- Synthesis of Complex Stereoheptads en Route to Daphnane Diterpene Orthoesters
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Tricyclic cores of the daphnane diterpene orthoesters (DDOs) are synthesized in 10 steps from readily available materials. Key to their assembly is the development of a stereocontrolled p-quinol functionalization sequence which enables rapid access to DDO C-ring stereopolyads from simple precursors. Problems encountered in stereo- and regioselectivity are highlighted and solved by exact changes in choreography, although it is shown that the undesired stereochemical outcomes also proceed with high selectivity.
- Nguyen, Long V.,Beeler, Aaron B.
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Read Online
- 2-Bromo-5-hydroxybenzaldehyde
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The molecules of the title compound, C7H5BrO2, form zigzag chains running along the b axis and are stacked in layers perpendicular to the a axis. Intermolecular bonding occurs through hydrogen bonds linking the hydroxyl and carbonyl groups, with an O...O distance of 2.804 (4) A. The Br atom deviates significantly from the plane of the ring and the aldehyde group is twisted by 7.1 (5)° around the Csp2-Carylbond. The geometry of the molecule in the crystal is compared to that given by ab initio quantum mechanical calculations for the isolated molecule, using a molecular orbital Hartree-Fock method and density functional theory.
- Matos Beja,Paixao,Ramos Silva,Alte Da Veiga,Rocha Gonsalves,Serra
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Read Online
- Synthesis of new Zn (II) complexes for photo decomposition of organic dye pollutants, industrial wastewater and photo-oxidation of methyl arenes under visible-light
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Synthesis of new Schiff's base Zn-complexes for photo-oxidation of methyl arenes and xylenes are reported under visible light irradiation conditions. All the synthesized new ligands and Zn-complexes are thoroughly characterized with various spectral analyses and confirmed as 1:1 ratio of Zn and ligand with distorted octahedral structure. The bandgap energies of the ligands are higher than its Zn-complexes. These synthesized new Zn(II) complexes are used for the photo-fragmentation of organic dye pollutants, photodegradation of food industrial wastewater and oxidation of methyl arenes which are converted into its respective aldehydes with moderate yields under visible light irradiation. The photooxidation reaction dependency on the intensity of the visible light was also studied. With the increase in the dosage of photocatalyst, the methyl groups are oxidized to get aldehydes and mono acid products, which are also identified from LC-MS data. Finally, [Zn(PPMHT)Cl] is with better efficiency than [Zn(PTHMT)Cl] and [Zn(MIMHPT)Cl] for oxidation of methyl arenes is reported under visible-light-driven conditions.
- Ahemed, Jakeer,Bhongiri, Yadagiri,Chetti, Prabhakar,Gade, Ramesh,Kore, Ranjith,Pasha, Jakeer,Pola, Someshwar,Rao D, Venkateshwar
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- Optimization of Manganese Coupling Reaction for Kilogram-Scale Preparation of Two Aryl-1,3-dione Building Blocks
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Aryl-1,3-diones represent a promising new class of herbicidal acetyl-CoA carboxylase (ACCase) inhibitors. The original synthesis of this structural motif employed in the research phase involved a selenium oxide mediated oxidation, the use of diazoacetate and aryl lead reagents, and a low temperature oxidation of an aryl lithium intermediate, so it was not well suited to large scale synthesis. For kilogram scale synthesis of the two aryl-1,3-dione building blocks (3 and 4), we developed an alternative route which employs a manganese or manganese-copper catalyzed alkyl Grignard coupling and a semi-pinacol rearrangement of an epoxide as the key steps. The optimized conditions could be of general interest as scalable methods for the synthesis of 2-alkyl substituted benzaldehydes and of 2-aryl-1,3-diones.
- Smejkal, Tomas,Gopalsamuthiram, Vijayagopal,Ghorai, Sujit K.,Jawalekar, Anup M.,Pagar, Dinesh,Sawant, Krishna,Subramanian, Srinivas,Dallimore, Jonathan,Willetts, Nigel,Scutt, James N.,Whalley, Louisa,Hotson, Matthew,Hogan, Anne-Marie,Hodges, George
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p. 1625 - 1632
(2017/10/25)
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- GPBP INHIBITORS AND USES AND SCALEABLE SYNTHESIS THEREOF
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The present invention provides compounds and compositions thereof that inhibit Goodpasture antigen binding protein. Also disclosed is use of the compounds for the treatment various diseases and disorders, including invasive tumors, for the inhibition of mesenchymal phenotype after epithelial-to-mesenchymal transition (EMT), and for detecting EMT in a tissue. A method of preparing the compounds of the invention and related compounds is also provided.
