胆酸酰氧基膦酸酯衍生物的合成及抗肿瘤活性

以胆酸和亚磷酸酯为原料,在缩合剂二环己基碳二亚胺(DCC)和4-二甲基吡啶(DMAP)的催化下进行酯化反应,合成了10个未见报道的胆酸酰氧基膦酸酯衍生物,所有目标化合物均经过TG,IR,1 H NMR,31P NMR和HRMS对其进行了结构确认.利用MTT法测定了目标化合物的抗肿瘤活性,结果显示:目标化合物4H,4I,4J对人肝癌细胞(HepG2)表现出较好的增殖抑制作用.     

脱氧胆酸裂口分子的微波合成

以固体K2CO3为载体,在微波辐射无溶剂条件下,脱氧胆酸甲酯与芳酰氯反应合成了9个新的脱氧胆酸裂口分子人工受体,其结构经1H NMR,IR,MS及元素分析表征.     

由醋酸去氢表雄酮合成熊去氧胆酸

探索了用植物源商业原料合成熊去氧胆酸的新方法. 以醋酸去氢表雄酮为原料, 以区域选择性烯丙位氧化、 Mistunbu反应和Luche还原为关键步骤, 通过9步反应, 以38.6%的总收率合成了熊去氧胆酸. 其中, 关键中间体4由化合物3经改进的烯丙位氧化反应以较高产率获得. 对关键的烯丙基氧化反应的条件进行了优化, 包括溶剂、 氧化剂和反应温度. 该方法原料易得、 产率较高, 并且有效地避免了动物源性原料的风险, 易于实现规模化合成, 因而具有较高的应用价值.     

甘氨熊(鹅)去氧胆酸的制备工艺

以2-氯-1,3-二（2,4,6-三甲基苯基）咪唑盐酸盐（IMesCl-Cl）作缩合剂,熊(鹅)去氧胆酸为原料,直接与甘氨酸乙酯盐酸盐反应,采用一锅法制得关键中间体甘氨熊（鹅）去氧胆酸乙酯2a和2b; 2a和2b在碱性条件下水解合成了甘氨熊（鹅）去氧胆酸3a和3b,总收率超过83%,其结构经¹H NMR, ¹³C NMR和HR-MS(ESI)确证。      

新型饱和脂肪酸胆酸缀合物的合成及抗胆结石活性研究

胆结石是常见多发病, 但临床缺乏有效的治疗药物. 饱和脂肪酸与胆酸的缀合物能有效预防胆固醇结晶、溶解体内胆固醇结石. 以胆酸或熊去氧胆酸24位羧基为连接位点, 以氨基酸为连接子, 通过酰胺键将载体与具有溶石活性的饱和脂肪酸偶联, 设计合成了一系列新型脂肪酸胆酸缀合物, 其结构经元素分析, IR, 1H NMR和MS光谱分析确证. 通过测定化合物对模型胆汁溶液胆固醇结晶及模型小鼠胆结石的溶解活性, 研究了其体内外溶石活性.     

氨基甲酸酯型脱氧胆酸分子裂缝的微波合成

在微波辐射条件下,以脱氧胆酸为隔离基,通过三光气桥连各种芳香胺,以良好的产率合成了一系列新的分子裂缝,其结构经1H NMR,IR,MS和元素分析确证.     

胆汁酸为载体的肝靶向一氧化氮释放药物的设计与合成

新型肝靶向一氧化氮释放药物对许多肝脏疾病具有较好的治疗作用. 以胆酸和熊去氧胆酸作为药物的载体, 以氨基酸作为联接子, 以氨基酸的α羧基模拟胆酸或熊去氧胆酸分子24位羧基的负电性, 最大限度地保持胆酸或熊去氧胆酸的结构特征, 通过酰胺键将载体与一氧化氮供体硝酸酯偶联, 设计并合成了一系列新型肝靶向一氧化氮释放偶合物, 其结构经元素分析, IR, 1H NMR和MS光谱分析确证. 利用四氯化碳及对乙酰氨基酚所致小鼠急性肝损伤模型研究化合物对小鼠急性肝损伤的修复作用.     

单手性臂石胆酸分子裂缝的微波合成

在微波辐射下,以石胆酸为隔离基,通过三光气桥连各种L-氨基酸甲酯,以较好的产率合成了一系列新的手性分子裂缝,其结构经1H NMR,IR,MS和元素分析确证.     

