,7-GLG-UDCA(10)的分子結(jié)構(gòu)Fig.8 Molecule structure of 7-GLG-UDCA(9) and 3,7-GLG-UDCA(10)

圖9所示的UDCA 衍生物可抑制鈉依賴性膽鹽轉(zhuǎn)運體(apical sodium dependent bile acid transporter，ASBT)效力，阻礙Na牛磺膽鹽共轉(zhuǎn)運體(Na+/taurocholate cotransporting polypeptide，NTCP)的親和力。ASBT和NTCP可與多種取代基結(jié)合，但是UDCA C-7位修飾得到的類似物大部分不能被ASBT或NTCP聚合轉(zhuǎn)運[28]。

圖9 C7,C24位取代的熊去氧膽酸衍生物分子結(jié)構(gòu)Fig.9 Molecule structure of ursodeoxycholic acid derivates at C7,C24

1.4 修飾11位的熊去氧膽酸衍生物 11位和12位同時被氘取代的UDCA衍生物 (見圖10)比放射性物質(zhì)更穩(wěn)定、安全，且質(zhì)譜結(jié)果與母體不同，口服可用于治療人的膽汁瘺[29]。

圖10 UDCA-d2 的分子結(jié)構(gòu)Fig.10 Molecule structure of UDCA-d2

1.5 23位修飾衍生物 23-甲基熊去氧膽酸(MUDCA)極少分泌到膽汁中，也很少與?；撬帷⒏拾彼峤Y(jié)合。在進入消化道后，MUDCA很快進入肝臟，對動物無毒；其硫酸鹽化、葡萄苷酸化后能抑制肝臟內(nèi)二次衍生物的積累，同時也抑制膽汁酸肝腸循環(huán)[30]。

細(xì)胞表面受體G蛋白偶聯(lián)膽汁酸受體1(G protein-coupled bile acid receptor 1，GP-BAR1)能夠激發(fā)膽汁酸活性，刺激人體能量消耗，減少飲食引起的肥胖，臨床上用于治療代謝紊亂，23(S)-MUDCA (見圖11)能夠與GP-BAR1相互作用，調(diào)節(jié)其非基因組功能[25]。

圖11 23(S)-甲基-UDCA的分子結(jié)構(gòu)Fig.11 Molecule structure of 23(S)-methyl-UDCA

1.6 24位修飾的熊去氧膽酸衍生物

1.6.1 酰胺類衍生物：在生物體內(nèi)，膽汁酸是膽固醇的代謝產(chǎn)物，它們的作用是促進脂肪和類脂的消化與吸收。在生物體內(nèi)，膽汁酸通常以游離態(tài)和結(jié)合態(tài)2種狀態(tài)存在。結(jié)合態(tài)主要是分別與甘氨酸和?；撬峤Y(jié)合為甘氨膽汁酸和?；悄懼帷８拾毙苋パ跄懰?GUDCA)和?；切苋パ跄懰?TUDCA)是熊體內(nèi)存在的結(jié)合膽汁酸。

與UDCA相比，GUDCA分子毒副作用更小，親水性更強[31]，具有較強的抗氧化作用，在臨床上可以作為抗氧化劑，用于治療高膽紅素血癥[32]。TUDCA能抑制家族腺瘤息肉病衍生的LT97結(jié)腸腺瘤細(xì)胞的增長[33]；TUDCA以有效地抑制不同類型細(xì)胞的凋亡為特征；TUDCA通過調(diào)制ER壓力對hASCs脂肪形成起決定性作用，被用作減肥藥物[34]；TUDCA也被用于治療糖尿病引起的視網(wǎng)膜病變[35]。

如圖12所示的UDCA衍生物能夠抑制腫瘤細(xì)胞增殖，并誘導(dǎo)其凋亡[36-38]?；衔?5能抑制前列腺癌細(xì)胞PC-3的生長?；衔?6能誘導(dǎo)HepG2細(xì)胞凋亡，效果比UDCA更好[37]，被用作治療肝癌的特效藥[38]。化合物16、17在一定濃度下對MCF-7，MDA-MB-231細(xì)胞有抗增殖作用。此外，人們發(fā)現(xiàn)新型膽汁酸衍生物對人類胸腺腫瘤細(xì)胞的毒性作用可以通過細(xì)胞凋亡進行調(diào)控[39-40]。

