- Molecular association via halogen bonding and other weak interactions in the crystal structures of 11-bromo-12-oxo-5β-cholan derivatives
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Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 2, methyl 11α-bromo-3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 3, methyl 11β-bromo-3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 4 and methyl 11,11-dibromo-3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 5 were synthesized. The crystal structures of these molecules were resolved to study the effect of bulky bromine atom in the steroid skeleton of cholic acid with different stereo-chemical orientations at C-11 on the two-dimensional arrangement of molecules and solid-state properties. All the molecules associate only via weak intermolecular interactions in their crystal structures, notable one being the Halogen Bonded assembly (C-Br...O) in 5.
- Salunke, Deepak B.,Hazra, Braja G.,Gonnade, Rajesh G.,Pore, Vandana S.,Bhadbhade, Mohan M.
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- Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: Design, synthesis and preliminary mechanism study
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In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.
- Qiu, Rongmao,Luo, Guoshun,Li, Xinyu,Zheng, Fan,Li, Haolin,Zhang, Jin,You, Qidong,Xiang, Hua
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- Chemical Synthesis of Rare Natural Bile Acids: 11α-Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids
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A method for the preparation of 11α-hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α-mesyloxy group of the methyl esters of 3α-acetate-12α-mesylate and 3α,7α-diacetate-12α-mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △11-3α-acetoxy and △11-3α,7α-diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α-hydroxylation of the △11-3α,24-diol and △11-3α,7α,24-triol intermediates with B2H6/tetrahydrofuran (THF); and (4) selective oxidation at C-24 of the resulting 3α,11α,24-triol and 3α,7α,11α,24-tetrol to the corresponding C-24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α-dihydroxy-5β-cholan-24-oic acid and 3α,7α,11α-trihydroxy-5β-cholan-24-oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.
- Namegawa, Kazunari,Iida, Kyoko,Omura, Kaoru,Ogawa, Shoujiro,Hofmann, Alan F.,Iida, Takashi
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- Amino functionalized novel cholic acid derivatives induce HIV-1 replication and syncytia formation in T cells
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Synthesis of C-11 azido/amino functionalized cholic acid derivatives has been achieved in excellent yields. Contrary to the previous prediction of analogous compounds to be HIV-1 protease inhibitors, in the present study these novel cholic acid derivatives induced host cell fusion during the progress of HIV-1 infection and produced multinucleated giant cells. This is the first report of syncytia induction and enhancement of viral replication in HIV-1 infected T cells by cholic acid derivatives.
- Salunke, Deepak B.,Ravi, Dyavar S.,Pore, Vandana S.,Mitra, Debashis,Hazra, Braja G.
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- Cyclocholates with 12-Oxo and 7,12-Oxo Groups
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Syntheses of bile acid cyclooligomers with 12- and 7,12-oxo groups (6a-d, 7a-c, 8a-b) by the Yamaguchi method are described. Cyclotrimerization is the principal reaction route for these cholic acid systems. Conversion of 7- and 12-hydroxy groups in cholic acid (la-b) to oxo groups (4a-c, 5a-c), followed by macrocyclization (6a-d, 7a-c, 8a-b) and selective reduction of the oxo groups back to hydroxy ones without cleaving the 24-carboxylic ester linkages (11) constitutes a new strategy in the synthesis of cyclocholates having unprotected hydroxy groups.
- Gao, Hongwu,Dias, Jerry Ray
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- Ring-closing metathesis towards functionalised pentacyclic steroids
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A new synthetic pathway towards pentacyclic steroids was described via a ring-closing metathesis reaction as the key step.
- Ibrahim-Ouali, Malika,Bouleghlem, Hocine,Aouf, Nour-Eddine
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- Synthesis of heterosteroids. First synthesis of oxa steroid from cholic acid
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We wish to report here a new and efficient partial synthesis of 3-oxa-5β-steroid, the first oxa steroid synthesized from cholic acid.
- Ibrahim-Ouali, Malika,Botsi-Nkomendi, Nicaise,Rocheblave, Luc
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- Dimeric cholaphanes with disulfide spacers
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New dimeric cholaphanes with disulfide spacers were prepared as potential supramolecular hosts. The spacers bind two identical steroidal subunits through C3, C3′ and C24, C24′ positions (head-to-head isomer–‘cis-dimer’; 5) or C3, C24′ and C3′, C24 positions (head-to-tail isomer–‘trans-dimer’; 4). Another cyclic dimer containing both disulfide and sulfide spacers in its structure (6) was also obtained.
- Tomkiel, Aneta M.,Kie?czewska, Urszula,Seroka, Barbara,?otowski, Zenon
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- Synthesis and cytotoxicity of A-homo-lactam derivatives of cholic acid and 7-deoxycholic acid
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Using cholic acid and deoxycholic acid as starting materials, a series of 3-aza-A-homo-4-one bile acid and 7-deoxycholic acid derivatives were synthesized by the esterification, oxidation, reduction, oximation and Beckman rearrangement etc. The cytotoxicity of the synthesized compounds against MGC 7901 (human ventriculi carcinoma cell line), hela (human cervical carcinoma cell line), SMMC 7404 (human liver carcinoma cell line) were investigated. The results showed that bile acid and 7-deoxycholic-acid derivatives with 3-aza-A-homo-4-one configuration bearing a 6-hydroximino or 12-hydroximino group displayed a distinct cytotoxicity to Hela tumor cell line. In particular, the IC50 values of the compounds 6 and 13 were 14.3 and 24.3 μmol/L against Hela human tumor cell line respectively. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.
- Huang, Yanmin,Chen, Sijing,Cui, Jianguo,Gan, Chunfang,Liu, Zhiping,Wei, Yingliang,Song, Huachan
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- Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both NO carrier and targeting ligand
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Novel liver-specific nitric oxide (NO) releasing drugs with bile acid as both the NO carrier and targeting ligand were designed and synthesized by direct nitration of the hydroxyl group in bile acids or the 3-O-hydroxyl alkyl derivatives, with the intact 24-COOH being preserved for hepatocyte specific recognition. Preliminary biological evaluation revealed that oral administrated targeted conjugates could protect mice against acute liver damage induced by acetaminophen or carbon tetrachloride. The nitrate level in the liver significantly increased after oral administration of 1e while nitrate level in the blood did not significantly change. Co-administration of ursodeoxycholic acid (UDCA) significantly antagonized the increase of nitrate in the liver resulted by administration of 1e.
- Jin, Xue-Yuan,Fan, Shi-Yong,Li, Hong-Wu,Shi, Wei-Guo,Chen, Wei,Wang, Hui-Fen,Zhong, Bo-Hua
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- A short synthesis of methyl 3α, 7α, 12α- triaminocholanoate, the 'triaza-analogue' of methyl cholate
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Triamine 2a, a facial amphiphile and precursor for anion receptors, has been prepared in just four steps from the inexpensive steroid cholic acid.
- Del Amo, Vicente,Bhattarai, Khadga,Nissinen, Maija,Rissanen, Kari,Pérez-Payán, M. Nieves,Davis, Anthony P.
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- Chemical synthesis of uncommon natural bile acids: The 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids
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The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ9(11)-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ9(11)-enes using m-chloroperbenzoic acid catalyzed by 4,4'-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9a-hydroxylation of the Δ9(11)-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The 1H- and 13C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids.