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Page/Page column 44; 55; 100
(2017/12/27)
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 00976
(2017/08/01)
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- Exploring the Strength of the H-Bond in Synthetic Models for Heme Proteins: The Importance of the N?H Acidity of the Distal Base
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The distal hydrogen bond (H-bond) in dioxygen-binding proteins is crucial for the discrimination of O2with respect to CO or NO. We report the preparation and characterization of a series of ZnIIporphyrins, with one of three meso-phenyl rings bearing both an alkyl-tethered proximal imidazole ligand and a heterocyclic distal H-bond donor connected by a rigid acetylene spacer. Previously, we had validated the corresponding CoIIcomplexes as synthetic model systems for dioxygen-binding heme proteins and demonstrated the structural requirements for proper distal H-bonding to CoII-bound dioxygen. Here, we systematically vary the H-bond donor ability of the distal heterocycles, as predicted based on pKavalues. The H-bond in the dioxygen adducts of the CoIIporphyrins was directly measured by Q-band Davies-ENDOR spectroscopy. It was shown that the strength of the hyperfine coupling between the dioxygen radical and the distal H-atom increases with enhanced acidity of the H-bond donor.
- Alberti, Mariza N.,Polyhach, Yevhen,Tzirakis, Manolis D.,T?dtli, Laura,Jeschke, Gunnar,Diederich, Fran?ois
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supporting information
p. 10194 - 10202
(2016/07/19)
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- Rapid formation of a stable boron-nitrogen heterocycle in dilute, neutral aqueous solution for bioorthogonal coupling reactions
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Combining 2-formylphenylboronic acid with 4-hydrazinylbenzoic acid in neutral aqueous solution at low, equimolar concentrations of the reagents results in a single, stable product, a 1,2-dihydro-1-hydroxy-2,3,1-benzodiazaborine, in a matter of minutes with no side products. Application of this reaction to protein conjugation demonstrates that the reaction is orthogonal to protein functional groups, and the resulting conjugate withstands SDS-PAGE analysis. This reaction should be particularly useful for couplings that must be performed with low concentrations of reagents under physiologically compatible conditions.
- Dilek, Ozlem,Lei, Zhen,Mukherjee, Kamalika,Bane, Susan
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supporting information
p. 16992 - 16995
(2015/12/01)
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- Assessment of mycobacterium tuberculosis pantothenate kinase vulnerability through target knockdown and mechanistically diverse inhibitors
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Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by the coaA gene is an essential pantothenate kinase in Mycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-Activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-type M. tuberculosis strain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in a M. tuberculosis knockdown strain with reduced PanK expression levels. Additionally, in vitro and in vivo survival kinetic studies performed with a M. tuberculosis PanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK in M. tuberculosis.
- Reddy, B. K. Kishore,Landge, Sudhir,Ravishankar, Sudha,Patil, Vikas,Shinde, Vikas,Tantry, Subramanyam,Kale, Manoj,Raichurkar, Anandkumar,Menasinakai, Sreenivasaiah,Mudugal, Naina Vinay,Ambady, Anisha,Ghosh, Anirban,Tunduguru, Ragadeepthi,Kaur, Parvinder,Singh, Ragini,Kumar, Naveen,Bharath, Sowmya,Sundaram, Aishwarya,Bhat, Jyothi,Sambandamurthy, Vasan K.,Bj?rkelid, Christofer,Jones, T. Alwyn,Das, Kaveri,Bandodkar, Balachandra,Malolanarasimhan, Krishnan,Mukherjee, Kakoli,Ramachandran, Vasanthi
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p. 3312 - 3326
(2014/06/09)
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- IMPROVED PROCESS FOR THE PREPARATION OF TREPROSTINIL AND DERIVATIVES THEREOF
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An improved method for the preparation of treprostinil and its derivatives is described. In contrast to prior art, this method utilizes an easily scalable enzymatic resolution of a key intermediate for making these compounds. Another significant improvement of the described method over prior methods is the regioselective Claisen rearrangement of a 5-allyloxy-benzaldehyde precursor, which is facilitated by a bromo substituent in 2-position.