圖12 HS-1183(15), HS-1030(16), HS-1133(17), HS-1068(18)的分子結(jié)構(gòu)Fig.12 Molecular structures of HS-1183(15), HS-1030(16), HS-1133(17), HS-1068(18)

磺酰胺類化合物具有較寬的抗菌活性和潛在的抗腫瘤作用[41-43]。圖13所示的一系列N-磺酰-3,7-二氧代-5β-膽烷-24-酰胺，對HCT-116、MCF-7、K562呈現(xiàn)良好的選擇性細(xì)胞毒性。尤其是化合物19對SGC-7901抑制效果較好，化合物20、21、22對人癌細(xì)胞系呈現(xiàn)高抑制活性[44]。

圖13 N-磺酰-3,7-二氧-5β-膽烷-24-酸的分子結(jié)構(gòu)Fig.13 Molecular structures of N-sulfuryl-3, 7-dioxo-5β-cholane-24-acid

圖14所示的UDCA磺酰胺類衍生物，對碳酸酐酶同工酶的抑制效果明顯；這些化合物在兔子體內(nèi)生物利用度比乙酰唑胺(acetazolamide)高[45]。

圖14 磺胺類藥物衍生物的分子結(jié)構(gòu)Fig.14 Molecular structure of sulfonamide derivatives

圖15所示的UDCA脂肪酸衍生物(27)，當(dāng)脂肪酸C鏈長于14時，此物對模型膽汁溶液膽固醇結(jié)晶具有明顯的抑制作用，能夠溶解小鼠膽結(jié)石[46]。

圖15 與脂肪酸共軛的熊去氧膽酸衍生物分子結(jié)構(gòu)Fig.15 Molecular structure of fatty acid conjugated with ursodeoxycholic acid

1.6.2 金屬配合物：化合物28、29是分子中含有Pt原子的UDCA衍生物(見圖16)，化合物29能抑制腫瘤細(xì)胞生長，抗腫瘤活性強，與母體鉑化合物相比，毒副作用低，在臨床上被用作治療肝癌的藥物[47-48]。

圖16 Bamet-D3(28)和Bamet-UD2(29) 的分子結(jié)構(gòu)Fig.16 Molecular structure of Bamet-D3(28), and Bamet-UD2(29)

1.6.3 雜環(huán)類：熊去氧膽酸衍生物 (圖17)能選擇性向肝臟傳遞NO，顯著增加肝臟中cGMP濃度，調(diào)節(jié)肝臟中血管的擴張和收縮力[49-50]。化合物30比UDCA具有更強的抵抗胺碘酮的毒性作用[51]。能夠有效抑制白介素、腫瘤壞死因子等多種炎性因子，對各種原因引起的肝損傷及炎癥、門靜脈高壓、肝硬化及肝纖維化均具有較好的治療作用[52-53]。

圖17 NCX-1000的分子結(jié)構(gòu)Fig.17 Molecular structure of NCX-1000

圖18所示的肝靶向一氧化氮釋放偶合物對四氯化碳及對乙酰氨基酚誘導(dǎo)的小鼠急性肝損傷具有顯著修復(fù)作用，除此之外，該偶合物具有良好的肝靶向性，且其肝靶向性優(yōu)于陽性藥化合物30[54]。

圖18 新型肝靶向釋放NO藥物的分子結(jié)構(gòu)Fig.18 Molecular structure of new liver targeted NO-releasing drugs

圖19所示的N-乙?；?S-(熊去氧膽烷基)半胱氨酸，在兔肝臟內(nèi)很容易被羧酸酯酶水解[55]。此化合物水解后，能起到UDCA與半胱氨酸的雙重藥學(xué)作用，且更容易吸收[56]。