熊去氧胆酸的合成

通过廉价易得的猪去氧胆酸为起始原料,以Shapiro反应为关键步骤,经酯化、选择性氧化、环氧化、脱保护等一系列反应成功合成了熊去氧胆酸,总产率为25.8%。在此基础上对该法进行了改良,使用硅基保护、Rubuttom氧化和Clemmensen还原来缩短反应路线,总产率达到28.8%。产物结构经1H NMR、13C NMR和HRMS确认。通过芘荧光探针法对结构相近的胆酸盐的聚集行为进行探究,可以推测临界胶束浓度只与结构中羟基的数量有关,而与羟基的构型没有直接联系。     

猪去氧胆酸化学——Ⅳ.从猪去氧胆酸立体选择性合成熊去氧胆酸和鹅去氧胆酸的新法

本文报道以猪去氧胆酸甲酯(4b)为原料立体选择性合成熊去氧胆酸(1)和鹅去氧胆酸(3)的新方法。从猪去氧胆酸甲酯出发经8步反应得熊去氧胆酸(1),总收率26％。经7步反应得鹅去氧胆酸甲酯(3b),总收率31％。     

Synthesis of new bio‐based hydrogels derived from bile acids by free‐radical photo‐polymerization

In this article, the study on the swelling and thermal behaviors of a new series of bile acid‐based polymeric hydrogels is reported. For this purpose, in the first step, the reduction of carboxyl acid groups of some common bile acids including cholic acid (CA), chenodeoxy cholic acid (CDCA), and lithocholic acid (LCA) to the corresponding alcohols by lithium aluminum hydride (LiAlH₄) in THF solution is performed. Then, hydroxyl functionalities of the obtained products are reacted with the acryloyl chloride in the presence of triethylamine (TEA). Finally, the cross‐linking reactions between acryloyl functionalized bile acids and methoxy poly(ethylene glycol) monomethacrylate (MPEGMA) are conducted by free‐radical photo‐polymerization technique at λ = 350 nm in the presence of 2,2‐Dimethoxy‐2‐phenylacetophenone (DMPA) as an initiator to achieve the desired bile acid‐based polymeric hydrogels. The resulting hydrogels and their intermediates are characterized by Fourier transform infrared (FT‐IR) and Proton nuclear magnetic resonance (¹H‐NMR) spectroscopies. The swelling and thermal behavior of the obtained hydrogels indicates that the hydrogel starting from cholic acid is more swellable and has enhanced thermostability compared to others. Thus, the results of this study offer beneficial insights to researchers working in particularly bio‐medical industry.     

Asymmetric induction by the cholestanic moiety on tropos species: synthesis and stereochemical characterization of bile acid-based biphenyl phosphites

Three different bile acid-derived biphenyl phosphites were synthesized, starting from cholic and deoxycholic acids and biphenol, and their stereochemical features were checked by CD and NMR spectroscopies. On the basis of the spectroscopic results, the capability of the cholestanic system to induce a prevalent sense of twist on the biphenyl moiety of the bile acid-derived phosphites as well as their tropos nature was inferred.     

Fluorescence properties of trans-ethyl-p-(dimethylamino) cinnamate in presence of bile acid host

The knowledge of the formation of bile acid micellar aggregates is of great importance because of the biological significance of these compounds and their pharmacological applications. The intramolecular charge transfer (ICT) fluorescence property of trans-ethyl-p-(dimethylamino) cinnamate is used to study the micelles formed by aggregation of three most important bile acids, viz. cholic acid, deoxycholic acid and chenodeoxycholic acid by steady state and picosecond time-resolved fluorescence spectroscopy. The ICT fluorescence band intensity was found to increase with concomitant blue shift with the addition of bile acids. The blue shift in ICT fluorescence maxima as well as decrease in nonradiative decay constants in presence of bile acids indicate the passage of the probe towards the micro domains formed from the aggregated bile acids. Binding constant of the probe with micelles as well as critical micelle concentration and average polarity parameter of the micellar environments were obtained from the variation of fluorescence intensity on increasing concentration of bile acids in the medium.     

Design,synthesis and application of new bile acid ligands with 1,2,3-triazole ring

New dimers have been obtained from propargyl ester of bile acids and α,α′-diazide-m-xylene by intermolecular 1,3-dipolar cycloaddition. These compounds have been used as ligands to form intermolecular hydrogen bonds with various aromatic acids. The structures of all products were confirmed by spectroscopic (¹H NMR, ¹³C NMR and FT-IR) analysis, mass spectrometry (ESI, MALDI) and PM5 semiempirical methods.     

Differentiation of various traditional Chinese medicines derived from animal bile and gallstone: simultaneous determination of bile acids by liquid chromatography coupled with triple quadrupole mass spectrometry

