- Synthesis, inhibition properties against xanthine oxidase and molecular docking studies of dimethyl N-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate and (N-benzyl-1H-1,2,3-triazole-4,5-diyl)dimethanol derivatives
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This study focused on synthesis various dimethyl N-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate and (N-benzyl-1H-1,2,3-triazole-4,5-diyl)dimethanol derivatives under the conditions of green chemistry without the use of solvent and catalysts. Their inhibition properties were also investigated on xanthine oxidase (XO) activity. All dimethanol and dicarboxylate derivatives exhibited significant inhibition activities with IC50 values ranging from 0.71 to 2.25 μM. Especially, (1-(3-bromobenzyl)-1H-1,2,3-triazole-4,5-diyl)dimethanol (5c) and dimethyl 1-(4-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylate (6 g) compounds were found to be the most promising derivatives on the XO enzyme inhibition with IC50 values 0.71 and 0.73 μM, respectively. Moreover, the double docking procedure was to evaluate compound modes of inhibition and their interactions with the protein (XO) at atomic level. Surprisingly, the docking results showed a good correlation with IC50 [correlation coefficient (R2 = 0.7455)]. Also, the docking results exhibited that the 5c, 6f and 6 g have lowest docking scores ?4.790, ?4.755, and ?4.730, respectively. These data were in agreement with the IC50 values. These results give promising beginning stages to assist in the improvement of novel and powerful inhibitor against XO.
- Yagiz, Güler,Noma, Samir Abbas Ali,Altundas, Aliye,Al-khafaji, Khattab,Taskin-Tok, Tugba,Ates, Burhan
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- Stealth Fluorescence Labeling for Live Microscopy Imaging of mRNA Delivery
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Methods for tracking RNA inside living cells without perturbing their natural interactions and functions are critical within biology and, in particular, to facilitate studies of therapeutic RNA delivery. We present a stealth labeling approach that can efficiently, and with high fidelity, generate RNA transcripts, through enzymatic incorporation of the triphosphate of tCO, a fluorescent tricyclic cytosine analogue. We demonstrate this by incorporation of tCO in up to 100% of the natural cytosine positions of a 1.2 kb mRNA encoding for the histone H2B fused to GFP (H2B:GFP). Spectroscopic characterization of this mRNA shows that the incorporation rate of tCO is similar to cytosine, which allows for efficient labeling and controlled tuning of labeling ratios for different applications. Using live cell confocal microscopy and flow cytometry, we show that the tCO-labeled mRNA is efficiently translated into H2B:GFP inside human cells. Hence, we not only develop the use of fluorescent base analogue labeling of nucleic acids in live-cell microscopy but also, importantly, show that the resulting transcript is translated into the correct protein. Moreover, the spectral properties of our transcripts and their translation product allow for their straightforward, simultaneous visualization in live cells. Finally, we find that chemically transfected tCO-labeled RNA, unlike a state-of-the-art fluorescently labeled RNA, gives rise to expression of a similar amount of protein as its natural counterpart, hence representing a methodology for studying natural, unperturbed processing of mRNA used in RNA therapeutics and in vaccines, like the ones developed against SARS-CoV-2.
- Baladi, Tom,Nilsson, Jesper R.,Gallud, Audrey,Celauro, Emanuele,Gasse, Cécile,Levi-Acobas, Fabienne,Sarac, Ivo,Hollenstein, Marcel R.,Dahlén, Anders,Esbj?rner, Elin K.,Wilhelmsson, L. Marcus
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supporting information
p. 5413 - 5424
(2021/05/04)
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- Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
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The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
- Li, Yali,Huang, Taomin,Lou, Bin,Ye, Deyong,Qi, Xiangyu,Li, Xiaoxia,Hu, Shuang,Ding, Tingbo,Chen, Yan,Cao, Yang,Mo, Mingguang,Dong, Jibin,Wei, Min,Chu, Yong,Li, Huiti,Jiang, Xian-Cheng,Cheng, Nengneng,Zhou, Lu
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supporting information
p. 864 - 882
(2019/01/04)
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- Lewis Base Catalyzed Intramolecular Reduction of Salicylaldehydes by Pinacol-Derived Chlorohydrosilane
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A newly developed stable chlorohydrosilane derived from pinacol is herein described. This was successfully used in the reduction of salicylaldehydes in reasonable to excellent yields (51–97 %). The ability of the hydrosilane to react as a reducing agent is increased upon the in situ formation of a trialkoxyhydrosilane and activation with a Lewis base, as further indicated by density functional theory studies. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was identified to be a suitable catalyst for this metal-free reduction, promoting the regio- and chemoselective reduction of aldehydes in ortho-position to phenols, despite the presence of vicinal ketones. The performance of pinacol-derived chlorohydrosilane in the reduction of salicylaldehydes was further observed to be superior to that of well-established commercially available chlorohydrosilanes.