圖19 UDCA-NAC的分子結(jié)構(gòu)Fig.19 Molecular structure of UDCA-NAC

圖20所示的哌嗪類膽汁酸衍生物33、34，對骨髓瘤細(xì)胞(KMS-11)、惡性膠質(zhì)癌細(xì)胞(GBM)和結(jié)腸癌細(xì)胞(HCT-116)的生長增殖活性有抑制作用。該雜環(huán)固醇類物質(zhì)有可能成為新型的抗癌藥[57]。哌嗪類熊去氧膽酸的酰胺衍生物35、36、37，能夠降低對人類結(jié)腸癌細(xì)胞株DLD-1、HCT-116、HT-29的生存能力[31]。

圖20 哌嗪基熊去氧膽酸衍生物的分子結(jié)構(gòu)Fig.20 Molecular structure of piperazinyl ursodeoxycholic acid derivates

熊去氧膽酸葡萄糖衍生物24-GLG-UDCA (見圖21)，水溶性大約是UDCA的13倍。其可用于注射，極大拓寬了其作為藥物的應(yīng)用途徑[15]。

圖21 24-GLG-UDCA的分子結(jié)構(gòu)Fig.21 Molecular structure of 24-GLG-UDCA

1.6.4 失碳甾體化合物：24-nor-熊去氧膽酸(nor-UDCA)是UDCA的短側(cè)鏈衍生物[58]，其側(cè)鏈少一個亞甲基基團，nor-UDCA與UDCA有著不同的物理化學(xué)和治療學(xué)的特性。nor-UDCA與UDCA在體內(nèi)也有不同的代謝機制；2者比較，UDCA對膽總管結(jié)扎(common bile duct ligated，CBDL)小鼠毒性比nor-UDCA大，而nor-UDCA能明顯改良選擇性膽管結(jié)扎(selective bile duct ligation，SBDL)小鼠肝臟損傷[59]；在治療肝臟纖維化方面，nor-UDCA比UDCA更有效果[60]。相比UDCA，nor-UDCA在體外直接抑制抗原呈遞細(xì)胞的性能，激活T細(xì)胞。因此，nor-UDCA是治療肝臟纖維化的潛在藥物[61]。

1.6.5 前藥類的熊去氧膽酸衍生物：作為內(nèi)源性天然配基，膽汁酸具有良好的生物兼容性，適合作肝靶向藥物載體[62]。圖22所示的UDCA的N-烷基酰胺衍生物39、40[63-64]，有可能作為前體藥成分，應(yīng)用于治療多種疾病[65]。

圖22 N- 羥烷基3α,7β-二羥基-5β-膽烷-24-酰胺的分子結(jié)構(gòu)Fig.22 Molecular structure of N- Hydroxyalkyl 3α, 7β-dihydroxy-5β-cholan-24-amide

Tolle-Sander等[66-67]將阿昔洛韋與熊去氧膽酸24位的羧基通過纈氨酸相連制成前藥，即熊去氧膽酸的纈氨酸酯，靶向作用于hAsBT，與單獨服用阿昔洛韋相比，該前藥的生物利用度顯著提高。

UDCA與去氫貝母堿通過酯鍵結(jié)合，形成的熊去氧膽酸去氫貝母堿酯衍生物，在相同劑量下，該衍生物比UDCA或去氫貝母堿的止咳化痰效果都好。該衍生物具有更好的生物活性和較低的毒副作用，可用作止咳化痰藥，代替?zhèn)鹘y(tǒng)中藥中的川貝和蛇膽，解決了這2種中藥的稀缺問題[68]。

2 結(jié)論與展望

UDCA是臨床上應(yīng)用廣泛的治療肝膽疾病的藥物，也可以用作藥物載體。UDCA衍生物大多具有不同的生物活性，具有潛在的藥用價值。隨著研究的深入，將會有更多的藥用性能更好的UDCA衍生物成為藥物，更好地為人類健康服務(wù)。

[1] Kitani K.Ursodeoxycholic acid for cholestatic diseases[J].Lancet,1988, 2(332): 8601-8649.

