- Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites
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The Fujiwara-Moritani reaction has had a profound contribution in the emergence of contemporary C-H activation protocols. Despite the applicability of the traditional approach in different fields, the associated reactivity and regioselectivity issues had
- Ali, Wajid,Anjana, S. S.,Bhattacharya, Trisha,Chandrashekar, Hediyala B.,Goswami, Nupur,Guin, Srimanta,Maiti, Debabrata,Panda, Sanjib,Prakash, Gaurav,Saha, Argha,Sasmal, Sheuli,Sinha, Soumya Kumar
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supporting information
p. 1929 - 1940
(2022/02/01)
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- Solvent role in the lipase-catalysed esterification of cinnamic acid and derivatives. Optimisation of the biotransformation conditions
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The esterification of cinnamic acid has been deeply investigated using ethanol as nucleophile and Candida antarctica lipase type B (CAL-B) as suitable biocatalyst. Special attention has been paid to the role that the solvent plays in the production of ethyl cinnamate. Therefore, volatile organic solvents and deep eutectic mixtures were employed in order to find optimal reaction conditions. Once that hexane was selected as the solvent of choice, other parameters that affect the enzyme activity were investigated in order to produce ethyl cinnamate with excellent yield. The CAL-B loading, nucleophile equivalents, temperature and reaction time have been identified as key parameters in the enzyme efficiency, and the potential of lipase-catalysed esterification has been finally exploited to produce a series of ethyl esters with different pattern substitutions on the aromatic ring.
- Suárez-Escobedo, Laura,Gotor-Fernández, Vicente
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- Selective Synthesis of Z-Cinnamyl Ethers and Cinnamyl Alcohols through Visible Light-Promoted Photocatalytic E to Z Isomerization
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A photocatalytic E to Z isomerization of alkenes using an iridium photosensitizer under mild reaction conditions is disclosed. This method provides scalable and efficient access to Z-cinnamyl ether and allylic alcohol derivatives in high yields with excellent stereoselectivity. Importantly, this method also provides a powerful strategy for the selective synthesis of Z-magnolol and honokiol derivatives possessing potential biological activity.
- Li, Hengchao,Chen, Hang,Zhou, Yang,Huang, Jin,Yi, Jundan,Zhao, Hongcai,Wang, Wei,Jing, Linhai
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supporting information
p. 555 - 559
(2020/02/05)
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- Meta -Selective C-H functionalisation of aryl boronic acids directed by a MIDA-derived boronate ester
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N-Methyliminodiacetic acid (MIDA) boronates are boronic acid derivatives which are stable to reduction, oxidation and transmetalation. This has led to their widespread use as boronic acid protecting groups (PGs) and in iterative cross-couplings. We describe herein the development of a novel MIDA derivative that acts in a dual manner, as a protecting group and a directing group (DG) for meta C(sp2)-H functionalisation of arylboronic acids. Palladium catalysed C-H alkenylations, acetoxylations and arylations are possible, at room temperature and under aerobic conditions. Deprotection to reveal the functionalised boronic acids is rapid and allows for full recovery of the DG. The technique allows the facile diversification of aryl boronic acids and their subsequent use in a range of reactions or in iterative processes.
- Cordier, Christopher J.,Spivey, Alan C.,White, Andrew J. P.,Williams, Alexander F.
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p. 3301 - 3306
(2020/04/08)
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- Synthesis and Preclinical Evaluation of an 18F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [18F]SynVesT-2
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Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. In vivo imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, autism, epilepsy, stroke, traumatic brain injury, post-traumatic stress disorder, depression, etc. Herein, we report the synthesis and evaluation of a new 18F-labeled SV2A PET imaging probe, [18F]SynVesT-2, which possesses fast in vivo binding kinetics and high specific binding signals in non-human primate brain.
- Baum, Evan,Cai, Zhengxin,Carson, Richard E.,Finnema, Sjoerd J.,Holden, Daniel,Huang, Yiyun,Labaree, David C.,Li, Songye,Lin, Shu-Fei,Lindemann, Marcel,Nabulsi, Nabeel,Pracitto, Richard,Ropchan, Jim,Shirali, Anupama,Toyonaga, Takuya,Wu, Xiaoai,Zhang, Wenjie
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p. 592 - 603
(2020/03/06)
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- Synthesis of 5,6-dehydrokawain and some fluorinated analogues
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An efficient methodology for the synthesis of 6-styrenylpyrone in a four-step sequence is reported. The reactions were performed under catalyst-free conditions with mild and affordable reagents to produce 5,6-dehydrokawain and fluorinated derivatives in good to excellent overall yields (72–86%) on a multigram scale. Two novel difluorinated derivatives are reported here for the first time.