- Assoah, Benedicta,Vale, Jo?o R.,Kalenius, Elina,Veiros, Luis F.,Candeias, Nuno R.
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supporting information
p. 2910 - 2917
(2018/06/27)
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- Rhodium-Catalyzed Annulations of 1,3-Dienes and Salicylaldehydes/2-Hydroxybenzyl Alcohols Promoted by 2-Ethylacrolein
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A rhodium-catalyzed 2-ethylacrolein-promoted protocol enables the annulation reactions of 1,3-dienes with either salicylaldehydes or 2-hydroxybenzyl alcohols leading to 2-alkylchroman-4-ones with high regioselectivity. This research highlights the use of 2-ethylacrolein which probably serves as a tool of bidentate coordination to rhodium intermediates. Mechanistic studies reveal that the transformation proceeds through the 1,4-hydroacylation pathway to access unsaturated linear ketones with subsequent oxo-Michael addition. (Figure presented.).
- Li, Hong-Shuang,Xiong, Yang,Zhang, Guozhu
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supporting information
p. 4246 - 4251
(2018/10/02)
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- A BMS - 191011 synthetic method
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The invention relates to a synthetic method for a compound BMS-191011. The method comprises the following steps: taking 4-trifluoromethyl benzoyl hydrazine as a raw material and performing steps of oxidative carbonylation, methyl protection, halogenation, amination, deprotection and the like to prepare BMS-191011. The synthetic method adopts a CO balloon for replacing phosgene, so that the reaction toxicity is reduced and the reaction operability is improved. The method has the characteristics of simple and easily available raw materials, mild reaction conditions and simple operation process.
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Paragraph 0044; 0046
(2017/08/23)
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- AZAINDOLE DERIVATIVES AND THEIR USE AS ERK KINASE INHIBITORS
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The present invention concerns a compound of formula (I): or one of its pharmaceutically acceptable salts, especially for use as inhibitors of the kinase ERK activity in particular ERK2 activity.
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Paragraph 0449-0451
(2017/06/13)
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- 2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling
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A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3 μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data.
- Delogu, Giovanna L.,Matos, Maria J.,Fanti, Maura,Era, Benedetta,Medda, Rosaria,Pieroni, Enrico,Fais, Antonella,Kumar, Amit,Pintus, Francesca
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p. 2308 - 2313
(2016/04/20)
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- Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO2 system
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Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO2 system generates salicyl alcohols in 65-97% yields. A remarkable rate-enhancement by water was observed, and NaBO2 appeared to serve the dual role of a suitable base and an efficient chelating reagent. This protocol possesses many advantages such as short reaction times, expanded substrate scope, and high mono- and regio-selectivities. The experimental results were explained by the calculations based on local ionisation energy minima, leading to a possible reaction mechanism.
- Li, Hui-Jing,Wu, Ying-Ying,Wu, Qin-Xi,Wang, Rui,Dai, Chun-Yang,Shen, Zhi-Lun,Xie, Cheng-Long,Wu, Yan-Chao
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p. 3100 - 3107
(2014/05/06)
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- One-pot transition-metal-free synthesis of dibenzo[b,f]oxepins from 2-halobenzaldehydes
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A one-pot transition-metal-free, base-mediated synthesis of dibenzo[b,f]oxepins was developed. The reaction of 2-halobenzaldehydes with (2-hydroxyphenyl)acetonitriles proceeds via a sequential aldol condensation and intramolecular ether formation reaction in the presence of Cs2CO 3 and molecular sieves in toluene.