[2]Zhang Y, Lu J, Dai W, et al.Combination Therapy of Ursodeoxycholic Acid and Corticosteroids for Primary Biliary Cirrhosis with Features of Autoimmune Hepatitis: A Meta-Analysis[J].Gastroent Res & Pract, 2013, 2013(3):299-301.

[3]Poupon RE, Balkau B, Eschwtge E.A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis UDCA-PBC Study Group[J].N Engl J Med, 1991, 324(22): 1548-1554.

[4]Shi J, Wu CY, Chen XY,et al.Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a metaanalysis of randomized controlled trials[J].Am J Gstroenterol, 2006, 101(7): 1529-1538.

[5]Saksena S, Tandon RK.Ursodeoxycholic acid in the treatment of liver diseases[J].Postgrad Med J, 1997, 850(25): 73-75.

[6]Hofmann AF.Pharmacology of ursodeoxycholic acid, An enterohepatic drug[J].Scand J Gastroenterol, 1994, 204(29): 1-15.

[7]Sharma R, Prichard D, Majer F, et al.Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators[J].J Med Chem, 2011, 54(1): 122-130.

[8]Dalpiaz A, Paganetto G, Pavan B, et al.Zidovudine and ursodeoxycholic acid conjugation: design of a new prodrug potentially able to bypass the active ef?ux transport systems of the central nervous system[J].Mol Pharm, 2012, 9(4): 957-968.

[9]Setchell KDR, Watson D, Balistreri WF, et al.A simple, rapid and non-invasive test of compliance to oral ursodeoxycholic acid (UDCA) therapy-detection of UDCA-sulfate:a specific urinary metabolite[J].Hepatology, 1991(14):261A.

[10]Nakamura K.Investigation of sulfate group position of urinary sulfated ursodeoxycholic acid in patients during ursodeoxycholic acid administration[J].Acta Hepatol Jpn, 1994, 35(11): 814-821.

[11]Kobayashi N, Katsumata H, Katayama H, et al.A monoclonal antibody-based enzyme-linked immunosorbent assay of ursodeoxycholic acid 3-sulfates in human urine[J].J Steroid Biochem, 2000, 72(5): 265-272.

[12]Setchell KDR.Sulfate conjugates of ursodeoxychloric acid, and their beneficial use in inflammatory disorders and other applications: China, 1211185[P].2009.

[13]李詠梅.熊去氧膽酸聯(lián)合還原型谷胱甘肽治療膽汁淤積性肝病療效觀察[J].中國誤診學(xué)雜志, 2012, 12(6):1320-1321.

[14]Majer F, Salomon JJ, Sharma R, et al.New fuorescent bile acids: Synthesis, chemical characterization, and disastereoselective uptake by Caco-2 cells of 3-deoxy 3-NBD-amino deoxycholic and ursodeoxycholic acid[J].Bioorgan Med Chem, 2012, 20(5): 1767-1778.

[15]Mandai T, Okumoto H, Nakanishi K, et al.Ursodeoxycholic acid derivatives and methods for producing them.US, 6,075,132[P].2000-6-13.

[16]Niwa T, Koshiyama T, Goto J, et al.Synthesis of N-acetylglucosaminides of unconjugated and conjugated bile acids[J].Steroids, 1992,57(11): 522-529.

[17]Kakiyama G, Muto A, Shimada M, et al.Chemical synthesis of 3β-sulfooxy-7β-hydroxy-24- nor-5-cholenoic acid: An internal standard for mass pectrometric analysis of the abnormal delta5-bile acids occurring in Niemann-Pick disease[J].Steroids, 2009, 74(9): 766-772.

[18]Meijide F, Trillo J V, Frutos S, et al.Formation of tubules by p-tert-butylphenylamide derivatives of chenodeoxycholic and ursodeoxycholic acids in aqueous solution[J].Steroids, 2012, 77(12): 1205-1211.

[19]Tellini VS, Jover A, Meijide F, et al.Supramolecular Structures Generated by a p-tert- Butylphenyl-amide Derivative of Cholic Acid: From Vesicles to Molecular Tubes[J].Adv Mater, 2007, 19(13): 1752-1756.