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Page/Page column 18
(2014/01/07)
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- Aromatic bromination of aldehydes and ketones using 1,3-di-n- butylimidazolium
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An environmentally benign and efficient process for the preparation of monobromo derivatives of aryl aldehydes and ketones was developed by simple and practical reactions of aryl aldehydes or ketones with 1,3-di-n-butylimidazolium tribromide ([BBIm]Br3), as a brominating reagent under solvent-free conditions in very high yields. The process has several advantages: high conversions, short reaction time, mild reaction conditions, simple workup with good to quantitative yields and re-usable ionic liquid.
- Borikar,Daniel
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experimental part
p. 531 - 536
(2012/07/01)
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- GPBP inhibition using Q2 peptidomimetics
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Disclosed are compounds of formula: that inhibiting GPBP activity, making them useful as therapeutics in antibody-mediated disorders, drug-resistant cancer, inflammation, protein misfolding and ER stress-mediated disorders, and aberrant apoptosis.
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Page/Page column 17
(2011/05/08)
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- Molecular design of small organic molecules based on structural information for a conformationally constrained peptide that binds to G-CSF receptor
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Based on structural information for a peptide (P8-2KAQ) that binds to granulocyte-colony stimulating factor receptor (G-CSFR), small ligands with a biaryl scaffold were designed and their binding affinities were evaluated.
- El-Haggar, Radwan,Kamikawa, Ken,Machi, Kazuya,Ye, Zhengmao,Ishino, Yuko,Tsumuraya, Takeshi,Fujii, Ikuo
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supporting information; experimental part
p. 1169 - 1172
(2010/06/15)
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- Facile p-toluenesulfonic acid-promoted para-selective monobromination and chlorination of phenol and analogues
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para-Regioselective bromination of phenol and analogues, promoted by p-toluenesulfonic acid, is achieved in high to excellent yields at room temperature with N-bromosuccinimide. Chlorination with N-chlorosuccinimide and catalysed by p-toluenesulfonic acid also gives para-chlorinated phenol analogues in good yields at room temperature. para-Bromination of phenol, promoted by p-toluenesulfonic acid, is achieved in excellent yields at room temperature with N-bromosuccinimide. p-Toluenesulfonic acid is also effective as a promoter of para-chlorination with N-chlorosuccinimide.
- Bovonsombat, Pakorn,Ali, Rameez,Khan, Chiraphorn,Leykajarakul, Juthamard,Pla-On, Kawin,Aphimanchindakul, Suraj,Pungcharoenpong, Natchapon,Timsuea, Nisit,Arunrat, Anchalee,Punpongjareorn, Napat
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experimental part
p. 6928 - 6935
(2010/10/01)
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- A novel simple and efficient bromination protocol for activated arenes
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An efficient, high yielding, and environmentally benign bromination using an alkali metal bromide as the bromine source is disclosed. Investigation of the protocol revealed that the method operates for activated arenes producing the corresponding monobrominated products in good to excellent yields.
- Tsoukala, Anna,Liguori, Lucia,Occhipinti, Giovanni,Bj?rsvik, Hans-Rene?
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supporting information; experimental part
p. 831 - 833
(2009/05/07)
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- An efficient, rapid, and regioselective bromination of anilines and phenols with 1-butyl-3-methylpyridinium tribromide as a new reagent/solvent under mild conditions
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1-Butyl-3-methylpyridinium tribromide, [BMPy]Br3 proves to be a highly efficient, regioselective reagent/solvent for nuclear bromination of various anilines and phenols. The synthesis and characterization of the room temperature ionic liquid [BMPy]Br3 (2) is described. The bromination was carried out in the absence of organic solvents and in most cases the only extraction solvent needed was water. The spent 1-butyl-3-methylpyridinium bromide (1) was easily recycled.
- Borikar, Sanjay P.,Daniel, Thomas,Paul, Vincent
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scheme or table
p. 1007 - 1009
(2009/05/11)
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- Synthesis of novel structurally simplified estrogen analogues with electron-donating groups in ring A
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A library of 25 novel estrogen analogues were prepared in five to eight steps from mostly commercially available substituted anisoles via bromination, formylation, Corey-Fuchs reaction, elimination, and Sonogashira reaction. Georg Thieme Verlag Stuttgart.