- Obi, Grace,Van Heerden, Fanie R.
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supporting information
p. 1482 - 1486
(2018/05/31)
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- Rh(III)-Catalyzed Enaminone-Directed C-H Coupling with α-Diazo-α-phosphonoacetate for Reactivity Discovery: Fluoride-Mediated Dephosphonation for C-C Coupling Reactions
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Rh(III)-catalyzed enaminone-directed C-H coupling with α-diazo-α-phosphonoacetate has been used for the identification of fluoride-mediated dephosphonation C-C coupling reactivity for the synthesis of 4-hydroxy-1-naphthoates. Intermolecular C-C coupling of α-phosphonoacetate and benzaldehyde for (E)-selective α,β-unsaturated ester synthesis has also been achieved.
- Song, Chao,Yang, Chen,Zeng, Hua,Zhang, Wenjing,Guo, Shan,Zhu, Jin
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supporting information
p. 3819 - 3823
(2018/07/22)
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- Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study
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A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile
- West, Thomas H.,Walden, Daniel M.,Taylor, James E.,Brueckner, Alexander C.,Johnston, Ryne C.,Cheong, Paul Ha-Yeon,Lloyd-Jones, Guy C.,Smith, Andrew D.
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supporting information
p. 4366 - 4375
(2017/04/04)
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- Piperlongumine derived cyclic sulfonamides (sultams): Synthesis and in?vitro exploration for therapeutic potential against HeLa cancer cell lines
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A novel modification of piperlongumine is designed, bearing a cyclic sulphonamide (sultam) and its synthesis is described. For the first time herein we report the synthesis and biological evaluation of the natural product derived cyclic sulfonamides using Grubbs second generation catalyst (Grubbs II) via ring closing metathesis approach. Synthesis of a series of piperlongumine derived sultams is done in a moderate to good yield using Wittig reaction, Ring-Closing Metathesis (RCM) and, amide synthesis by using mixed anhydride, approach. All synthesized compounds were evaluated for anticancer activity and some demonstrated dose dependent reduction in HeLa cell growth. Of these 7, 10 and 14 significantly reduced the cell growth. Consequently their calculated GI50values were found to be 0.1 or 0.1?μM.
- Lad, Nitin P.,Kulkarni, Sarang,Sharma, Rajiv,Mascarenhas, Malcolm,Kulkarni, Mahesh R.,Pandit, Shivaji S.
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p. 870 - 878
(2016/12/18)
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- 5,6-dihydropyrrolo[2,1-a]isoquinolines as alternative of new drugs with cytotoxic activity
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In this study, the pyrrolo[2,1-a]isoquinolines 4a–n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cyt
- Chávez-Santos, Rosa María,Torres-Ochoa, Rubén Omar,Ramírez-Apan, María Teresa,Martínez, Roberto,Reyes-Gutiérrez, Paul Eduardo
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p. 973 - 981
(2018/11/02)
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- Ligand-accelerated non-directed C-H functionalization of arenes
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The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.
- Wang, Peng,Verma, Pritha,Xia, Guoqin,Shi, Jun,Qiao, Jennifer X.,Tao, Shiwei,Cheng, Peter T. W.,Poss, Michael A.,Farmer, Marcus E.,Yeung, Kap-Sun,Yu, Jin-Quan
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p. 489 - 493
(2017/11/28)
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- Stereodivergent allylic substitutions with aryl acetic acid esters by synergistic iridium and lewis base catalysis
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The preparation of all possible stereoisomers of a given chiral molecule bearing multiple stereocenters by a simple and unified method is a significant challenge in asymmetric catalysis. We report stereodivergent allylic substitutions with aryl acetic acid esters catalyzed synergistically by a metallacyclic iridium complex and benzotetramisole. Through permutations of the enantiomers of the two chiral catalysts, all four stereoisomers of the products bearing two adjacent stereocenters are accessible with high diastereoselectivity and enantioselectivity. The resulting chiral activated ester products can be converted readily to enantioenriched amides, unactivated esters, and carboxylic acids in a onepot manner.