[20]Gibson JC, Township H, Capuano LR.Prevention and Treatment of Colorectal Cancer by 6-Fluoroursodeoxycholic Acid (6-FUDCA): US, 426340 B1[P].2002-7-30.

[21]Roda A, Pellicciari R, Polimeni C, et al.Metabolism, Pharmacokinetics, and Activity of a New 6-Fluoro Analogue of Ursodeoxycholic Acid in Rats and Hamsters[J].Gastroenterology, 1995, 108(4): 1204-1214.

[22]Pellicciari R, Roda A, Frigerio G.Fluorinated bile acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them: US, 5166374[P].1992-11-24.

[23]Konigsberger K, Chen GP, Vivelo J, et al.An Expedient Synthesis of 6-Fluoroursodeoxycholic Acid[J].Org Process Res Dev, 2002, 6(5): 665-669.

[24]Ferrari M, Pellicciari R.Process for preparing 3α(β)-7α(β)-dihydroxy-6α(β)-Alkyl-5β-chol acid: US, 7,994,352 B2[P].2011-9-9.

[25]Yu DD, Sousa KM, Mattern DL, Wagner J, et al.Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled Bile acid receptor 1 (GP-BAR1, TGR5) agonists[J].Bioorg Med Chem, 2015, 23(7): 1613-1628.

[26]Scolastico C, Sirtori C, Kritchevsky D.Novel derivatives of ursodeoxycholic acid: US, 4,440,688[P].1984-4-3.

[27]Kobayashi N, Kubota K, Oiwa H, et al.Idiotype-anti-idiotype-based noncompetitive enzyme-linked immunosorbent assay of ursodeoxycholic acid 7-N-acetylglucosaminides in human urine with subfemtomole range sensitivity[J].J Immunol Methods, 2003, 272(1-2): 1-10.

[28]Kolhatkar V, Polli JE.Structural requirements of bile acid transporters: C-3 and C-7 modifcations of steroidal hydroxyl groups[J].Eur J Pharm Sci, 2012, 46(1-2): 86-99.

[29]Tohma M, Nakata Y, Yamada H, et al.Quantitative determination of ursodeoxycholic acid and its deuterated derivative in human bile by gas chromatography-mass fragmentography[J].Chem Pharm Bull, 1981, 29(1): 137-145.

[30]Roda A, Aldini R, Grigolo B, et al.23-Methyl- a,7beta-dihydroxy-5beta-cholan-24-oic Acid: Dose- Response Study of Biliary Secretion in Rat[J].Hepatolcigy, 1988, 8(6): 1571-1576.

[31]Brossard D, Lechevrel M, Kihel LE, et al.Synthesis and biological evaluation of bile carboxamide derivatives with pro-apoptotic effect on human colon adenocarcinoma cell lines[J].Eur J Med Chem, 2014(86):279-290.

[32]Silva SL,Vaz AR, Diogenes MJ, et al.Neuritic growth impairment and cell death by unconjugated bilirubin is mediated by NO and glutamate, modulated by microglia, and prevented by glycoursodeoxycholic acid and interleukin-10[J].Neuropharmacology, 2012, 62(7): 2398-2408.

[33]Heumen BWHV, Roelofs HML, Morsche RHMT, et al.Celecoxib and tauroursodeoxycholic acid cotreatment inhibits cell growth in familial adenomatous polyposis derived LT97 colon adenoma cells[J].Exp Cell Res, 2012, 318(7): 819-827.

[34]Cha BH, Kim JS, Ahn JC, et al.The role of tauroursodeoxycholic acid on adipogenesis of human adipose-derived stem cells by modulation of ER stress[J].Biomaterials, 2014, 35(9): 2851-2858.

[35]Gaspar JM, Martins A, Cruz R, et al.Taurourdeoxycholic acid protects retinal neural cells from cell death induced by prolonged exposure to elevated glucose[J].Neuroscience, 2013, 253(17): 380-388.

[36]Im E, Choi YH, Paik KJ, et al.Novel bile acid derivatives induce apoptosis via a p53-independent pathway in human breast carcinoma cells[J].Cancer Lett, 2001, 163(1): 83-93.

