- Amide/Ester Cross-Coupling via C-N/C-H Bond Cleavage: Synthesis of β-Ketoesters
-
Activated primary, secondary, and tertiary amides were coupled with enolizable esters in the presence of LiHMDS to obtain good yields of β-ketoesters at room temperature. Notably, this protocol provides an efficient, mild, and high chemoselectivity method
- Chen, Jiajia,Joseph, Devaneyan,Xia, Yuanzhi,Lee, Sunwoo
-
p. 5943 - 5953
(2021/04/02)
-
- Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5
-
CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure-affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.
- Ortiz Zacarías, Natalia V.,Van Veldhoven, Jacobus P. D.,Den Hollander, Lisa S.,Dogan, Burak,Openy, Joseph,Hsiao, Ya-Yun,Lenselink, Eelke B.,Heitman, Laura H.,Ijzerman, Adriaan P.
-
p. 11035 - 11053
(2019/12/24)
-
- Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors
-
AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 μM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.
- Zheng, Xuehua,Jiang, Zan,Li, Xiaolin,Zhang, Chen,Li, Zhe,Wu, Yinuo,Wang, Xinhua,Zhang, Chao,Luo, Hai-bin,Xu, Jun,Wu, Deyan
-
supporting information
p. 5934 - 5943
(2018/11/23)
-
- Self-assembled squares and triangles by simultaneous hydrogen bonding and metal coordination
-
Through the combination of hydrogen bonding and metal-templated self-assembly, molecular squares and molecular triangles are observed in chloroform solution upon the complexation of hydrogen-bonded dimers of para-pyridyl-substituted 2-ureido-4-[1H]-pyrimi
- Marshall, Laura J.,De Mendoza, Javier
-
supporting information
p. 1548 - 1551
(2013/07/05)
-
- CHEMICAL COMPOUNDS
-
The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
- -
-
Page/Page column 132
(2010/11/04)
-
- Novel synthesis of methyl ketones based on the blaise reaction
-
A facile two-step synthesis of methyl ketones from alkyl nitriles via the Blaise conversion of nitriles into -keto esters and acid-mediated hydrolysis followed by decarboxylation of the resulting -keto esters is described. Copyright Taylor & Francis Group, LLC.
- Rao, H. Surya Prakash,Padmavathy,Vasantham,Rafi, Shaik
-
experimental part
p. 1825 - 1834
(2009/10/02)
-
- Synthesis of novel &β-lactone inhibitors of fatty acid synthase
-
Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a β-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the α- and β-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.
- Richardson, Robyn D.,Knowles, Lynn M.,Cieplak, Piotr,Smith, Jeffrey W.,Ma, Gil,Oyola, Yatsandra,Zancanella, Manuel,Romo, Daniel
-
scheme or table
p. 5285 - 5296
(2010/04/02)
-
- Isolation and crystal structures of both enol and keto tautomer intermediates in a hydration of an alkyne-carboxylic acid ester catalyzed by iridium complexes in water
-
Hydration of tetrolic acid ethyl ester as an alkyne-carboxylic acid ester catalyzed by an Ir-aqua complex [IrIIICp*(bpy)(OH 2)]2+ (1, Cp* = η5-C 5Me5, bpy = 2,2′-bipyridine) in water provides ethyl acetoacetate as a β-keto acid ester. We report the successful isolation of both an Ir-enol tautomer intermediate [IrIIICp*(bpy){CH 3C(OH)=CC(O)OC2H5}]+ (2) and an Ir-keto tautomer intermediate [IrIIICp*(bpy){CH 3C(O)-CHC(O)OC2H5}]+ (3) in the catalytic hydration by optimizing the conditions of the isolation, such as pH of the solution, reaction time, and selection of counteranions. The structures of the enol and keto complexes with characteristic Ir-(sp2carbon) bond and Ir-(sp3 carbon) bond, respectively, were unequivocally determined by X-ray analysis, IR, electrospray ionization mass spectrometry (ESI-MS), and NMR studies including 1H, 13C, distortionless enhancement by polarization transfer (DEPT) and correlation spectroscopy (COSY) experiments. It was confirmed that the hydration of tetrolic acid ethyl ester catalyzed by 2 or 3 as initial catalysts provides ethyl acetoacetate. Mechanism of the catalytic hydration of tetrolic acid ethyl ester as an alkyne-carboxylic acid ester is discussed based on isotopic labeling experiments with the Ir-enol and Ir-keto tautomers.