- Tietze, Lutz F.,Vock, Carsten A.,Krimmelbein, Ilga K.,Nacke, Linda
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experimental part
p. 2040 - 2060
(2009/12/27)
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- Total synthesis of bulbophylol-B
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The first total synthesis of bulbophylol-B (1) has been achieved with the longest linear sequence of 12 steps and an overall yield of 17.9% via a new and practical approach to construct the dihydrodibenz[b,f]oxepin skeleton employing Wittig, selective reduction, and intramolecular Ullmann reactions as key steps.
- Lin, Jinshun,Zhang, Weige,Jiang, Nan,Niu, Zeyu,Bao, Kai,Zhang, Liang,Liu, Dailin,Pan, Chao,Yao, Xinsheng
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experimental part
p. 1938 - 1941
(2009/09/25)
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- Regioselective aromatic electrophilic bromination with dioxane dibromide under solvent-free conditions
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Highly regioselective ring bromination of aromatic compounds has been accomplished with high yields and good purity using dioxane dibromide (DD) under solvent-free conditions. Notable features of this methodology include operational simplicity, rapid reactions, excellent control over the degree of bromination, and tolerance of various functional groups during the reaction. Copyright Taylor & Francis Group, LLC.
- Chaudhuri, Subrata Kumar,Roy, Sanchita,Saha,Bhar, Sanjay
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p. 581 - 585
(2007/10/03)
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- Synthesis of novel spinosyn a analogues by Pd-mediated transformations
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The concept of modern crop protection demands for a continuous supply of new or modified established pesticides to avoid the development of serious resistances. Recent reports on the insecticidal spinosyns 1 and 2 show that also this class of pest managing agents is increasingly exposed to the formation of resistances. The synthesis of new derivatives is therefore highly desirable. We describe in this paper a convergent approach towards novel enantiopure spinosyn A analogues of type 3, which is based on investigations of structure-activity relationships and employs a twofold Heck reaction as key step for the preparation of the tricyclic backbone assembly.
- Tietze, Lutz F.,Brasche, Gordon,Grube, Alexander,Boehnke, Niels,Stadler, Christian
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p. 8543 - 8563
(2008/04/01)
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- Synthesis and evaluation of aminomethyl dihydrocinnamates as a new class of PPAR ligands
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PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
- Warshawsky, Alan M.,Alt, Charles A.,Brozinick, Joseph T.,Harkness, Allen R.,Hawkins, Eric D.,Henry, James R.,Matthews, Donald P.,Miller, Anne R.,Misener, Elizabeth A.,Montrose-Rafizadeh, Chahrzad,Rhodes, Gary A.,Shen, Quanrong,Vance, Jennifer A.,Udodong, Uko E.,Wang, Minmin,Zhang, Tony Y.,Zink, Richard W.
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p. 6328 - 6333
(2007/10/03)
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- GLUCAGON RECEPTOR ANTAGONISTS, PREPARATION AND THERAPEUTIC USES
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The present invention discloses novel compounds of Formula I, or pharmaceutically acceptable salts thereof, which have glucagon receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I as well as methods of using them to treat diabetic and other glucagon related metabolic disorders, and the like.
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Page/Page column 46
(2010/02/15)
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- Rigid pyrrolidone modulators of pkc
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Compounds of the general formula (I): wherein substituents at R1, R2, R3 and R4 have any of the values defined in the specification, and their pharmaceutically acceptable salts, are PKC modulators and are useful for treating diseases, such as, for example, cancers including prostate cancer, inflammatory, autoimmune and neurological disorders including Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising compounds of formula (I), processes for preparing compounds of formula (I), and intermediates useful for preparing compounds of formula (I).
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Page/Page column Sheet 2
(2010/02/05)
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- Multi-kiloscale enantioselective synthesis of a vitronectin receptor antagonist
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The development of a novel, cost-effective synthesis of the vitronectin receptor antagonist SB-273005 became necessary as the compound proceeded to Phase 1. A practical synthesis of the compound presented challenges to the process chemist. Chief among the challenges was developing an enantioselective route to the compound. Second was either developing a scalable Mitsunobu coupling of the side chain to the main body or finding alternate chemistry. In this paper we will describe the chemistry we developed which allowed us to make over a hundred kilograms of SB-273005 by a process that we believe is suitable for even larger scale manufacturing.