- Iida, Takashi,Namegawa, Kazunari,Nakane, Naoya,Iida, Kyoko,Hofmann, Alan Frederick,Omura, Kaoru
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- Synthesis and micellar mimic properties of bile acid trimers
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Two fan-shaped bile acid trimers have been synthesized via Cu I-catalyzed azide-alkyne cycloaddition (CuAAC) 'click chemistry', and their extraction experiments of cresol red sodium (CR) and pyrene were investigated in the polar and non-polar solvents, respectively. The transmission electron microscopy (TEM) results showed that the homogenous hollow capsules formed with the diameter size range of 40-70 nm in a solution of water and acetone. Thus the amphiphilicity of fan-shaped bile acid trimers might be used as the promising candidate in biological and drug delivery applications.
- Lu, Jinrong,Liu, Chulong,Hu, Jun,Ju, Yong
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- First synthesis of thia steroids from cholic acid
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Heterosteroids remain interesting due to their potential biological activities. This prompted us to synthesize novel thia steroids possessing the heteroatom in the A-ring. We set out to describe a new and versatile method for preparing 3-thia steroids from cholic acid via a selective oxidation of one hydroxyl group, a BaeyerVilliger oxidation and a photolysis as the key steps. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are reported.
- Ibrahim-Ouali, Malika,Rocheblave, Luc
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- Cholic acid dimers as invertible amphiphilic pockets: Synthesis, molecular modeling, and inclusion studies
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Two dimers of cholic acid were synthesized through simple covalent linkers. The dimers form invertible molecular pockets in media of different polarity; hydrophobic pockets are formed in water and hydrophilic pockets are formed in organic media. Fluorescence studies show that pockets formed by these dimers can serve as invertible hosts for the hydrophobic guest pyrene and the hydrophilic guest coumarin 343. The molecular pocket also enhances dissolution of the weakly soluble cresol red sodium salt in organic media. Molecular modeling was performed to better understand the host-guest complexation process of the invertible amphiphilic pockets. The calculated free energy changes indicate that the two dimers form the most stable complexes with coumarin 343 at a host to guest ratio of 2:2, whereas the host to guest ratio differs in the formation of complexes with pyrene for the two dimers. The dimer with the shorter, less flexible linker seems to form host-guest complexes that are more stable in both water and organic solvents.
- Zhang, Meng,Levaray, Nicolas,Daniel, Josée R.,Waldron, Karen C.,Zhu
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- Discovery of novel cholic acid derivatives as highly potent agonists for G protein-coupled bile acid receptor
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In this study, fourteen new cholic acid (CA) derivatives were designed and synthesized, and the GloSensor cAMP accumulation assay indicated that all derivatives could activate the Takeda G protein-coupled receptor 5 (TGR5). Methylation of 7- and 12-hydroxyl groups in CA significantly increased TGR5 agonism for the new derivatives. For example, 7,12-dimethoxy derivative B1 exhibited 78-fold higher potency for TGR5 than the 7,12-dihydroxyl derivative A1 and 258-fold higher potency than CA itself. On the other hand, A1 positively modulated chenodeoxycholic acid (CDCA) functional activity in TGR5, whereas B1 did not show similar activity. Molecular docking experiments indicated that A1 formed a hydrogen bond between the 12-OH and amino acid Thr131 of TGR5, which is significant for its allosteric property. However, methylation at the 12-hydroxyl group in CA (derivative B1) disrupted this pivotal H-bond. Therefore, the free 12-hydroxyl group is essential for the CA derivatives in TGR5 allosteric agonism. Overall, we discovered a highly potent TGR5 agonist, B1, which can be used as lead compound for further study.
- Chen, Xin,Hou, Wenwen,Lu, Xin,Luo, Zhijie,Qian, Mingcheng,Sun, Jingjing,Wu, Yi,Xue, Caile,Zhang, Qianxi,Zhao, Shuai
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- METHOD FOR THE PREPARATION OF ARAMCHOL
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It is provided a method for the preparation of 3β-arachidylamido-7α,12α-dihydroxy-5β-cholan-24-carboxylic acid comprising the step of: d) reacting compound (IV) with methane sulphonyl chloride to get methyl 7α,12α-diacetyloxy-3α-mesyloxy-5β-cholan-24-oate (V).
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Page/Page column 25-26
(2021/07/17)
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- Characterization of novel fluorescent bile salt derivatives for studying human bile salt and organic anion transporters
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Bile salts, such as cholate, glycocholate, taurocholate, and glycochenodeoxycholate, are taken up from the portal blood into hepatocytes via transporters, such as the Na+-taurocholate–cotransporting polypeptide (NTCP) and organic anion–transporting polypeptides (OATPs). These bile salts are later secreted into bile across the canalicular membrane, which is facilitated by the bile salt export pump (BSEP). Apart from bile salt transport, some of these proteins (e.g., OATPs) are also key transporters for drug uptake into hepatocytes. In vivo studies of transporter function in patients by using tracer compounds have emerged as an important diagnostic tool to complement classic liver parameter measurements by determining dynamic liver function both for diagnosis and monitoring progression or improvement of liver diseases. Such approaches include use of radioactively labeled bile salts (e.g., for positron emission tomography) and fluorescent bile salt derivatives or dyes (e.g., indocyanine green). To expand the list of liver function markers, we synthesized fluorescent derivatives of cholic and chenodeoxycholic acid by conjugating small organic dyes to the bile acid side chain. These novel fluorescent probes were able to block substrate transport in a concentration-dependent manner of NTCP, OATP1B1, OATP1B3, OATP2B1, BSEP, and intestinal apical sodium-dependent bile salt transporter (ASBT). Whereas the fluorescent bile acid derivatives themselves were transported across the membrane by OATP1B1, OATP1B3, and OATP2B1, they were not transport substrates for NTCP, ASBT, BSEP, and multidrug resistance-related protein 2. Accordingly, these novel fluorescent bile acid probes can potentially be used as imaging agents to monitor the function of OATPs. SIGNIFICANCE STATEMENT Synthetic modification of common bile acids by attachment of small organic fluorescent dyes to the bile acid side chain resulted in bright, fluorescent probes that interact with hepatic and intestinal organic anion [organic anion–transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1], bile salt uptake (Na+-taurocholate–cotransporting polypeptide, apical sodium-dependent bile salt transporter), and bile salt efflux (bile salt export pump, multidrug resistance-related protein 2) transporters. Although the fluorescent bile salt derivatives are taken up into cells via the OATPs, the efflux transporters do not transport any of them but one.
- Euler, Adriana,Leuenberger, Michele,Lochner, Martin,Stieger, Bruno,H?usler, Stephanie,H?hn, Vera
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p. 346 - 357
(2021/06/08)
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- G protein coupled cholic acid receptor endogenous ligand derivatives and preparation method and application thereof in anti-tumor activity
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The invention belongs to the field of medicinal chemistry, and particularly discloses G protein coupled cholic acid receptor endogenous ligand derivatives and a preparation method and application thereof in anti-tumor activity. Different cholic acid parent structures are used as raw materials, esterification reaction is carried out under the action of a catalyst, methylation is carried out after protection by a protecting group, and a series of novel cholic acid series derivatives are finally obtained through deprotection, hydrolysis reaction and amide coupling reaction. An MTT colorimetric method is used for carrying out anti-cancer activity test on the synthesized new derivatives, and the results show that the series of synthesized G protein coupled cholic acid receptor endogenous ligand derivatives have better anticancer activity.