- Jiang, Xingyu,Beiger, Jason J.,Hartwig, John F.
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supporting information
p. 87 - 90
(2017/05/16)
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- Iridium-Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates
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Enantioselective allylic substitution with enolates derived from aliphatic esters under mild conditions remains challenging. Herein we report iridium-catalyzed enantioselective allylation reactions of silyl ketene acetals, the silicon enolates of esters, to form products containing a quaternary carbon atom at the nucleophile moiety and a tertiary carbon atom at the electrophile moiety. Under relatively neutral conditions, the allylated aliphatic esters were obtained with excellent regioselectivity and enantioselectivity. These products were readily converted into primary alcohols, carboxylic acids, amides, isocyanates, and carbamates, as well as tetrahydrofuran and γ-butyrolactone derivatives, without erosion of enantiomeric purity.
- Jiang, Xingyu,Hartwig, John F.
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supporting information
p. 8887 - 8891
(2017/07/17)
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- Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection
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A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure-activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4-28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa Mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure-activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly.
- Zhou, Kun,Chen, Dongdong,Li, Bin,Zhang, Bingyu,Miao, Fang,Zhou, Le
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- Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides
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The in situ reduction of ferrocenyl cyclopropylimines to the corresponding amines triggers a facile oxidative ring-opening to yield the formal four-electron oxidation products: N-ferrocenylmethyl β-hydroxyamides. This process is believed to proceed via generation of a ferrocinium ion in the presence of air, leading to facile formation of a distonic radical cation that is ultimately trapped by oxygen.
- Gee, Yi Sing,Goertz, Neils J. M.,Gardiner, Michael G.,Hyland, Christopher J. T.
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supporting information
p. 2498 - 2503
(2016/03/01)
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- HETEROCYCLIC AMIDES AS KINASE INHIBITORS
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Disclosed are compounds having the formula: (I) wherein R1, R2, and R3 are as defined herein, and methods of making and using the same.
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Page/Page column 86
(2016/12/07)
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- Quantitative Structure-Property Relationship (QSPR) models for a local quantum descriptor: Investigation of the 4- and 3-substituted-cinnamic acid esterification
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In this work, the theoretical description of the 4- and 3-substituted-cinnamic acid esterification with different electron donating and electron withdrawing groups was performed at the B3LYP and M06-2X levels, as a two-step process: the O-protonation and the nucleophile attack by ethanol. In parallel, an experimental work devoted to the synthesis and characterization of the substituted-cinnamate esters has also been performed. In order to quantify the substituents effects, quantitative structure-property relationship (QSPR) models based on the atomic charges, Fukui functions and the Frontier Effective-for-Reaction Molecular Orbitals (FERMO) energies were investigated. In fact, the Fukui functions, f+C and f-O, indicated poor correlations for each individual step, and in contrast with the general literature, the O-protonation step is affected both by the FERMO energies and the O-charges of the carbonyl group. Since the process was shown to not be totally described by either charge- or frontier-orbitals, it is proposed to be frontier-charge-miscere controlled. Moreover, the observed trend for the experimental reaction yields suggests that the electron withdrawing groups favor the reaction and the same was observed for Step 2, which can thus be pointed out as the determining step.
- Rodrigues-Santos, Cláudio E.,Echevarria, Aurea,Sant'Anna, Carlos M.R.,Bitencourt, Thiago B.,Nascimento, Maria G.,Bauerfeldt, Glauco F.
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supporting information
p. 17493 - 17510
(2015/12/01)
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- A Simple and Efficient Access to Naphtho[b]furans by Claisen Rearrangement/Cyclization of Bromonaphthyl 3-Phenylallyl Ethers
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A transition-metal-free Claisen rearrangement/cyclization reaction was developed for the synthesis of naphthofuran derivatives from bromonaphthyl 3-phenylallyl ethers. The nature of the base employed in this reaction plays an important role in determining the ratio for the formation of naphthofuran and naphthol products. By using K2CO3 as base and DMF as solvent, we have synthesized a variety of functionalized naphthofurans in good to high yields (49-92 %) and with satisfactory selectivities.