- Wallace, Michael D.,McGuire, Michael A.,Yu, Marvin S.,Goldfinger, Lynn,Liu, Li,Dai, Wenning,Shilcrat, Susan
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p. 738 - 743
(2013/09/03)
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- PROCESS AND INTERMEDIATES FOR PREPARING BENZAZEPINES
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Disclosed is a new process and intermediates for preparing benzazepines of Formula wherein R1 and R2 are as defined herein.
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Page 26-27; 32
(2010/02/09)
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- Unforeseen formation of 2-bromo-3-hydroxybenzaldehyde by bromination of 3-hydroxybenzaldehyde
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Contrary to literature reports, bromination of 3-hydroxybenzaldehyde can afford both 2-bromo-5-hydroxybenzaldehyde and 2-bromo-3-hydroxybenzaldehyde, but 4-bromo-3-hydroxybenzaldehyde was not detected. 2-Bromo-3-hydroxybenzaldehyde was converted into 2-(benzyloxy)-1-bromo-5-methoxy-7-methylnaphthalene. X-ray crystallographic analysis supports the identity of 2-bromo-3- hydroxybenzaldehyde.
- Van Otterlo, Willem A. L.,Michael, Joseph P.,Fernandes, Manuel A.,De Koning, Charles B.
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p. 5091 - 5094
(2007/10/03)
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- Studies toward the total synthesis of mumbaistatin, a highly potent glucose-6-phosphate translocase inhibitor. Synthesis of a mumbaistatin analogue
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A strategy for the total synthesis of the highly potent glucose-6-phosphate translocase inhibitor mumbaistatin (1) and structural analogues was elaborated. Such compounds represent a lead structure in the development of potential new drugs for the treatment of diabetes. To evaluate the general strategy, the close mumbaistatin analogue 10 was synthesized in a convergent manner. The anthraquinone building block 20 was efficiently prepared via aryne/phthalide annulation. After conversion of 20 into the corresponding 9,10-dimethoxyanthracene-1-carbaldehyde derivative (13), coupling with a lithiated arene (12) and subsequent multiple oxidation under Jones conditions yielded the mumbaistatin analogue 10. The preparation of the functionalized arene intermediates was achieved exploiting highly regioselective bromination and ortho-lithiation reactions.
- Kaiser, Florian,Schwink, Lothar,Velder, Janna,Schmalz, Hans-Guenther
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p. 9248 - 9256
(2007/10/03)
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- Structure revision of medermycin/lactoquinomycin a and of related C-8 glycosylated naphthoquinones.
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[reaction: see text] On the basis of chemical and spectral data, the structure of the medermycin/lactoquinomycin A has been revised, which has also led to the revision of related C-glycosylated naphthoquinone antibiotics such as lactoquinomycin B, menoxymycins A and B, G15-F, and G15-G.
- Leo, Pierre-Marc,Morin, Christophe,Philouze, Christian
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p. 2711 - 2714
(2007/10/03)
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- Use of molecular weight-enlarged catalysts in a process for asymmetric, continous hydrogenation, novel molecular weight-enlarged ligands and catalysts
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The first embodiment of the present invention provides a process, which includes: in a continuous process in a membrane reactor, asymmetrically hydrogenating at least one C=C, C=N or C=O double bond with a catalyst. Another embodiment of the present invention provides a ligand, which includes at least one di-1,3-aminophosphine homochiral active center; optionally, a linker; and a molecular weight-enlarging polymer; wherein the active center is bound to the molecular weight-enlarging polymer through the linker or is bound directly to the molecular weight-enlarging polymer; and wherein the linker is defined in the claims. Another embodiment of the present invention provides a process for preparing the above-noted ligand, and a catalyst that includes the above-noted ligand.
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- Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth
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In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCδ, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCα or δ isozymes.