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Paragraph 0014; 0024; 0083-0086
(2021/05/29)
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- Method for synthesizing deoxycholic acid
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The invention provides a method for synthesizing deoxycholic acid. The method comprises the steps of esterifying cholic acid to obtain a compound I, oxidizing to obtain a compound II, performing protection to obtain a compound III, brominating to obtain a compound IV, reducing to obtain a compound V, eliminating to obtain a compound VI, reducing and hydrogenating to obtain a compound VII, and performing ester hydrolysis to obtain deoxycholic acid. The reaction formula is shown in the description, wherein R1 in the formula III, the formula VI, the formula V, the formula VI and the formula VII is selected from benzoyl or p-toluenesulfonyl; and R2 is selected from methyl, ethyl or tertiary butyl. The synthesis method overcomes the defects of long reaction steps, expensive used reagents, difficulty in purification, low yield and the like in the prior art, and provides a novel method which is rapid in reaction, easy in purification, high in yield and suitable for commercial mass production.
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Paragraph 0036-0037
(2021/06/26)
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- Engineering Regioselectivity of a P450 Monooxygenase Enables the Synthesis of Ursodeoxycholic Acid via 7β-Hydroxylation of Lithocholic Acid
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We engineered the cytochrome P450 monooxygenase CYP107D1 (OleP) from Streptomyces antibioticus for the stereo- and regioselective 7β-hydroxylation of lithocholic acid (LCA) to yield ursodeoxycholic acid (UDCA). OleP was previously shown to hydroxylate testosterone at the 7β-position but LCA is exclusively hydroxylated at the 6β-position, forming murideoxycholic acid (MDCA). Structural and 3DM analysis, and molecular docking were used to identify amino acid residues F84, S240, and V291 as specificity-determining residues. Alanine scanning identified S240A as a UDCA-producing variant. A synthetic “small but smart” library based on these positions was screened using a colorimetric assay for UDCA. We identified a nearly perfectly regio- and stereoselective triple mutant (F84Q/S240A/V291G) that produces 10-fold higher levels of UDCA than the S240A variant. This biocatalyst opens up new possibilities for the environmentally friendly synthesis of UDCA from the biological waste product LCA.
- Grobe, Sascha,Badenhorst, Christoffel P. S.,Bayer, Thomas,Hamnevik, Emil,Wu, Shuke,Grathwol, Christoph W.,Link, Andreas,Koban, Sven,Brundiek, Henrike,Gro?johann, Beatrice,Bornscheuer, Uwe T.
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supporting information
p. 753 - 757
(2020/12/01)
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- Synthesis method of 3[alpha],6[alpha](beta),12[alpha]-trihydroxyl-5[beta]-cholic acid
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The invention discloses a preparation method of 3[alpha],6[alpha],12[alpha]-trihydroxyl-5[beta]-cholic acid and 3[alpha],6[beta],12[alpha]-trihydroxyl-5[beta]-cholic acid. 3[alpha],7[alpha],12[alpha]-trihydroxyl-5[beta]-cholic acid is taken as a raw material, and 3[alpha],6[alpha],12[alpha]-trihydroxyl-5[beta]-cholic acid and 3[alpha],6[beta],12[alpha]-trihydroxyl-5[beta]-cholic acid are obtainedthrough ten steps such as Mukaiyama aldol condensation reaction, oxidative cracking, reduction removal and the like . The synthesis method has the characteristics of green and high efficiency.
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Paragraph 0023; 0027
(2020/10/14)
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- Method for efficiently synthesizing Aramchol
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The invention discloses a method for efficiently synthesizing Aramchol. The method comprises the following steps: firstly, generating an intermediate b-methyl cholate through esterification reaction of methanol and cholic acid molecules; reacting an alkylbenzene sulfonyl chloride with a specific structure with methyl cholate in the presence of an acid-binding agent, and selectively reacting with 3-hydroxyl of cholic acid molecules to synthesize a key intermediate c-3 alpha-O-alkylbenzene sulfonyl methyl cholate; and then protecting free hydroxyl in the intermediate c, and removing the free hydroxyl after the amidation reaction is finished, so that the problems of side reaction of acyl chloride and the free hydroxyl, serious emulsification phenomenon in the reaction process and difficulty in separation are effectively avoided.
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Paragraph 0076-0079
(2020/05/01)
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- Synthesis of new cisplatin derivatives from bile acids
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A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity.
- ?otowski, Zenon,Hryniewicka, Agnieszka,Morzycki, Jacek W.,Rárová, Lucie,Seroka, Barbara,Sicinski, Rafal R.,Tomkiel, Aneta M.
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- Chenodeoxycholic acid derivative or pharmaceutically acceptable salt thereof, and preparation method and applications thereof
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The invention discloses a chenodeoxycholic acid derivative with a structure as shown in general formula I or a medicinal salt thereof, and a preparation method and application of the chenodeoxycholicacid derivative. The chenodeoxycholic acid derivative can up-regulate the transcription levels of FXR mRNA and SHP mRNA, can obviously activate FXR, and can be used for preparing drugs for treating orpreventing hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis, type II diabetes mellitus and other diseases related to blood fat.
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Paragraph 0039; 0040; 0041
(2020/03/12)
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- New technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials
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The invention discloses a new technology for efficiently synthesizing Aramchol by utilizing cholic acid and arachidic acid as raw materials. According to the new technology disclosed by the invention,a 3- hydroxyl group of cholic acid is activated by selecting para-butyl benzene sulfonyl chloride in larger steric hindrance and the like, 3alpha-O-para-butyl benzene sulfonyl methyl cholate, chiral3-C can be attacked by an azide group just through a direction against an alkylbenzene sulfonyloxy group of a leaving group during a nucleophilic substitution reaction process of the 3alpha-O-para-butyl benzene sulfonyl methyl cholate and sodium azide, inversion of 3-C configuration of a product-3-azido methyl cholate is ensured, and a firm foundation is laid for controlling the optical purity ofa final product-Aramchol.
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Paragraph 0055-0059
(2019/04/04)
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- Influence of Conformational Change and Interligand Hydrogen Bonding in a Chiral Metal-Organic Cage
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We report about the coordination-driven self-assembly of a chiral bis-pyridyl ligand (1), synthesized from steroidal cholic acid, with Pd(II) ions to form a chiral metal-organic Pd2(1)4 cage. The self-assembly of the cage was facilitated by favorable conformational change in the alkyl chain of the cholic acid. Interligand hydrogen bonding played a crucial role in directing the formation of a C4 symmetric cage among different possible isomers, as suggested by DFT studies, and control experiments with different ligands.