- Wang, Wei,Huang, Jin,Zhou, Rong,Jiang, Zhi-Jie,Fu, Hai-Yan,Zheng, Xue-Li,Chen, Hua,Li, Rui-Xiang
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supporting information
p. 2442 - 2446
(2015/08/18)
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- 2-Hydroxy-1,10-phenanthroline vs 1,10-Phenanthroline: Significant ligand acceleration effects in the Palladium-Catalyzed Oxidative Heck reaction of arenes
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A series of bidentate monoanionic nitrogen ligands were designed and applied in the Pd-catalyzed oxidative Heck reaction of arenes with alkenes. Significant ligand-accelerated effects were observed, and direct C-H functionalized products were formed in high yields with meta-selectivity.
- Ying, Cheng-Hao,Yan, Shao-Bai,Duan, Wei-Liang
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supporting information
p. 500 - 503
(2014/04/03)
-
- Discovery of heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands with single-digit nanomolar potency: Opening avenues towards the first SV2A positron emission tomography (PET) ligands
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The role of the synaptic vesicle protein 2A (SV2A) protein, target of the antiepileptic drug levetiracetam, is still mostly unknown. Considering its potential to provide in vivo functional insights into the role of SV2A in epileptic patients, the development of an SV2A positron emission tomography (PET) tracer has been undertaken. Using a 3D pharmacophore model based on close analogues of levetiracetam, we report the rationale design of three heterocyclic non-acetamide lead compounds, UCB-A, UCB-H and UCB-J, the first single-digit nanomolar SV2A ligands with suitable properties for development as PET tracers. Avenues towards imaging... of synaptic vesicle protein 2A (SV2A) in vivo were opened after the rationale discovery of the first non-acetamide SV2A ligands, displaying single-digit nanomolar potency, using a 3D pharmacophore model. An extensive profiling of the most potent compounds allowed the identification of three leads (see figure) as potential candidates for positron emission tomography (PET) ligand development.
- Mercier, Joel,Archen, Laurence,Bollu, Veronique,Carre, Stephane,Evrard, Yves,Jnoff, Eric,Kenda, Benoit,Lallemand, Benedicte,Michel, Philippe,Montel, Florian,Moureau, Florence,Price, Nathalie,Quesnel, Yannick,Sauvage, Xavier,Valade, Anne,Provins, Laurent
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p. 693 - 698
(2014/05/06)
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- Controlled mono- and double-Heck reaction catalyzed by a dicarbene dipalladium complex
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The phosphine-free mono- and double-Heck reaction of terminal olefins with electron-deficient and electron-rich aryl halides (iodides and bromides) is described. These reactions are catalyzed by the dicarbene dipalladium complex 1 by controlling the stoichiometry of the aryl halide and the olefine, the loading of the palladium catalyst, as well as using different base, and with or without additive. The procedure of double-Heck reaction allows β,β- diarylation and β,β′-diarylation of terminal olefins and affords trisubstituted olefins in good to excellent yields.
- Li, Yunfei,Liu, Gang,Cao, Changsheng,Wang, Shuzhan,Li, Yuling,Pang, Guangsheng,Shi, Yanhui
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p. 6241 - 6250
(2013/07/27)
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- Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging
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SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood-brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of th
- Fabio, Karine,Guillon, Christophe,Lacey, Carl J.,Lu, Shi-Fang,Heindel, Ned D.,Ferris, Craig F.,Placzek, Michael,Jones, Graham,Brownstein, Michael J.,Simon, Neal G.
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experimental part
p. 1337 - 1345
(2012/03/26)
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- A two-step ball milling method synthesizes and purifies α,β-unsaturated esters
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Over the last decade, solvent-free methods have been gaining interest as replacements for traditional organic chemistry techniques. While solvent-free methods are well known for many processes, a simple, solvent-free purification procedure that supplements them does not exist. We report the solvent-free synthesis of α,β-unsaturated esters using a solvent-free Horner-Wadsworth-Emmons (HWE) reaction using high-speed ball milling (HSBM). We were able to perform the HWE reaction on a variety of aldehydes, and isolate their respective a,b-unsaturated esters in high yields, purities, and diastereoselectivities. The Royal Society of Chemistry.
- Shearouse, William C.,Korte, Chelsea M.,Mack, James
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experimental part
p. 598 - 601
(2011/05/08)
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- GSK-3BETA INHIBITOR
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For the purpose of providing a GSK-3β inhibitor containing a 2-aminopyridine compound or a salt thereof or a prodrug thereof useful as an agent for the prophylaxis or treatment of a GSK-3β-related pathology or disease, the present invention provides a GSK-3β inhibitor containing a compound represented by the formula (IA): wherein each symbol is as defined in the specification. or a salt thereof or a prodrug thereof.
