- Regioselective β-Csp3-Arylation of β-Alanine: An Approach for the Exclusive Synthesis of Diverse β-Aryl-β-amino Acids
-
An approach for the synthesis of a variety of new β-aryl-β-amino acids has been developed via a palladium-catalyzed auxiliary-directed regioselective Csp3-H arylation of the unactivated β-methylene bond of β-alanine. The use of 8-aminoquinoline amide as an auxiliary efficiently directs the desired regioselective β-Csp3-H functionalization. The developed protocol enables the easy and straightforward access to several high-value β-aryl-β-amino acids useful for peptide engineering, starting from inexpensive and readily available β-alanine precursors in moderate to excellent yields.
- Chowdhury, Sushobhan,Vaishnav, Roopal,Panwar, Namita,Haq, Wahajul
-
-
Read Online
- Perfluorinated markers for hypoxia detection: Synthesis of sulfur-containing precursors and [18F]-labelling
-
Synthetic pathways of two novel sulfurated precursors for [ 18F]-labelling by oxidative fluorodesulfurization reaction are described. A three-step sequence starting from N-phthalimido-β-alanine allows the preparation of a new trithioorthoester as valuable precursor of the synthesis of [18F]-3,3,3-trifluoropropylamine, a convenient radiolabelled intermediate for [18F]-EF3. A five-step sequence for the preparation of methyl 4-phthalimido-2,2-difluoropropanedithioate from ethyl 2,2-difluoropropanoate, via the key conversion step of α,α′- difluorothioamidate to the corresponding α,α′- difluorodithioester, and the first results of its use as precursor for oxidative fluorodesulfurization in [18F]-radiochemistry are also presented.
- Cheguillaume, Arnaud,Gillart, Jacques,Labar, Daniel,Gregoire, Vincent,Marchand-Brynaert, Jacqueline
-
-
Read Online
- Stereoselective sulfoxide formation from a thioproline derivative
-
Oxidation of the PEP inhibitor, thioprolylpyrrolidine derivative 3 affords a mixture of the two possible trans- and cis-sulfoxide isomers 4 and 5. 3-Chloroperbenzoic acid oxidation resulted almost exclusive formation of the trans-isomer (α-sulfoxide, 4, d.e. >99% in CHCl3), whereas when NaIO4 was used the cis isomer (β-sulfoxide, 5) was also obtained, the ratio of the isomers varying with the reaction conditions applied. The structures of the separated isomers 4 and 5 were assigned on the basis of the aromatic solvent-induced shifts (ASIS) in the NMR spectra.
- Kanai, Karoly,Podanyi, Benjamin,Bokotey, Sandor,Hajdu, Felix,Hermecz, Istvan
-
-
Read Online
- Synthesis of N-trifluoromethyl amides from carboxylic acids
-
Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formed derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.
- Flavell, Robert R.,Liu, Jianbo,Parker, Matthew F. L.,Toste, F. Dean,Wang, Sinan,Wilson, David M.
-
supporting information
p. 2245 - 2255
(2021/08/12)
-
- Quinazolinyl carboxylic ester derivative containing isoindolone group and application thereof
-
The invention discloses a quinazolinyl carboxylic ester derivative containing an isoindolone group, and the derivative has a structural general formula shown as the specification, wherein R is aryl substituted alkyl, aryl substituted cyclolky or biaryl. According to the invention, the novel isoindolone group-containing quinazolinyl carboxylic ester derivative is synthesized, can effectively inhibit the growth of antibiotic-sensitive or drug-resistant bacteria, and has a new action mechanism.
- -
-
Paragraph 0056-0058; 0062-0064
(2021/01/04)
-
- Binuclear Pd(I)-Pd(I) Catalysis Assisted by Iodide Ligands for Selective Hydroformylation of Alkenes and Alkynes
-
Since its discovery in 1938, hydroformylation has been thoroughly investigated and broadly applied in industry (>107 metric ton yearly). However, the ability to precisely control its regioselectivity with well-established Rh- or Co-catalysts has thus far proven elusive, thereby limiting access to many synthetically valuable aldehydes. Pd-catalysts represent an appealing alternative, yet their use remains sparse due to undesired side-processes. Here, we report a highly selective and exceptionally active catalyst system that is driven by a novel activation strategy and features a unique Pd(I)-Pd(I) mechanism, involving an iodide-assisted binuclear step to release the product. This method enables β-selective hydroformylation of a large range of alkenes and alkynes, including sensitive starting materials. Its utility is demonstrated in the synthesis of antiobesity drug Rimonabant and anti-HIV agent PNU-32945. In a broader context, the new mechanistic understanding enables the development of other carbonylation reactions of high importance to chemical industry.
- Zhang, Yang,Torker, Sebastian,Sigrist, Michel,Bregovi?, Nikola,Dydio, Pawe?
-
supporting information
p. 18251 - 18265
(2020/11/02)
-
- A Convenient One-Pot Synthesis of 1,5-Disubstituted Tetrazoles Containing an Amino or a Carboxy Group
-
Abstract: A convenient method is proposed for constructing the tetrazole ring by a one-pot reaction of amides with phosphorus oxychloride and sodium azide. A series of 1,5-disubstituted tetrazoles containing an amino or a carboxy group, which present interest as buildings blocks for the synthesis of biologically active substances, were obtained.
- Obushak, M. D.,Pokhodylo, N. T.,Shyyka, O. Ya.