- Sen, Shovan Kumar,Natarajan, Ramalingam
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supporting information
p. 7180 - 7188
(2019/06/11)
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- 1,3-Dibromo-5,5-dimethylhydantoin as a Precatalyst for Activation of Carbonyl Functionality
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Activation of carbonyl moiety is one of the most rudimentary approaches in organic synthesis and is crucial for a plethora of industrial-scale condensation reactions. In esterification and aldol condensation, which represent two of the most important reactions, the susceptibility of the carbonyl group to nucleophile attack allows the construction of a variety of useful organic compounds. In this context, there is a constant need for development of and improvement in the methods for addition-elimination reactions via activation of carbonyl functionality. In this paper, an advanced methodology for the direct esterification of carboxylic acids and alcohols, and for aldol condensation of aldehydes using widely available, inexpensive, and metal-free 1,3-dibromo-5,5-dimethylhydantoin under neat reaction conditions is reported. The method is air- and moisture-tolerant, allowing simple synthetic and isolation procedures for both reactions presented in this paper. The reaction pathway for esterification is proposed and a scale-up of certain industrially important derivatives is performed.
- ?ebular, Klara,Bo?i?, Bojan ?.,Stavber, Stojan
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supporting information
(2019/08/01)
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- Oral Delivery of Cholic Acid-Derived Amphiphile Helps in Combating Salmonella-Mediated Gut Infection and Inflammation
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A major impediment to developing effective antimicrobials against Gram-negative bacteria like Salmonella is the ability of the bacteria to develop resistance against existing antibiotics and the inability of the antimicrobials to clear the intracellular bacteria residing in the gastrointestinal tract. As the critical balance of charge and hydrophobicity is required for effective membrane-targeting antimicrobials without causing any toxicity to mammalian cells, herein we report the synthesis and antibacterial properties of cholic acid-derived amphiphiles conjugated with alkyl chains of varied hydrophobicity. Relative to other hydrophobic counterparts, a compound with hexyl chain (6) acted as an effective antimicrobial against different Gram-negative bacteria. Apart from its ability to permeate the outer and inner membranes of bacteria; compound 6 can cross the cellular and lysosomal barriers of epithelial cells and macrophages and kill the facultative intracellular bacteria without disrupting the mammalian cell membranes. Oral delivery of compound 6 was able to clear the Salmonella-mediated gut infection and inflammation, and was able to combat persistent, stationary, and multi-drug-resistant clinical strains. Therefore, our study reveals the ability of cholic acid-derived amphiphiles to clear intracellular bacteria and Salmonella-mediated gut infection and inflammation.
- Yadav, Kavita,Yavvari, Prabhu Srinivas,Pal, Sanjay,Kumar, Sandeep,Mishra, Deepakkumar,Gupta, Siddhi,Mitra, Madhurima,Soni, Vijay,Khare, Neha,Sharma, Priyanka,Srikanth, Chittur V.,Kapil, Arti,Singh, Archana,Nandicoori, Vinay Kumar,Bajaj, Avinash
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p. 721 - 732
(2019/02/19)
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- Mimicking Enzymes: Asymmetric Induction inside a Carbamate-Based Steroidal Cleft
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Cholic acid has been elaborated into a carbamate-based tripodal architecture, which is able to promote an asymmetric organic transformation inside its chiral cavity. The nature of this steroidal catalyst has been disclosed by quantum-chemical calculations. It comprises the preorganization and confinement of the reagents within the cavity of the steroid to form a supramolecular complex held together by means of cooperative H-bond contacts. This operational mode resembles that of some enzymes.
- Concellón, Carmen,Martín, Judith,Gallegos, Miguel,Fanjul-Mosteirín, Noé,Costales, Aurora,Pendás, ángel Martín,Del Amo, Vicente
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supporting information
p. 3994 - 3997
(2019/06/17)
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- Esterification of aryl/alkyl acids catalysed by n-bromosuccinimide under mild reaction conditions
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N-halosuccinimides (NXSs) are well-known to be convenient, easily manipulable and low-priced halogenation reagents in organic synthesis. In the present work, N-bromosuccinimide (NBS) has been promoted as the most efficient and selective catalyst among the NXSs in the reaction of direct esterification of aryl and alkyl carboxylic acids. Comprehensive esterification of substituted benzoic acids, mono-, di- and tri-carboxy alkyl derivatives has been performed under neat reaction conditions. The method is metal-free, air- and moisture-tolerant, allowing for a simple synthetic and isolation procedure as well as the large-scale synthesis of aromatic and alkyl esters with yields up to 100%. Protocol for the recycling of the catalyst has been proposed.
- ?ebular, Klara,Bo?i?, Bojan ?.,Stavber, Stojan
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- New cholic acid analogs: Synthesis and 17β-hydroxydehydrogenase (17β-HSD) inhibition activity
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The 17β-hydroxysteroid dehydrogenase (17β-HSD) enzyme family is involved in the biosynthesis of active steroids and its inhibition constitutes an interesting approach for treating estrogen-, androgen-dependent cancers and osteoporosis. In this study, a new series of cholic acid analogs was designed with the goal of improving the biological activity as 17β-HSD1 and 17β-HSD2 inhibitors. To this end, 23-cholyl amides 4-7, 3-O-p-toluenesulfonyl-23-cholyl amides 10-12, 23-cholyl-carbohydrazide 14, carbothioamide analog 15, and 23-cholyl-acylhydrazone derivatives 18-22 were synthesized from cholic acid (3) via coupling, sulfonation and substitution reactions. Basic treatment of keto group of 5 with p-bromoaniline afforded 8, meanwhile acidic treatment of 3 with thiosemicarbazide furnished the 23-cholyl-thiadiazole derivative 16. The synthesized compounds were evaluated for their inhibition activity against 17β-HSD1 and 17β-HSD2, and were found inactive at 1.0 μm concentration (inhibition 10%). However, the steroids 12, 21 and 22 showed inhibition of 21.1, 23.9 and 21.3%, respectively, against 17β-HSD2 at the same concentration. Therefore, these steroidal analogs can be further structurally modified to optimize their inhibition activity against 17β-HSD2 for the development of potential therapeutics.
- Al-Masoudi, Najim A.,Sami, Abbas,Abdul-Rida, Nabeel A.,Fortscher, Martin
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p. 211 - 233
(2018/03/21)
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- Chenodeoxycholic acid derivatives, preparation method thereof and medical application thereof
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The invention relates to the field of medicinal chemistry, relates to chenodeoxycholic acid derivatives, a preparation method thereof and a medical application thereof, in particular to a kind of chenodeoxycholic acid derivatives with a general formula of (I), a preparation method thereof, a pharmaceutical composition comprising the compounds and medical application thereof, especially used as drugs for preventing or treating hyperlipidaemia, type II diabetes, atherosis and non-alcoholic steatohepatitis. The formula is shown in the description.
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Paragraph 0039; 0040; 0041
(2018/06/26)
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- PROCESS FOR THE PREPARATION OF DEOXYCHOLIC ACID
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The present invention provides a process for preparation of deoxycholic acid or salt thereof; the process comprises the steps of reacting the compound of formula II to obtain a compound of formula III; the compound of formula III is converted to a compound of formula IV and the compound of formula IV is converted to deoxycholic acid. The present invention also provides a process for the purification of deoxycholic acid or salt thereof.