[37]Suh H, Jung EJ, Kim TH, et al.Antiangiogenic activity of ursodeoxycholic acid and its derivatives[J].Cancer Lett, 1997, 113(1-2): 117-122.

[38]Park YH, Kim JA, Baek JH, et al.Induction of apoptosis in hepG2 human hepatocellular carcinoma cells by a novel derivative of ursodeoxycholic acid (UDCA)[J].Arch Pharm Res, 1997, 20(1): 29-33.

[39]Ime EO, Lee S, Suh H, et al.A novel ursodeoxycholic acid derivative induces apoptosis in human MCF-7 breast cancer cells[J].Pharm Pharmacol Commun, 1999, 5(4): 293-298.

[40]Im EO, Choi YH, Paik KJ, et al.Novel bile acid derivatives induce apoptosis via a p53-independent pathway in human breast carcinoma cells[J].Cancer Lett, 2001, 163(1): 83-93.

[41]Winum JY, Rami M, Scozzafava A, et al.Carbonic anhydrase IX: a new druggable target for the design of antitumor agents[J].Med Res Rev, 2008, 28(3): 445-463.

[42]Fournal M, Trachy-bourget MC, Yan PT, et al.Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors[J].Cancer Res, 2002, 62(15): 4325-4330.

[43]Mohan R, Banerjee M, Ray A, et al.Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation[J].Biochemistry, 2006, 45(17): 5440-5449.

[44]Ren J, Wang Y, Wang J, et al.Synthesis and antitumor activity of N-sulfonyl-3,7-dioxo-5beta-cholan 24-amides, ursodeoxycholic acid derivatives[J].Steroids, 2013, 78(1): 53-58.

[45]Temperini C, Scozzafava AL, Supuran CT.Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators[J].Bioorg & Med Chem Lett, 2005, 15(23): 5136-5141.

[46]李美英, 劉河, 何新華,等.新型飽和脂肪酸膽酸綴合物的合成及抗膽結(jié)石活性研究[J].有機化學(xué), 2009, 3(3): 420-425.

[47]Lafuna M, Martinez-diez, MC, Monte MJ, et al.Liver Organotropism and Biotransformation of a Novel Platinum-Ursodeoxycholate Derivative, Bamet-UD2, with Enhanced Antitumour Activity[J].J Drug Target, 2001, 9(3): 185-200.

[48]Dominguez MF, Macias RIR, Izco-basurko I, et al.Low in Vivo Toxicity of a Novel Cisplatin-Ursodeoxycholic Derivative (Bamet-UD2) with Enhanced Cytostatic Activity versus Liver Tumors.Journal of pharmacology and experimental therapeutics[J].J Pharmacol Exp Ther, 2001, 297(3): 1106-1112.

[49]Fiorucci S, Antonelli E, Brancaleone V, et al.NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid,ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver[J].J Hepatol, 2003, 39(6):932-939.

[50]Fiorucci S, Antonellie E, Morelli A.Nitric oxide and portal hypertension: a nitric oxide-releasing derivative of ursodeoxycholic acid that selectively releases nitric oxide in the liver[J].Digest Liver Dis, 2003, 35(Suppl 2): S61-69.

[51]Amine OC, Aziz E, Allal C, et al.Combining ursodeoxycholic acid or its NO-releasing derivative NCX-1000 with lipophilic antioxidants better protects mouse hepatocytes against amiodarone toxicity[J].Can J Physiol Pharmacol, 2007, 85(2): 233-242.

[52]Fiorucci S, Mencarelli A, Palazzetti B, et al.An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity[J].P Natl Acad Sci USA, 2001, 98(5): 2652-2657.

[53]Fiorucci S, Antonelli E, Morelli O,et al.NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension[J].P Natl Acad Sci USA, 2001, 98(15): 8897-8902.

[54]李美英, 何新華, 陶林,等.膽汁酸為載體的肝靶向一氧化氮釋放藥物的設(shè)計與合成[J].有機化學(xué), 2008, 28(12):2170-2174.