- Choi, Young Lok,Lim, Hye Sun,Lim, Hwan Jung,Heo, Jung-Nyoung
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supporting information
p. 5102 - 5105,4
(2012/12/12)
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- Biomimetic formation of 2-tropolones by dioxygenase-catalysed ring expansion of substituted 2,4-cyclohexadienones
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Substituted 2-tropolone natural products are found in plants and fungi. Their biosynthesis is thought to occur by ring expansion from a cyclohexadienone precursor, but this reaction has not previously been demonstrated experimentally. Treatment of 6-hydroxy-6-hydroxymethylcyclohexa-2,4-dienone with the non-haem iron(II)-dependent extradiol catechol dioxygenase MhpB from Escherichia coli results in the formation of the 2-tropolone ring-expansion product through a pinacol-type rearrangement. Three further substituted cyclohexa-2,4-dienone analogues were prepared, and treatment of each analogue was found to give the substituted 2-tropolone ring-expansion product. This ring expansion could also be effected nonenzymatically by treatment with 1,4,7-triazacyclononane and FeCl2. This is a novel transformation for non-haem iron-dependent enzymes, and this is the first experimental demonstration of the proposed ring-expansion reaction in tropolone biosynthesis.
- Xin, Meite,Bugg, Timothy D. H.
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experimental part
p. 272 - 276
(2010/10/21)
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- A convenient method to reduce hydroxyl-substituted aromatic carboxylic acid with NaBH4/Me2SO4/B(OMe)3
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The reduction of hydroxyl-substituted aromatic carboxylic acid with NaBH4/Me2SO4/B(OMe)3 is described. Borane is generated by the reaction of NaBH4 with Me2SO4 in THF, which is as efficient as the commercial one. B(OMe)3 has been successfully applied to increase the reactivity and selectivity of this reaction. The optimum ratio of borane/B(OMe)3/acid is studied, and a variety of hydroxyl-substituted aromatic acids are reduced in good yields.
- Zhou, Yuhan,Gao, Guchao,Li, Hui,Qu, Jingping
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p. 3260 - 3263
(2008/09/20)
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- Mechanism-based thrombin inhibitors: Design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative
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New 2-oxo-2H-1-benzopyran derivatives were prepared to optimize 2a,b, initially developed as mechanism-based α-chymotrypsin (α-CT) inhibitors, into potent and selective thrombin (THR) inhibitors. From this study, 22, characterized by a 2-(N-ethyl-2′-oxoacetamide)-5′- chlorophenyl ester side chain, was shown to be a good THR inhibitor (k i/KI = 3455 M-1·s-1), displaying an excellent selectivity profile against other serine proteases such as factor Xa, trypsin, and α-CT. Docking analysis of this compound into the different protein structures revealed the molecular basis responsible for its potency and selectivity.
- Frédérick, Rapha?l,Robert, Séverine,Charlier, Caroline,Wouters, Johan,Masereel, Bernard,Pochet, Lionel
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p. 3645 - 3650
(2008/02/09)
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- Substituents on quinone methides strongly modulate formation and stability of their nucleophilic adducts
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Electronic perturbation of quinone methides (QM) greatly influences their stability and in turn alters the kinetics and product profile of QM reaction with deoxynucleosides. Consistent with the electron-deficient nature of this reactive intermediate, electron-donating substituents are stabilizing and electron-withdrawing substituents are destabilizing. For example, a dC N3-QM adduct is made stable over the course of observation (7 days) by the presence of an electron-withdrawing ester group that inhibits QM regeneration. Conversely, a related adduct with an electron-donating methyl group is very labile and regenerates its QM with a half-life of approximately 5 h. The generality of these effects is demonstrated with a series of alternative quinone methide precursors (QMP) containing a variety of substituents attached at different positions with respect to the exocyclic methylene. The rates of nucleophilic addition to substituted QMs measured by laser flash photolysis similarly span 5 orders of magnitude with electron-rich species reacting most slowly and electron-deficient species reacting most quickly. The reversibility of QM reaction can now be predictably adjusted for any desired application.
- Weinert, Emily E.,Dondi, Ruggero,Colloredo-Melz, Stefano,Frankenfield, Kristen N.,Mitchell, Charles H.,Freccero, Mauro,Rokita, Steven E.