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Paragraph 0120
(2018/12/13)
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- Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptidess
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In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-free Cmax values (0.06, 0.66, 2.57, and 7.79 μM, respectively) spanning the reported in vitro IC50 values for OATP1B1 and OATP1B3 (≤1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v.2H4-pitavastatin, 0.2 mg/kg) was increased 1.2-, 2.4-, 3.8-, and 4.5-fold, respectively. Plasma of RIF-dosed cynomolgus monkeys was subjected to a liquid chromatography-tandem mass spectrometry method that supported the analysis of 30 different BAs. Monkey urine was profiled, and we also determined that the impact of RIF on BA renal clearance was minimal. Although sulfated BAs comprised only 1% of the plasma BA pool, a robust RIF dose response (maximal ?50-fold increase in plasma AUC) was observed for the sulfates of five BAs [glycodeoxycholate (GDCA-S), glycochenodeoxycholate (GCDCA-S), taurochenodeoxycholate, deoxycholate (DCA-S), and taurodeoxycholate (TDCA-S)]. In vitro, RIF (≤100 μM) did not inhibit cynomolgus monkey liver cytosol-catalyzed BA sulfation and cynomolgus monkey hepatocyte-mediated uptake of representative sulfated BAs (GDCA-S, GCDCA-S, DCA-S, and TDCA-S) was sodium-independent and inhibited (≥70%) by RIF (5 μM); uptake of taurocholic acid was sensitive to sodium removal (74% decrease) and relatively refractory to RIF (≤21% inhibition). We concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs and that exploration of their utility as circulating human OATP biomarkers is warranted.
- Thakare, Rhishikesh,Gao, Hongying,Kosa, Rachel E.,Bi, Yi-An,Varma, Manthena V. S.,Cerny, Matthew A.,Sharma, Raman,Kuhn, Max,Huang, Bingshou,Liu, Yiping,Yu, Aijia,Walker, Gregory S.,Niosi, Mark,Tremaine, Larry,Alnouti, Yazen,Rodrigues, A. David
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supporting information
p. 721 - 733
(2017/06/27)
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- Fluorous-tag assisted synthesis of bile acid-bisphosphonate conjugates: Via orthogonal click reactions: An access to potential anti-resorption bone drugs
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The synthesis of a small collection of novel bile acid-bisphosphonate (BA-BP) conjugates as potential drug candidates is reported. The disclosed methodology relied on the installation of azide and thiol functionalities at the head and tail positions, respectively, of the BA scaffold and its subsequent decoration by orthogonal click reactions (copper-catalyzed azide-alkyne cycloaddition, thiol-ene or thiol-yne coupling) to introduce BP units and a fluorophore. Because of the troublesome isolation of the target conjugates by standard procedures, the methodology culminated with the functionalization of the BA scaffold with a light fluorous tag to rapidly and efficiently purify intermediates and final products by fluorous solid-phase extraction.
- Massarenti, Chiara,Bortolini, Olga,Fantin, Giancarlo,Cristofaro, Dario,Ragno, Daniele,Perrone, Daniela,Marchesi, Elena,Toniolo, Gianluca,Massi, Alessandro
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p. 4907 - 4920
(2017/07/10)
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- Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls
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The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs. The direct reactivity of triplet BP with BSs in the initial step was evaluated by determining the kinetic rate constants using laser flash photolysis (LFP). The BP triplet decay was monitored (λmax = 520 nm) upon addition of increasing BS concentrations, and the obtained rate constant values indicated a reactivity of the methine hydrogen atoms in the order of C-3 2 than under O2, also supporting the role of the oxygen-quenchable triplet in the dehydrogenation process. Furthermore, irradiation of deaerated aqueous solutions of sodium cholate in the presence of KPMe provided the oxo-analogs, 3[O],7[O]-CA, 3[O]-CA and 7[O]-CA, arising from the HAT process.
- Miro,Marin,Miranda
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supporting information
p. 2679 - 2683
(2016/03/05)
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- COMPOUND FOR TREATING CLOSTRIDIUM DIFFICILE
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The invention relates to compounds, compositions and polymers comprising a first component adapted to promote germination of Clostridium difficile (C.diff) and a second component which acts as an antimicrobial agent. Said compounds, compositions and polymers are useful for destroying C.diff where conventional antimicrobial agents are unsuccessful. The compositions can be formulated as coating or materials which actively destroy C.diff which come into contact with it. The germination promotion is induced by bile salts. The invention also relates to the use of such materials as a treatment for C.diff associated diseases and toxic megacolon.
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Page/Page column 24
(2016/06/14)
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- Design and synthesis of new conjugates of bile acids with salicylic, acetylsalicylic and nicotinic acids
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A new bile acids conjugates have been obtained from 3α-bromoacetoxy derivatives of lithocholic, deoxycholic and cholic acids with salicylic, acetylsalicylic or nicotinic acids. These new conjugates were confirmed by spectroscopic(1H-,13C NMR, FT-IR) analysis, mass spectrometry (ESI-MS) and semiempirical methods (PM5) as well as in silico (PASS) studies. Methods: This work reports an original synthesis and physicochemical properties of new conjugates of bile acid derivatives with salicylic (SA), acetylasalicylic (ASA) or nicotinic (NA) acids. The 3α- bromoacetates of bile acids were prepared with good yield according to the literature procedures. The structures of all synthesized compounds were determined from their 1H- And 13C-NMR, FT-IR as well as ESI-MS spectra. Moreover, PM5 calculations were performed on all the products. Additionally, in silico studies PASS (Prediction of Activity Spectra for Substances) were performed for all compounds. Results: The direct alkylation reaction of the carboxylate ions from SA, ASA or NA with methyl litocholate 3α- bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate with a catalytic amount of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) in dry toluene is reliable and simple. This esterification method enables to obtain stable esters with very good yields and without any decomposition, e.g. decarboxylation or other degradation processes. The most frequently predicted types of biological activity (than 90%) are: Cholesterol antagonist, antihypercholesterolemic, alkenylglycerophosphocholine hydrolase inhibitor and hypolipemic. The synthesised steroidal conjugates were characterised by 1H and 13C NMR as well as FT-IR spectroscopy. The lowest HOF values were observed for cholic acid derivatives. The number of hydroxyl groups in the bile acid skeleton lowers the value of the determinant of HOF. In addition HOF lowest values observed for conjugates with aspirin. This can be explained by reducing the reactivity of the phenol group of salicylic acid. Hydrogen bonding between hydroxyl group of cholic acid and carbonyl group of aspirin also reduces HOF. This fact can be explained by reduction of electrostatic and steric interactions between the steroid skeletons. Conclusion: In conclusion, nine new conjugates of bile acids were prepared from methyl litocholate 3α-bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate with a salicylic acid (SA), acetylsalicylic acid (ASA), as well as nicotinic acid (NA) with catalytic amount DBU in dry toluene at 95°C for 24 hours. All new compounds were characterized by 1H NMR,13C NMR, FT-IR as well as ESI-MS. Molecular structure of all conjugates was performed by PM5 semiempirical method. Additionally, analyses of the biological prediction activity spectra for conjugates of bile acids with SA, ASA and NA prepared herein are examples of in silico studies of chemical compounds. Estimation of the pharmacotherapeutic potential has been accomplished for the synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). Given the a combination of two types of biologically active compounds these conjugates may find applications in medicinal chemistry, biology, and in pharmacology.