[55]Mitamura K, Sakai T, Nakai R, et al.Synthesis of the 3-sulfates of N-acetylcysteine conjugated bile acids (BA-NACs) and their transient formation from BA-NACs and subsequent hydrolysis by a rat liver cytosolic fraction as shown by liquid chromatography/ electrospray ionization-mass spectrometry[J].Anal Bioanal Chem, 2011, 400(7): 2061-2072.

[56]Mitamura K, Watanabe S, Sakai T, et al.Chemical synthesis of N-acetylcysteine conjugates of bile acids and in vivo formation in cholestatic rats as shown by liquid chromatography/electrospray ionization-linear ion trap mass spectrometry[J].J Chromatogr B, 2009, 877(25): 2630-2638.

[57]Brossard D, Kihel LE, Clement M, et al.Synthesis of bile acid derivatives and in vitro cytotoxic activity with pro-apoptotic process on multiple myeloma(KMS-11), glioblastoma multiforme (GBM), and colonic carcinoma (HCT-116) human cell lines[J].Eur J Med Chem, 2010, 45 (7): 2912-2918.

[58]Trauner M, Halilbasic E, Claudel T.Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders[J].Dig Dis, 2015, 33:433-439.

[59]Fickert P, Pollheimer MJ, Silbert D, et al.Differential effects of norUDCA and UDCA in obstructive cholestasis in mice[J].J Hepatol, 2013, 58(6): 1201-1208.

[60]Buko VU, Lukivskaya OY, Naruta EE, et al.Protective Effects of Norursodeoxycholic Acid Versus Ursodeoxycholic Acid on Thioacetamide-induced Rat Liver Fibrosis[J].J Clin Exp, Hepatol,2014, 4(4): 293-301.

[61]Sombetzki M, Fuchs CD, Fickert P, et al.24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis[J].J Hepatol, 2015, 62(4): 871-878.

[62]張盈, 楊碩, 李靈芝.肝靶向給藥體系研究進展[J].中國新藥雜志, 2013(8): 923-927.

[63]Willemen HM, Vermonden T, Marcelis ATM, et al.N-Cholyl amino acid alkyl esters—a novel class of organogelators[J].Eur J Org Chem, 2001, 2001(12): 2329-2335.

[64]Valkonen A, Lahtinen M, Virtanen E, et al.Bile acid amidoalcohols:

simple organogelators[J].Biosens Bioelectron, 2004, 20(6): 1233-1241.

[65]Valkonen A, Lahtinen M, Kolehmainen E.Synthesis and structural study of bile acid amidoalcohols[J].Steroids, 2008, 73(12): 1228-1241.

[66]Tolle-sander S, Lenta KA, Maeda DY, et al.Increased acyclovir oral bioavailability via a bile acid conjugate[J].Mol Pharm, 2003, 1(1):40-48.

[67]Balakrishnan A, Polli JE.Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug target[J].Mol Pharm, 2006, 3(3): 223-230.

[68]Zhang JL, Wang H, Pi HF, et al.Structural analysis and antitussive evaluation of five novel esters of verticinone and bile acids[J].Steroids, 2009, 74(4-5): 424-434.

(編校：王儼儼)

Progress of ursodeoxycholic acid derivatives and their bioactivities

HU Xiang-zheng1,2Δ, ZANG Zhen-zhen1

(1.College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; 2.College of Chemical Engineering and Materials Science, Tianjin University of Science and Technology, Tianjin 300457, China)

Ursodeoxycholic acid, a kind of natural steroid compound, is synthesized from bear body.It is an important medicine in clinic and can be used to treat liver diseases.Most of ursodeoxycholic acid derivatives have pharmaceutical performance.Research progress of ursodeoxycholic acid derivatives in terms of preparation and bioactivity was described and application prospects were outlooked in this paper.

derivatives of ursodeoxycholic acid; synthesis; application; bioactivities

10.3969/j.issn.1005-1678.2016.07.59

胡祥正，通信作者，男，博士，教授、碩士生導(dǎo)師，研究方向：抗腫瘤藥物的開發(fā)應(yīng)用及生物材料的合成，E-mail：huxzh@tust.edu.cn。

O629.21

A