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p. 11940 - 11947
(2007/10/03)
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- Efficient Procedure for Preparing Salicyl Alcohols
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A new convenient procedure was developed for selective ortho-hydroxymethylation of phenols by reaction of paraformaldehyde with a mixture of phenol and orthoboric acid. The method is general for phenols containing no strong electron-withdrawing substituents; it allows preparation of o-hydroxybenzyl alcohols of high purity in a high yield.
- Belyanin,Filimonov,Krasnov
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p. 103 - 105
(2007/10/03)
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- Nucleotide Delivery from cycloSaligenyl-3′-azido-3′-deoxythymidine Monophosphates (cycloSal-AZTMP)
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The application of our cycloSaligenyl- (cycloSal) pronucleotide concept to the approved anti-HIV dideoxynucleoside 3′-azido-3′-deoxythymidine AZT (1) is reported. This pronucleotide concept has been designed to deliver the corresponding 3′-azido-3′-deoxythymidine monophosphate AZTMP (2) by selective chemical hydrolysis from the lipophilic precursors cycloSal-AZTMP 4a-h. All derivatives 4a-h were synthesized using differently substituted salicyl alcohols 7a-h as starting materials. In hydrolysis studies, compounds 4 decomposed selectively releasing AZTMP (2) and the salicyl alcohols 7 following the designed tandem reaction. Furthermore, due to the electronic properties introduced by substituents, the half-lives of the triesters 4 could be ajusted over a wide range. Phosphotriesters 4 exhibited considerable biological activity in HIV-1 and HIV-2 infected wild-type human T-lymphocyte (CEM/O) cells, whereas, contrary to our expectations, nearly all activity was lost in HIV-2 infected thymidine-kinase-deficient CEM cells.
- Meier, Chris,De Clercq, Eric,Balzarini, Jan
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p. 837 - 846
(2007/10/03)
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- Cyclo-saligenyl-2',3'-dideoxy-2',3' didehydroythymidinemonophosphate (cyclosal-d4TMP) - A new pro-nucleotide approach
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The synthesis of cycloSal-d4TMP 3a-g as new pro-nucleotide approach for d4TMP 2 is described. Phosphotriesters 3 release the d4TMP 2 selectively by a controlled, chemically induced tandem reaction. CycloSa1-phosphotriesters 3 exhibited high biological activity against HIV-1/HIV-2 in CEM cells which was completely retained in CEM TK- cells.
- Meier, Chris,Lorey, Martina,De Clercq, Eric,Balzarini, Jan
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p. 1303 - 1306
(2007/10/03)
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- As
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The synthesis of cycloSal-AZTMPs 3a-h as new pro-nucleotides of AZTMP 2 is described. Phosphotriesters 3 selectively release AZTMP 2 by a controlled, chemically induced tandem reaction. Cyc/oSal-AZTMPs 3 exhibited high biological activity in HIVl/HIV-2 infected CEM/O cells but lost their activity nearly completely in CEM/TK cells. Copyright
- Meier, Chris,De Clercq, Eric,Balzarini, Jan
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p. 793 - 796
(2007/10/03)
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- New synthesis and antitumor activity of cyclosalderivatives of 5-fluoro-2′-deoxyuridinemonophosphate
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An improved synthesis of 5′-cycloSal-FdUMP 3a-g and 3′,5′-bis-cycloSalFdUMP 9a-g as potential prodrugs of FdU 1 is described. In hydrolysis studies, phosphotriesters 3 released FdUMP 2 selectively by a tandem reaction. The biological activity of cycloSal-phosphotriesters 3 and 9 was evaluated in different cell lines. Copyright
- Lorey, Martina,Meier, Chris,De Clercq, Eric,Balzarini, Jan
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p. 789 - 792
(2007/10/03)
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- Cyclic saligenyl phosphotriesters of 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) - A new pro-nucleotide approach
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The synthesis of a new pro-nucleotide approach for d4TMP 2 based on cycloSal-4TMP 3a-d is described. Phosphotriesters 3 release d4TMP 2 selectively by a controlled, chemically induced tandem reaction. CycloSal-phosphotriesters 3 exhibited high biological activity against HIV-1/ HIV-2 in CEM cells which was retained in CEM TK- cells.