- Pospieszny, Tomasz,Brycki, Bogumil
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p. 302 - 309
(2016/05/11)
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- Design and synthesis of new conjugates of bile acids with salicylic, acetylsalicylic and nicotinic acids
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Backgroung: A new bile acids conjugates have been obtained from 3α-bromoacetoxy derivatives of lithocholic, deoxycholic and cholic acids with salicylic, acetylsalicylic or nicotinic acids. These new conjugates were confirmed by spectroscopic (1H-, 13C NMR, FT-IR) analysis, mass spectrometry (ESI-MS) and semiempirical methods (PM5) as well as in silico (PASS) studies. Methods: This work reports an original synthesis and physicochemical properties of new conjugates of bile acid derivatives with salicylic (SA), acetylasalicylic (ASA) or nicotinic (NA) acids. The 3α- bromoacetates of bile acids were prepared with good yield according to the literature procedures. The structures of all synthesized compounds were determined from their 1H- and 13C-NMR, FT-IR as well as ESI-MS spectra. Moreover, PM5 calculations were performed on all the products. Additionally, in silico studies PASS (Prediction of Activity Spectra for Substances) were performed for all compounds. Results: The direct alkylation reaction of the carboxylate ions from SA, ASA or NA with methyl litocholate 3α- bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate with a catalytic amount of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) in dry toluene is reliable and simple. This esterification method enables to obtain stable esters with very good yields and without any decomposition, e.g. decarboxylation or other degradation processes. The most frequently predicted types of biological activity (than 90%) are: cholesterol antagonist, antihypercholesterolemic, alkenylglycerophosphocholine hydrolase inhibitor and hypolipemic. The synthesised steroidal conjugates were characterised by 1H and 13C NMR as well as FT-IR spectroscopy. The lowest HOF values were observed for cholic acid derivatives. The number of hydroxyl groups in the bile acid skeleton lowers the value of the determinant of HOF. In addition HOF lowest values observed for conjugates with aspirin. This can be explained by reducing the reactivity of the phenol group of salicylic acid. Hydrogen bonding between hydroxyl group of cholic acid and carbonyl group of aspirin also reduces HOF. This fact can be explained by reduction of electrostatic and steric interactions between the steroid skeletons. Conclusion: In conclusion, nine new conjugates of bile acids were prepared from methyl litocholate 3α-bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate with a salicylic acid (SA), acetylsalicylic acid (ASA), as well as nicotinic acid (NA) with catalytic amount DBU in dry toluene at 95°C for 24 hours. All new compounds were characterized by 1H NMR, 13C NMR, FT-IR as well as ESI-MS. Molecular structure of all conjugates was performed by PM5 semiempirical method. Additionally, analyses of the biological prediction activity spectra for conjugates of bile acids with SA, ASA and NA prepared herein are examples of in silico studies of chemical compounds. Estimation of the pharmacotherapeutic potential has been accomplished for the synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). Given the a combination of two types of biologically active compounds these conjugates may find applications in medicinal chemistry, biology, and in pharmacology.
- Pospieszny, Tomasz,Brycki, Bogumil
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p. 302 - 309
(2016/05/24)
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- Synthesis and characterization of novel dendritic compounds bearing a porphyrin core and cholic acid units using "click chemistry"
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Four novel dendritic molecules bearing a porphyrin core and peripheral cholic acid units (TPPh(Zn) Tetra-CA, TPPh(2H) Tetra-CA, TPPh(Zn) Octa-CA and TPPh(2H) Octa-CA) have been synthesized by the "click chemistry" approach, using azide-alkyne couplings. These compounds are fully characterized by 1H and 13C NMR spectroscopy and MALDI-TOF. The optical properties of the dendronized porphyrins are studied by absorption and fluorescence spectroscopy in different solvents, in order to study the amphiphilic properties of the cholic acid units in combination with the optical response of the porphyrin unit. After complexation with Zn, the metallated porphyrins (TPPh(Zn) tetra-CA and TPPh(Zn) octa-CA) tend to form J-aggregates in solvents of different polarity, whereas the free base porphyrins TPPh(2H) tetra-CA and TPPh(2H) octa-CA behaved differently. The aggregation phenomenon has been investigated by varying the polarity of the environment, temperature and metallation.
- Aguilar-Ortíz, Edgar,Lévaray, Nicolas,Vonlanthen, Mireille,Morales-Espinoza, Eric G.,Rojas-Aguirre, Yareli,Zhu, Xiao Xia,Rivera, Ernesto
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p. 110 - 120
(2016/05/19)
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- 11 -SUBSTITUTED BILE ACID DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND USE OF THESE COMPOUNDS AS MEDICAMENTS
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The present invention discloses a novel bile acid derivatives having substituted nitrogen functionality at C-11 and process for synthesis thereof. These C-11 substituted bile acid derivatives shows anticancer and antimycobacterial activity.
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Paragraph 0052
(2015/06/25)
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- Synthesis of new steroidal inhibitors of P-glycoprotein-mediated multidrug resistance and biological evaluation on K562/R7 erythroleukemia cells
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A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/β-pregnane-3,20-dione or 5β-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2′R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/β-pregnane-3,20-dione, among which the 5β-H-7α-benzoyloxy-11α-(2′R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 μM versus 1.2 and 10.6 μM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5β-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 μM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.
- De Ravel, Marc Rolland,Alameh, Ghina,Melikian, Maxime,Mahiout, Zahia,Emptoz-Bonneton, Agnès,Matera, Eva-Laure,Lomberget, Thierry,Barret, Roland,Rocheblave, Luc,Walchshofer, Nadia,Beltran, Sonia,El Jawad, Lucienne,Mappus, Elisabeth,Grenot, Catherine,Pugeat, Michel,Dumontet, Charles,Le Borgne, Marc,Cuilleron, Claude Yves
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supporting information
p. 1832 - 1845
(2015/04/21)
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- Spectroscopic methods and theoretical studies of bromoacetyl substituted derivatives of bile acids
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The structure of seven bromoacetyl substituted derivatives of bile acids have been characterized by 1H MMR, 13C NMR, 2D NMR, FT-IR and mass spectrometry (ESI-MS) as well as PM5 semiempirical and B3LYP ab initio methods. Estimation of the pharmacotherapeutic potential has been accomplished for the synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). Bile acids, bromoacetyl substituted derivatives, Prediction of Activity Spectra for Substances, spectroscopic methods, PM5 and B3LYP calculations.
- Pospieszny, Tomasz,Koenig, Hanna,Kowalczyk, Iwona,Brycki, Bogumil
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- Synthesis, molecular structure and spectral properties of new aminos-teroid analogs of squalamine derivatives
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New quaternary alkylammonium conjugates of steroids were obtained by two step reaction of methyl esters of bile acids with bromoacetic acid bromide, followed by bimolecular nucleophilic substitution with a long chain tertiary alkylamine. The structures of products were confirmed by spectroscopic (H-NMR, C-NMR, and FT-IR) analysis, mass spectrometry (ESI-MS) as well as PM5 semiempirical methods. The biological activity of the synthesized compounds has been estimated on the basis of Prediction of Activity Spectra for Substances (PASS).