Animal biles and gallstones are popularly used in traditional Chinese medicines, and bile acids are their major bioactive constituents. Some of these medicines, like cow-bezoar, are very expensive, and may be adulterated or even replaced by less expensive but similar species. Due to poor ultraviolet absorbance and structural similarity of bile acids, effective technology for species differentiation and quality control of bile-based Chinese medicines is still lacking. In this study, a rapid and reliable method was established for the simultaneous qualitative and quantitative analysis of 18 bile acids, including 6 free steroids (cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, hyodeoxycholic acid, and ursodeoxycholic acid) and their corresponding glycine conjugates and taurine conjugates, by using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). This method was used to analyze six bile-based Chinese medicines: bear bile, cattle bile, pig bile, snake bile, cow-bezoar, and artificial cow-bezoar. Samples were separated on an Atlantis dC₁₈ column and were eluted with methanol–acetonitrile–water containing ammonium acetate. The mass spectrometer was monitored in the negative electrospray ionization mode. Total ion currents of the samples were compared for species differentiation, and the contents of bile acids were determined by monitoring specific ion pairs in a selected reaction monitoring program. All 18 bile acids showed good linearity (r² > 0.993) in a wide dynamic range of up to 2000-fold, using dehydrocholic acid as the internal standard. Different animal biles could be explicitly distinguished by their major characteristic bile acids: tauroursodeoxycholic acid and taurochenodeoxycholic acid for bear bile, glycocholic acid, cholic acid and taurocholic acid for cattle bile, glycohyodeoxycholic acid and glycochenodeoxycholic acid for pig bile, and taurocholic acid for snake bile. Furthermore, cattle bile, cow-bezoar, and artificial cow-bezoar could be differentiated by the existence of hyodeoxycholic acid and the ratio of cholic acid to deoxycholic acid. This study provided bile acid profiles of bile-based Chinese medicines for the first time, which could be used for their quality control.     

Determination of Free Bile Acids in Raw Materials and Bulk Products by HPLC and GC

Abstract

A procedure based on two chromatographic methods with different selectivities (HPLC and GC) was developed for the quality control assay of free bile acids in raw materials from animals and bulk products utilized in the pharmaceutical industry. HPLC was carried out without preliminary derivatization using an Ultrasphere ODS column with UV detection at 210 nm and methanol-acetonitrile-acetate buffer as the mobile phase. For GC, bile acids were converted into their trifluoroacetyl-hexafluoroisopropyl derivatives and analysed on a SE-52 capillary column with flame-ionization detection. Bile acid levels in hydrolysed ox bile, in bulk cholic and deoxycholic acid determined by HPLC correlated with results obtained by GC, with the exception of the analytes present in low concentrations (less than 3% w/w) detectable only by GC. HPLC-UV is the more suitable technique for routine analyses of free bile acids in pharmaceutical matrices owing to its simplicity and rapidity. However, because of the low sensitivity and specificity of the UV detection, the accuracy of the HPLC assay should be verified by comparison with GC.     

高效液相色谱／光散射检测器测定肝病病人血清中的胆汁酸

利用反相高效液相色谱／挥发激光散射检测器发展了分析胆汁酸的新方法。采用甲醇和乙酸铵缓冲液混合溶液为冲洗体系，梯度淋洗，１０种甘氨型和牛磺型胆汁酸有２５ｍｉｎ内完成基线分离。方法简单快速，不需衍生，血清榈经预处理，平均回收率为９６．１％，在４－５０，ｇ／Ｌ浓度范围内对峰面积与浓度进行线性回归分析，回归系数０．９９１５－０．９９８２之间可用于正常人和肝硬化病人血清中胆汁酸的测定。     

Diastereomeric molecular recognition and binding behavior of bile acids by L/D-tryptophan-modified beta-cyclodextrins

[reaction: see text] Binding behavior of L- and D-tryptophan-modified beta-cyclodextrins (L/D-Trp-beta-CD) (1 and 2) with four bile acids, i.e., cholate (CA), deoxycholate (DCA), glycocholate (GCA), and taurocholate (TCA), has been investigated by fluorescence, circular dichroism, and 2D-NMR spectroscopies and fluorescence lifetime measurement, as well as isothermal titration microcalorimetry. From the induced circular dichroism (ICD) and 2D NMR spectra, it is deduced that the D-Trp moiety of 2 attached to beta-CD is more deeply self-included in the cavity than that of the antipodal L-Trp moiety of 1, indicating appreciably enantioselective binding of the chiral sidearm by beta-CD. Interestingly, the original difference in conformation between 1 and 2 led to quite a large difference in affinity toward DCA, giving 3.3 times higher binding ability for 2 than for 1. Thermodynamically, the inclusion complexation of 1 and 2 with bile acids was entirely driven by favorable enthalpy change (DeltaH degrees) with accompanying negative entropy change (DeltaS degrees). The stronger binding of bile acids by L/D-Trp-beta-CD is attributable to higher enthalpic gains. The combined use of the calorimetric and NMR ROESY spectral examinations revealed the correlation between the thermodynamic parameters and the role of sidearm conformation in modified beta-cyclodextrins.     

Design and Synthesis of New Bile AcidSterol Conjugates Linked via 1,2,3‐Triazole Ring

A new steroid conjugates have been obtained from bile acids and sterol derivatives using ‘click chemistry’. Intermolecular 1,3‐dipolar cycloaddition of the propargyl ester of bile acids (lithocholic, deoxycholic, and cholic acid) and azide derivatives of sterols (ergosterol and cholesterol) gave a new bile acid? sterol conjugates linked with a 1,2,3‐triazole ring. The structures of all products were confirmed by spectroscopic (¹H‐ and ¹³C‐NMR, and FT‐IR) analyses, mass spectrometry (ESI‐MS), and in silico biological activity evaluation methods (PASS), as well as PM5 semiempirical methods.