- Kanemitsu, Hironobu,Uehara, Keiji,Fukuzumi, Shunichi,Ogo, Seiji
-
supporting information; scheme or table
p. 17141 - 17147
(2009/04/13)
-
- Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors
-
The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.
- Lager, Erik,Nilsson, Jakob,stergaard Nielsen, Elsebet,Nielsen, Mogens,Liljefors, Tommy,Sterner, Olov
-
p. 6936 - 6948
(2008/12/21)
-
- Synthesis of 4-alkyl- and 4-(ω-chloroalkyl)-3-hydroxy-5- alkylidenebutenolides based on cyclizations of 4-alkyl- and 4-(ω- chloroalkyl)-1,3-bis(trimethylsilyloxy)buta-1,3-dienes with oxalyl chloride
-
4-Alkyl- and 4-(ω-chloroalkyl)-1,3-bis(trimethylsilyloxy)buta-1,3- dienes were prepared from ethyl acetoacetate in three steps. Their cyclization with oxalyl chloride allowed an efficient synthesis of 4-alkyl- and 4-(ω-chloroalkyl)-5-alkylidenebutenolides. Georg Thieme Verlag Stuttgart.
- Nguyen, Van Thi Hong,Bellur, Esen,Appel, Bettina,Langer, Peter
-
p. 2865 - 2872
(2008/02/07)
-
- Nitroalkanes and ethyl glyoxalate as common precursors for the preparation of both β-keto esters and α,β-unsaturated esters
-
β-Nitro acrylic esters, obtained by the reaction of nitroalkanes and ethyl glyoxalate, are the key building blocks for the immediate synthesis of both the title compounds. In fact, their treatment with titanium trichloride produce the direct conversion to the β-keto esters, while their reaction with sodium boron hydride gives the one-pot synthesis of α,β- unsaturated esters through formal substitution of the vinylic nitro group with an hydrogen.
- Ballini, Roberto,Fiorini, Dennis,Palmieri, Alessandro
-
p. 7027 - 7029
(2007/10/03)
-
- A general synthesis of dioxolenone prodrug moieties
-
A general method for the synthesis of dioxolenone prodrug moieties from appropriately substituted β-ketoesters is described. This novel and versatile sequence allows for the synthesis of alkyl- or aryl-substituted dioxolenone alcohols 8 or bromides 9. Coupling of the bromides 9 to prepare bis-dioxolenone phosphonate prodrug esters is also presented.
- Sun, Chong-Qing,Cheng, Peter T.W.,Stevenson, Jay,Dejneka, Tamara,Brown, Baerbel,Wang, Tammy C.,Robl, Jeffrey A.,Poss, Michael A.
-
p. 1161 - 1164
(2007/10/03)
-
- Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ET(A) receptor selectivity
-
Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity. Copyright (C) 1999 Elsevier Science Ltd.
- Boyd, Steven A.,Mantei, Robert A.,Tasker, Andrew S.,Liu, Gang,Sorensen, Bryan K.,Henry Jr., Kenneth J.,Von Geldern, Thomas W.,Winn, Martin,Wu-Wong, Jinshyun R.,Chiou, William J.,Dixon, Douglas B.,Hutchins, Charles W.,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.
-
p. 991 - 1002
(2007/10/03)
-
- N-SUBSTITUTED QUINOLINES
-
Novel N-substituted quinolines of the formula useful in the treatment of cardiovascular illnesses having an alteration in the vasomotricity and a process for their preparation.
- -
-
-
- Interaction of 1,4-dihydropyridine and pyridine derivatives with adenosine receptors: Selectivity for A3 receptors
-
1,4-Dihydropyridine and pyridine derivatives bound to three subtypes of adenosine receptors in the micromolar range. Affinity was determined in radioligand binding assays at rat brain A1 and A(2A) receptors using [3H]- (R)-PIA [[sup
- Van Rhee, A. Michiel,Jiang, Ji-Long,Melman, Neli,Olah, Mark E.,Stiles, Gary L.,Jacobson, Kenneth A.
-
p. 2980 - 2989
(2007/10/03)
-
- TRIAZOLOPYRIMIDINE DERIVATIVES WHICH ARE ANGIOTENSIN II RECEPTOR ANTAGONISTS, THEIR METHODS OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT
-
The present invention relates to the derivatives of the formula STR1 and their tautomeric forms, as well as their addition salts, and to their use in therapeutics, especially for the treatment and prevention of cardiovascular diseases and in particular for the treatment of hypertension, cardiac insufficiency and diseases of the arterial wall, especially atherosclerosis.