- Pospieszny, Tomasz,Koenig, Hanna,Kowalczyk, Iwona,Brycki, Bogumi?
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p. 674 - 684
(2015/11/09)
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- Cholanamide components for organic alloys; Expanding the scope of nanoporous steroidal ureas
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Amide-linked side-chains can substitute for esters in crystalline nanoporous steroidal ureas (NSPUs). This efficient conjugation method increases the versatility of NPSUs, and should aid the inclusion of complex functional units in the crystal channels. The Royal Society of Chemistry 2014.
- Travaglini, Leana,Bridgland, Lydia N.,Davis, Anthony P.
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supporting information
p. 4803 - 4805
(2014/05/06)
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- PROCESS FOR PREPARING HIGH PURITY URSODEOXYCHOLIC ACID
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The present invention describes a process for the synthesis of ursodeoxycholic acid wherein the purification of the crude ursodeoxycholic acid (containing approximately 13-15% of chenodeoxycholic acid impurity) takes place first passing through a salification with imidazole and a subsequent purification via "methyl ester", which allows a finished product with an extremely low content of known "cheno and "litho" impurities to be obtained. The present invention also describes the recovery steps of cholic acid and 3α-hydroxy-7-ketocholanic acid from the mother liquors of process intermediates.
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Page/Page column 4; 7; 8
(2014/02/16)
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- Synthesis of cholate-based pyridinium receptor and its recognition toward L-tryptophan
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Four cholate-based pyridinium compounds were synthesized and their binding abilities toward unmodified amino acids were investigated by UV spectroscopy and fluorescence emission spectroscopy. Studies revealed that the recognition process involved hydrogen bonding, electrostatic force, and π-π interaction. The receptor 4a was found to recognize l-tryptophan specifically, and the complex was studied by 1H NMR spectroscopy. The receptors 4b and 4c showed very little recognition ability toward l-tryptophan, indicating the important role of the benzyl group at pyridinium ring.
- Li, Dazhi,Yang, Yunxu,Yang, Chao,Hu, Biwei,Huo, Baolong,Xue, Lingwei,Wang, Aizhi,Yu, Feifei
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p. 1223 - 1229
(2014/02/14)
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- Tripodal bile acid architectures based on a triarylphosphine oxide core obtained by copper-catalysed [1,3]-dipolar cycloaddition: Synthesis and preliminary aggregation studies
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We report the synthesis and aggregation behaviour of new water-soluble, bile acid derived tripodal architectures based on a core derived from triphenylphosphine oxide. We employed the well-established copper-catalysed [1,3]-dipolar cycloaddition (CuAAC) for the construction of these tripodal molecules. The aggregation behaviour of these molecules in aqueous media was studied by different analytical methods such as dye solubilisation, dynamic light scattering, NMR and AFM. These molecular architectures also offer an additional advantage in aiding understanding of the influence of the nature of the bile acid backbone and of the configuration at the steroid C-3 position in these architectures; to the best of our knowledge this has not been reported in the literature. The unique gelation properties of the α-derivatives were explained through molecular modelling studies and the mechanical behaviour of these gels was studied by rheology experiments. A series of new tripodal architectures were synthesised through coupling of bile acids (cholic and deoxycholic) to a triarylphosphine oxide core through click reactions, and their aggregation was studied by different analytical techniques. The influence of configuration on the aggregation processes of these tripodal architectures was highlighted. Copyright
- Thota, Bala N. S.,Savyasachi, Aramballi J.,Lukashev, Nikolay,Beletskaya, Irina,Maitra, Uday
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p. 1406 - 1415
(2014/03/21)
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- Tripodal Bile Acid Architectures Based on a Triarylphosphine Oxide Core Obtained by Copper-Catalysed [1,3]-Dipolar Cycloaddition: Synthesis and Preliminary Aggregation Studies
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We report the synthesis and aggregation behaviour of new water-soluble, bile acid derived tripodal architectures based on a core derived from triphenylphosphine oxide. We employed the well-established copper-catalysed [1,3]-dipolar cycloaddition (CuAAC) for the construction of these tripodal molecules. The aggregation behaviour of these molecules in aqueous media was studied by different analytical methods such as dye solubilisation, dynamic light scattering, NMR and AFM. These molecular architectures also offer an additional advantage in aiding understanding of the influence of the nature of the bile acid backbone and of the configuration at the steroid C-3 position in these architectures; to the best of our knowledge this has not been reported in the literature. The unique gelation properties of the α-derivatives were explained through molecular modelling studies and the mechanical behaviour of these gels was studied by rheology experiments.
- Thota, Bala N. S.,Savyasachi, Aramballi J.,Lukashev, Nikolay,Beletskaya, Irina,Maitra, Uday
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p. 1406 - 1415
(2015/10/05)
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- Synthesis, spectroscopic and theoretical studies of new quaternary n,n-dimethyl-3-phthalimidopropylammonium conjugates of sterols and bile acids
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New quaternary 3-phthalimidopropylammonium conjugates of steroids were obtained by reaction of sterols (ergosterol, cholesterol, cholestanol) and bile acids (lithocholic, deoxycholic, cholic) with bromoacetic acid bromide to give sterol 3β-bromoacetates and bile acid 3a-bromoacetates, respectively. These intermediates were subjected to nuclephilic substitution with N,N-dimethyl-3-phthalimidopropylamine to give the final quaternary ammonium salts. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry (ESI-MS, MALDI) as well as PM5 semiempirical methods and B3LYP ab initio methods. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS).
- Brycki, Bogumil,Koenig, Hanna,Kowalczyk, Iwona,Pospieszny, Tomasz
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p. 4212 - 4233
(2014/05/20)
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- Bile acid amphiphiles with tunable head groups as highly selective antitubercular agents
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Tuberculosis faces major challenges for its cure due to (a) long treatment period, (b) emergence of drug resistance bacteria, and (c) poor patient compliance. Disrupting the membrane integrity of mycobacteria as a therapeutic strategy has not been explored well as the rigid, waxy, and hydrophobic nature of mycobacterial lipids does not allow binding and penetration of charged amtimicrobial amphiphiles and peptides. Here, we present a new concept that fine-tuning of the charged head group modulates the specificity of amphiphiles against bacterial membranes. We show that hard-charged amphiphiles interact with mycobacterial trehalose dimycolates and penetrate through rigid mycobacterial membranes. In contrast, soft-charged amphiphiles specifically inhibit the growth of both E. coli and S. aureus via electrostatic interactions. These subtle variations between interactions of amphiphiles and bacterial membranes could be explored further to design more specific and potent antimycobacterial agents. This journal is
- Bansal, Sandhya,Singh, Manish,Kidwai, Saqib,Bhargava, Priyanshu,Singh, Ashima,Sreekanth, Vedagopuram,Singh, Ramandeep,Bajaj, Avinash
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p. 1761 - 1768
(2014/12/11)
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- Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts
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The aim of the present work is to develop two-channel emitters to probe local hydrophobicity by means of fluorescence quenching within different biomimetic supramolecular environments. To achieve this goal, the dansyl (Dns) and tryptophan (Trp) fluorophores have been covalently attached to cholic acid (CA) in order to ensure simultaneous incorporation of the two emitting units into the same compartment. In principle, the two fluorophores of the synthesized Dns-CA-Trp probes could either exhibit an orthogonal behavior or display excited state interactions. The fluorescence spectra of 3β-Dns-CA-Trp showed a residual Trp emission band at ca. 350 nm and an enhanced Dns maximum in the 500-550 nm region. This reveals a partial intramolecular energy transfer, which is consistent with the Dns and Trp singlet energies. Thus, the two photoactive units are not orthogonal; nevertheless, 3β-Dns-CA-Trp seems appropriate as a two-channel reporter for the supramolecular systems of interest. Fluorescence quenching of 3β-Dns-CA-Trp by iodide (which remains essentially in bulk water) was examined within sodium cholate, sodium taurocholate, sodium deoxycholate and mixed micelles. Interestingly, a decrease in the emission intensity of the two bands was observed with increasing iodide concentrations. The most remarkable effect was observed for mixed micelles, where the quenching rate constants were one order of magnitude lower than in solution. As anticipated, the quenching efficiency by iodide decreased with increasing hydrophobicity of the microenvironment, a trend that can be correlated with the relative accessibility of the probe to the ionic quencher. This journal is
- Gomez-Mendoza,Marin, M. Luisa,Miranda, Miguel A.