- Meier, Chris,Lorey, Martina,De Clercq,Balzarini, Jan
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- Cyclo-saligenyl-5-fluoro-2′-deoxyuridinemonophosphate (cycloSal-FdUMP), A new prodrug approach for fdump
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The synthesis of cycloSal-FdUMP 3a-d as a new prodrug approach for FdU 1 is described. Phosphotriesters 3 release the FdUMP 2 selectively by a controlled, chemically induced tandem reaction in hydrolysis studies. The biological activity (IC50) of cycloSal-phosphotriesters 3 was evaluated in FM3A/O cells and FM3A/TK- cells. Copyright
- Lorey, Martina,Meier, Chris,De Clercq, Eric,Balzarini, Jan
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p. 1307 - 1310
(2007/10/03)
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- 2-Nucleos-5'-O-yl-4H-1,3,2-benzodioxaphosphinin-2-oxide - ein neues Konzept fuer lipophile, potentielle Prodrugs biologisch aktiver Nucleosidmonophosphate
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Keywords: AIDS; Chemotherapie; Phosphotriester-Prodrugs; Prodrugs; Thymidinderivate
- Meier, Chris
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- Rational Design of Templates for Intramolecular O,N-Acyl Transfer via Medium-Sized Cyclic Intermediates Derived from L-Cysteine. Definition of an Experimental Maximum in Effective Molarity through the Study of "Tunable" Templates
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Rate constants and effective molarities for intramolecular O,N-acyl transfer have been measured for a series of unsymmetrical disulfides derived from cysteine and having the general structure H-Cys(S-XY-OAc)-OMe, for which XY is a rigid molecular spacing element that maintains a fixed OS distance lying in the range of 4.5-6.5 Angstroem.A synthetic route is described to 4-hydroxy-6-mercaptodibenzothiophene, involving lithiation of 4-methoxydibenzothiophene followed by reaction with elemental sulfur and positional isomer separation.A maximum effective molarity (EM) value of 5 M is seen for 4,6-disubstituted dibenzofuran function (OS = 5.45 Angstroem) while EM values of less than 0.1 M are seen for 4,6-disubstituted phenoxathiin and 4,6-disubstituted dibenzothiophene functions (OS = 3.90 and 6.30 Angstroem, respectively).Distance calculations and estimates of strain energy based on torsional and van der Waals terms are used to show that this result is consistent with a cyclic transition state containing one conformation of the cysteine framework.Energy minimization calculations were carried out by using a novel null-vector procedure for finding allowed torsional motions.They imply that the transition state for O,N-acyl transfer is strained by ca. 6 kcal/mol in the dibenzofuran case.
- Kemp, D. S.,Carey, Robert I.,Dewan, John C.,Galakatos, Nicholas G.,Kerkman, Daniel,Leung, See-Lap
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p. 1589 - 1603
(2007/10/02)
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- Enthalpies, Free Energies, and Entropies of Transfer of Phenols from Nonpolar Solvents to Water
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The enthalpies of transfer of seven phenols from 1-octanol to water and from toluene to water were determined by calorimetry.In the case of two phenols, whose rate of solution in water was found to be too slow for measurement by the usual heat of solution method, a new two-phase titration method was employed.The free energies of transfer between these solvents were determined by measuring the appropriate partition coefficients.The nature of the nonpolar solvent (toluene or 1-octanol) was found to cause large changes in the average values of the thermodynamic parameters of transfer into water, as well as changes in the ordering of the phenols in the series with respect to these transfer parameters.A curious correlation was observed between the octanol-water partition coefficients and the toluene -> water entropies of transfer.
- Haberfield, Paul,Kivuls, Juris,Haddad, Michael,Rizzo, Thomas
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p. 1913 - 1916
(2007/10/02)
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- Production of o-hydroxybenzyl alcohols
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A novel process for producing o-hydroxybenzyl alcohols useful as raw materials or intermediates in chemical or pharmaceutical industries, which comprises reacting phenols or naphthols with aromatic boronic acids and aldehydes in the presence of organic carboxylic acids, followed by degradation of the cyclic ester intermediates.
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