- -
-
-
- PYRAZOLOPYRIMIDINE DERIVATIVES WHICH ARE ANGIOTENSIN II RECEPTOR ANTAGONISTS
-
The present invention relates to the derivatives of the formula STR1 and their tautomeric forms, as well as their addition salts, and to their use in therapeutics, especially for the treatment and prevention of cardiovascular diseases and in particular for the treatment of hypertension, cardiac insufficiency and diseases of the arterial wall, especially atherosclerosis.
- -
-
-
- Intramolecular H-Transfer Reactions During the Decomposition of Alkylhydroperoxides in Hydrocarbons as the Solvents
-
Eight defined primary and secondary alkylhydroperoxides were decomposed in n-alkanes as the solvent, mostly in the presence of manganese stearate.In all cases the corresponding alcohols and carbonyl compounds were formed as the main products with yields of 60-90percent.Besides, difunctional products were formed by an intramolecular H-transfer in the alkoxy radicals corresponding to the starting hydroperoxides.Products possibly formed by an intramolecular H-transfer in the corresponding alkylperoxy radical could be found only in the case of 4-methyl-2-hydroperoxy pentane.The amount of products formed by intramolecular H-transfer depended on the nature of the C-H bond in δ-position to the original hydroperoxy group and lay between 4percent (primary C-H in the case of 4-hydroperoxy heptane) and 13percent (tertiary C-H in the case of 2-hydroperoxy-5-methyl hexane) with respect to the starting hydroperoxide.The amount of products formed by oxidative attack of the alkoxy and alkylperoxy radicals at the normal paraffins used as the solvents was unexpectedly low (always less than 10percent with respect to the starting hydroperoxide).An increment system is proposed for the calculation of 13C-nmr shifts in alkyl hydroperoxides.
- Jinsheng, Li,Pritzkow, Wilhelm,Voerckel, Volkmar
-
-
- Triazolopyrimidines which are angiotensin II receptor antagonists and pharmaceutical compositions in which they are present
-
The present invention relates to the derivatives of the formula STR1 and their tautomeric forms, as well as their addition salts, and to their use in therapeutics, especially for the treatment of cardiovascular diseases and in particular for the treatment of hypertension, cardiac insufficiency and diseases of the arterial wall.
- -
-
-
- SUBSTITUTED QUINOLINES AS ANGIOTENSIN II ANTAGONISTS
-
Substituted quinolines of the formula (I), are angiotensin II antagonists, STR1 and useful in the treatment of hypertension, ocular hypertension and certain CNS disorders.
- -
-
-
- Structure-Activity Relations. Part 12. Antibacterial Activity of a Series of 2,4-Diamino-6-substituted 5-(4-pyridylmethylamino)pyrimidines and 2,4-Diamino-5-(4-substituted benzylamino)pyrimidines.
-
A series of 6-substituted 2,4-diamino-5-(4-pyridylamino)pyrimidines and of 2,4-diamino-5-(4-substituted benzylamino)pyrimidines has been prepared.Their antibacterial activity towards L. casei, S. aureus and E. coli has been investigated.These activities have been successfully correlated by Hansch-type relations.Dependence on both lipophilicity and electronic (polar) factors has been found.The results are related to the structure and interactions with the receptor.
- Bowden, Keith,Bright, Andrew C.
-
p. 514 - 539
(2007/10/02)
-
- Highly Selective Heterogeneous Palladium-Catalyzed Hydrogenations Using Triethoxysilane and Water
-
Treatment of alkenes or alkynes at ambient temperature with triethoxysilane and 5 mol percent of palladium(II) acetate in a mixture of tetrahydrofuran and water affords the corresponding hydrogenated products.Excellent chemoselectivities and stereoselectivities can be abtained using this process.
- Tour, James M.,Cooper, Joel P.,Pendalwar, Shekhar L.
-
p. 3452 - 3453
(2007/10/02)
-
- Macrocyclic Lactone Formation through Sulfide Contraction. Synthesis of (+/-)-Diplodialide A
-
A methodology for the synthesis of macrocyclic β-keto-lactones from ω-hydroxy thioamides is described.The hydroxy thioamides were esterified with chloroacetyl chloride, and the resulting chloro esters underwent Eschenmoser sulfide contraction when treated with sodium iodide, diisopropylethylamine, and triethyl phosphite in acetonitrile.The β-keto lactones were obtained in 25-58 percent yield.The utility of the method was demonstrated by synthesis of diplodialide A.
- Ireland, Robert E.,Brown, Frank R.
-
p. 1868 - 1880
(2007/10/02)
-