- Qiao, Lixin,Zhao, Lian-Yun,Rong, Suo-Bao,Wu, Xiong-Wu,Wang, Shaomeng,Fujii, Teruhiko,Kazanietz, Marcelo G,Rauser, Laura,Savage, Jason,Roth, Bryan L,Flippen-Anderson, Judith,Kozikowski, Alan P
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p. 955 - 959
(2007/10/03)
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- Binding and preliminary evaluation of 5-hydroxy- and 10-hydroxy- 2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as dopamine receptor ligands
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The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10- hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D1-like and D2-like subtypes. All compounds showed very low D1 affinities. This could be ascribed to the absence of a catechol nucleus or of the β-phenyldopamine pharmacophore. Only the N-methyl-5- hydroxy- (5a), N-methyl-10-hydroxy-(6a), and N-methyl-4-bromo-10-methoxy- 2,3,12,12a-tetrahydro-1H-[1]-benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D2 receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)-ethylamine moiety does not meet the requirements of the D2 agonist pharmacophore: namely, the 2-(3- hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D4 receptors, and only 5a showed low affinity for rat recombinant D3 receptors. Analysis of the influence of Na+ on [3H]spiperone binding showed that 5a displays a potential dopamine D2 agonist profile, whereas 6a probably has a dopamine D2 antagonist activity. The D2 agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells.
- Claudi, Francesco,Di Stefano, Antonio,Napolitani, Fabrizio,Cingolani, Gian Mario,Giorgioni, Gianfabio,Fontenla, Josè A.,Montenegro, Gisela Y.,Rivas, Maria E.,Rosa, Elizabeth,Michelotto, Barbara,Orlando, Giustino,Brunetti, Luigi
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p. 599 - 608
(2007/10/03)
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- Selective endothelin a receptor antagonists. 4. Discovery and structure- activity relationships of stilbene acid and alcohol derivatives
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This publication describes the synthesis and optimization of a novel series of stilbene endothelin antagonists. Analysis of the SAR established for previous papers in this series prompted the design and synthesis of (Z)- 4-phenyl-5-(3-benzyloxyphenyl)pent-4-enoic acid 3 which was found to be a moderately active inhibitor of the binding of [125I]ET-1 to ET(A) receptors with an IC50 of 6 μM. More interestingly, the intermediate compound (E)-2-phenyl-3-(3-benzyloxyphenyl)propenoic acid 5 was equiactive with 3. Optimization of 5 resulted in the preparation of (E)2-phenyl-3-(2- cyano-5-(thien-3-ylmethoxy))phenylpropenoic acid 18 (RPR111723) which had an IC50 in the binding assay of 80 nM on the ET(A) receptor and a pK(B) of 6.5 in the functional assay, measured on rat aortic strips. Reduction of the acid group of 5 gave the first nonacidic ET(A) antagonist in our series, (E)-2- phenyl-3-(3-benzyloxyphenoxy)prop2-enol 6 with an IC50 of 20 μM. Optimization of 6 resulted in the preparation of 2-(2-methylphenyl)-3-(2- cyano-5-(thien3-ylmethyl)phenyl)prop-2-enol 33 with an IC50 of 300 nM on the ET(A) receptor.
- Astles, Peter C.,Brown, Thomas J.,Halley, Frank,Handscombe, Caroline M.,Harris, Neil V.,McCarthy, Clive,McLay, Iain M.,Lockey, Peter,Majid, Tahir,Porter, Barry,Roach, Alan G.,Smith, Christopher,Walsh, Roger
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p. 2745 - 2753
(2007/10/03)
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- Bromination with Concomitant Debenzylation of Some Aromatic Aldehydes Containing Benzyloxy Substituents
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During the study of bromination of m-benzyloxybenzaldehyde with bromine in carbon tetrachloride at room temperature, it has been observed that besides bromination concomitant debenzylation also occurs.This being a novel observation, the study has been extended to 3-benzyloxy-4-methoxy-, 2-benzyloxy-3-methoxy-, 3,4-dibenzyloxy- and 4-benzyloxy-3-methoxy-benzaldehydes.In all but the last case, ready debenzylation with bromination occurs.Thus, the essential requirement for debenzylation is that the benzyl ether group should be either meta or ortho to the aldehydic function.The orientation of substituents in the reaction products has been determined by PMR and UV spectral studies.
- Natarajan, S.,Rajeswari, S.,Chandrasekaran, S.,Pai, B. R.,Shanmuganathan, Sp.,Rao, K. Usha
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