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p. 8499 - 8504
(2015/01/09)
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- Synthesis of various secosteroidal macrocycles by ring-closing metathesis
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We set out to describe an efficient and versatile method for preparing secosteroidal macrocycles from cholic acid, via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are reported.
- Ibrahim-Ouali, Malika,Romero, Eugénie
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p. 651 - 661
(2013/07/11)
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- Design, synthesis, and mechanistic investigations of bile acid-tamoxifen conjugates for breast cancer therapy
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We have synthesized two series of bile acid tamoxifen conjugates using three bile acids lithocholic acid (LCA), deoxycholic acid (DCA), and cholic acid (CA). These bile acid-tamoxifen conjugates possess 1, 2, and 3 tamoxifen molecules attached to hydroxyl groups of bile acids having free acid and amine functionalities at the tail region of bile acids. The in vitro anticancer activities of these bile acid-tamoxifen conjugates show that the free amine headgroup based cholic acid-tamoxifen conjugate (CA-Tam3-Am) is the most potent anticancer conjugate as compared to the parent drug tamoxifen and other acid and amine headgroup based bile acid-tamoxifen conjugates. The cholic acid-tamoxifen conjugate (CA-Tam3-Am) bearing three tamoxifen molecules shows enhanced anticancer activities in both estrogen receptor +ve and estrogen receptor -ve breast cancer cell lines. The enhanced anticancer activity of CA-Tam3-Am is due to more favorable irreversible electrostatic interactions followed by intercalation of these conjugates in hydrophobic core of membrane lipids causing increase in membrane fluidity. Annexin-FITC based FACS analysis showed that cells undergo apoptosis, and cell cycle analysis showed the arrest of cells in sub G0 phase. ROS assays showed a high amount of generation of ROS independent of ER status of the cell line indicating changes in mitochondrial membrane fluidity upon the uptake of the conjugate that further leads to the release of cytochrome c, a direct and indirect regulator of ROS. The mechanistic studies for apoptosis using PCR and western analysis showed apoptotsis by intrinsic and extrinsic pathways in ER +ve MCF-7 cells and by only an intrinsic pathway in ER -ve cells. In vivo studies in the 4T1 tumor model showed that CA-Tam3-Am is more potent than tamoxifen. These studies showed that bile acids provide a new scaffold for high drug loading and that their anticancer activities strongly depend on charge and hydrophobicity of lipid-drug conjugates.
- Sreekanth, Vedagopuram,Bansal, Sandhya,Motiani, Rajender K.,Kundu, Somanath,Muppu, Sravan Kumar,Majumdar, Tapodhara Datta,Panjamurthy, Kuppusamy,Sengupta, Sagar,Bajaj, Avinash
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p. 1468 - 1484
(2013/10/01)
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- Deciphering the role of charge, hydration, and hydrophobicity for cytotoxic activities and membrane interactions of bile acid based facial amphiphiles
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We synthesized four cationic bile acid based facial amphiphiles featuring trimethyl ammonium head groups. We evaluated the role of these amphiphiles for cytotoxic activities against colon cancer cells and their membrane interactions by varying charge, hydration and hydrophobicity. The singly charged cationic Lithocholic acid based amphiphile (LCA-TMA1) is most cytotoxic, whereas the triply charged cationic Cholic acid based amphiphile (CA-TMA 3) is least cytotoxic. Light microscopy and Annexin-FITC assay revealed that these facial amphiphiles caused late apoptosis. In addition, we studied the interactions of these amphiphiles with model membrane systems by Prodan-based hydration, DPH-based anisotropy, and differential scanning calorimetry. LCA-TMA1 is most hydrophobic with a hard charge causing efficient dehydration and maximum perturbations of membranes thereby facilitating translocation and high cytotoxicity against colon cancer cells. In contrast, the highly hydrated and multiple charged CA-TMA3 caused least membrane perturbations leading to low translocation and less cytotoxicity. As expected, Chenodeoxycholic acid and Deoxycholic acid based amphiphiles (CDCA-TMA2, DCA-TMA2) featuring two charged head groups showed intermediate behavior. Thus, we deciphered that charge, hydration, and hydrophobicity of these amphiphiles govern membrane interactions, translocation, and resulting cytoxicity against colon cancer cells.
- Singh, Manish,Singh, Ashima,Kundu, Somanath,Bansal, Sandhya,Bajaj, Avinash
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p. 1926 - 1937
(2013/07/11)
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- Anti-Diabetic Compounds
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The preset invention relates to a new oral anti-diabetic compound prepared by synthesizing a steroid and a guanide or biguanide, which is eliminated via the hepatic route, instead of the renal route, to avoid adverse effects of Metformin, such as renal dysfunction. A pharmaceutical composition comprising the compound of the invention and the method for treating diabetes using the compound are also provided.
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Paragraph 0051; 0052
(2013/07/31)
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- Novel approach to determining the absolute configurations at the C3-positions of various types of sterols based on an induced circular dichroism
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Circular dichroism (CD) spectra of the 2,2′-binaphthyl ester derived from Δ5-sterols showed not bisignate CD but diagnostic CD bands at around 210 and 240 nm. These bands might be attributable to an interaction between an olefinic chromophore and a binaphthyl one. Various types of unsaturated sterols were thus derivatized followed by complete hydrogenation, to give saturated sterols. As a result, CD spectra of the binaphthyl derivatives of the saturated sterols showed bisignate curves centered at 240 nm (3S(β): positive chirality; 3R(α): negative one). This suggested a straightforward and practical method for discriminating the absolute stereogenic center at the C-3 positions of sterols based on an induced CD. This finding should contribute significantly to the analysis of metabolites of various types of sterols.
- Fujiwara, Toshio,Taniguchi, Yuka,Katsumoto, Yukiteru,Tanaka, Takeyuki,Ozeki, Minoru,Iwasaki, Hiroki,Node, Manabu,Yamashita, Masayuki,Hosoi, Shinzo
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p. 1198 - 1204
(2012/11/07)
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