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Page/Page column 27
(2011/04/13)
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- Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier
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By employing pharmacophore-based design and the privileged fragments reassembly, a series of piperidine-/tropane-/piperazine-bridged CCR5 antagonists were designed and synthesized via an efficient convergent synthesis strategy, with focus on the optimal choice of the basic center carrier structure. Significantly, the 4-amino-4-methylpiperidine bridged 1-acyl-1,3-propanediamine compounds were identified as a new class of nanomolar CCR5 antagonists, providing an efficient approach and novel scaffolds for further development of potent CCR5 inhibitors.
- Fan, Xing,Zhang, Hu-Shan,Chen, Li,Long, Ya-Qiu
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experimental part
p. 2827 - 2840
(2010/08/22)
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- Sodium 2-(2-pyridin-3-ylethylamino)sulfonate: an efficient ligand and base for palladium-catalyzed Heck reaction in aqueous media
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The first successful Pd(OAc)2, N-donor ligand and base mediated Heck coupling reaction of aryl halides and alkenes in water is described. The corresponding Heck products were obtained in good to excellent yields.
- Pawar, Shivaji S.,Dekhane, Deepak V.,Shingare, Murlidhar S.,Thore, Shivaji N.
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p. 4252 - 4255
(2008/09/21)
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- Synthesis of catechins via thiourea/AuCl3-catalyzed cycloalkylation of aryl epoxides
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(Chemical Equation Presented) A diversity-oriented approach for the synthesis of structurally diverse catechins was achieved in good yields via thiourea/AuCl3/AgOTf-catalyzed annulations of aryl epoxides under mild conditions. This new protocol provides a highly efficient entry to a library of catechins-derived natural products, notably anti-HIV agent 8-C-ascorbyl-(-)-epigallocatechin.
- Liu, Yongxiang,Li, Xiben,Lin, Guang,Xiang, Zheng,Xiang, Jing,Zhao, Mingzhe,Chen, Jiahua,Yang, Zhen
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p. 4625 - 4629
(2008/09/20)
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- Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators
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The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).
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Page/Page column 15
(2008/06/13)
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- Bicyclic amide derivatives and their use as muscle relaxants
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Novel compounds of formula (1) together with their salts and solvates have a number of uses in medicine, in particular as central muscle relaxants.
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- Bicyclic amide derivatives and their use as muscle relaxants
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Novel compounds of formula (I) STR1 wherein R1, R2, R3 and R4 are each selected from hydrogen and fluoro and at least one and not more than two is fluoro; R5 is selected from hydrogen and C1 -C4 alkyl; R6 is selected from hydrogen, C1 -C4 ally and hydroxy; or R5 and R6 together with the ring carbon form a carbonyl group; R7 is selected from hydrogen and hydroxy, R8 and R9 are each selected from hydrogen, C1 -C4 alkyl and cyclo(C3 or C4) alkyl or together with the nitrogen form a morpholino group; and X is selected from a bond, methylene and --O-- and is always a bond or --O-- when any of R5, R6 and R7 is other than hydrogen and is always a bond when R5 and R6 together with the ring carbon form a carbonyl group; and their salts and solvates have a number of uses as central muscle relaxants. In particular, treatment of conditions associated with abnormally raised skeletal muscle tone. They are of special value in the relaxation of skeletal muscle in spastic, hypertonic and hyperkinetic conditions.
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- Inhibition of uridine phosphorylase: Synthesis and structure-activity relationships of aryl-substituted 5-benzyluracils and 1-[(2- hydroxyethoxy)methyl]-5-benzyluracils
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A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesized and tested for inhibition of murine liver uridine phosphorylase (UrdPase). Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine- induced anemia in animal models. We prepared a series of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a good inhibitor of UrdPase (IC50 of 0.46 μM), to develop a compound with enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substituted 5-benzyluracils found several 5-(3- alkoxybenzyl) analogues of 5-benzyluracil with enhanced potency. The acyclovir side chain, the (2-hydroxyethoxy)methyl group, was substituted on the more potent aryl-substituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC50s of 0.047 and 0.027 μM, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in rats. Plasma uridine levels were elevated 3-9-fold by compound levels that ranged from 8 to 50 μM.
- Orr,Musso,Boswell,Kelley,Joyner,Davis,Baccanari
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p. 3850 - 3856
(2007/10/02)
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