-
p. 802 - 812
(2020/07/03)
-
- A chemically contiguous hapten approach for a heroin-fentanyl vaccine
-
Background: Increased death due to the opioid epidemic in the United States has necessitated the development of new strategies to treat addiction. Monoclonal antibodies and antidrug vaccines provide a tool that both aids addiction management and reduces the potential for overdose. Dual drug vaccines formulated by successive conjugation or by mixture have certain drawbacks. The current study examines an approach for combatting the dangers of fentanyl-laced heroin, by using a hapten with one epitope that has domains for both fentanyl and heroin. Results: We evaluated a series of nine vaccines developed from chemically contiguous haptens composed of both heroin- and fentanyl-like domains. Analysis of the results obtained by SPR and ELISA revealed trends in antibody affinity and titers for heroin and fentanyl based on epitope size and linker location. In antinociception studies, the best performing vaccines offered comparable protection against heroin as our benchmark heroin vaccine, but exhibited attenuated protection against fentanyl compared to our fentanyl vaccine. Conclusion: After thorough investigation of this strategy, we have identified key considerations for the development of a chemically contiguous heroin-fentanyl vaccine. Importantly, this is the first report of such a strategy in the opioid-drug-vaccine field.
- Natori, Yoshihiro,Hwang, Candy S.,Lin, Lucy,Smith, Lauren C.,Zhou, Bin,Janda, Kim D.
-
supporting information
p. 1020 - 1031
(2019/06/08)
-
- Rh(III)-Catalyzed C-H Amidation of Arenes with N-Methoxyamide as an Amidating Reagent
-
The Rh(III)-catalyzed amidation of C(sp2)-H bonds has been reported by employing the N-methoxyamide as a novel amino source. An excellent level of functional group tolerance can be achieved when N-methoxyamide derivatives are used as the amidating reagents. Importantly, several known bioactive compounds such as Aminalon, Pregabalin, Gabapentin, and Probenecid can be transformed to effective amidating reagents, as a way to facilitate the development of new bioactive molecules.
- Ju, Guodong,Li, Guobao,Qian, Guanwen,Zhang, Jingyu,Zhao, Yingsheng
-
supporting information
p. 7333 - 7336
(2019/10/08)
-
- A Direct Approach to Decoration of Bioactive Compounds via C-H Amination Reaction
-
The development of new methods to achieve the direct synthesis of bioactive organic molecules is always an important topic in organic synthesis. We hereby demonstrate that N-methoxyamide is an excellent amino source in the iridium-catalyzed intermolecular C-H amination reaction. The linkage of two bioactive organic molecules can be well achieved with this new protocol. More than 20 examples of decorated bioactive compounds were reported, which can facilitate the discovery of new bioactive molecules.
- Ju, Guodong,Yuan, Chunchen,Wang, Dongjie,Zhang, Jingyu,Zhao, Yingsheng
-
supporting information
p. 9852 - 9855
(2019/12/24)
-
- Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis
-
Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
- Savino, Salvatore,Toscano, Annamaria,Purgatorio, Rosa,Profilo, Emanuela,Laghezza, Antonio,Tortorella, Paolo,Angelelli, Mariacristina,Cellamarea, Saverio,Scala, Rosa,Tricarico, Domenico,Thomas Marobbio, Carlo Marya,Perna, Filippo,Vitale, Paola,Agamennone, Mariangela,Dimiccoli, Vincenzo,Tolomeo, Anna,Scilimati, Antonio
-
p. 184 - 200
(2018/09/18)
-
- ω-Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase
-
Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure–activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (Ki) of 1–19 μm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases—monoacylglycerol lipase and fatty acid amide hydrolase—were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.
- Dato, Florian M.,Sheikh, Miriam,Uhl, Rocky Z.,Schüller, Alexandra W.,Steinkrüger, Michaela,Koch, Peter,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
-
p. 1833 - 1847
(2018/09/10)
-
- Synthesis method of cosmetic dipeptide
-
The invention discloses a synthesis method of cosmetic dipeptide and belongs to the technical field of polypeptide synthesis. The synthesis method comprises the following steps: protecting alanine byphthalic anhydride to prepare phthaloyl-protected alanine; then reacting with an acyl chlorination reagent to generate a corresponding acyl chloride product; enabling histamine and hexamethyldisilazane to react to obtain a silane protection object of histamine; then reacting with the acyl chloride product to obtain phthaloyl-protected dipeptide; finally, carrying out deprotection under a specificcondition to obtain the cosmetic dipeptide, wherein the cosmetic dipeptide is decarboxycarnosine. The synthesis method provided by the invention does not utilize a condensing agent and has the advantages of cheap and easy-to-obtain raw materials, few byproducts and high yield (the total yield is 78.6 to 86.4 percent); the dipeptide with high purity (the purity is higher than 99 percent) is easy toobtain; the cost is reduced and the synthesis method is suitable for large-batch production.
- -
-
Paragraph 0029; 0030; 0034; 0035
(2019/01/10)
-
- COMPOUNDS, COMPOSITIONS, AND METHODS FOR INCREASING CFTR ACTIVITY
-
The invention encompasses compounds such as compounds having the Formula (I) or (II), compositions thereof, and methods of modulating CFTR activity. The invention also encompasses methods of treating a condition associated with CFTR activity or condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound.
- -
-
Paragraph 0131
(2017/01/23)
-
- HETEROARYL PYRIDONE AND AZA-PYRIDONE AMIDE COMPOUNDS
-
Heteroaryl pyridone and aza-pyridone amide compounds of Formula (I) are provided, and various substituents including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk, and for treating cancer and immune disorders such as inflammation mediated by Btk. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
- -
-
Page/Page column 103
(2015/01/16)
-
- Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents
-
Abstract Two series of phenothiazine derivatives were designed and synthesized. All compounds were tested for anti-tuberculosis activities against Mycobacterium tuberculosis H37RV. In comparison with mother compound of chlorpromazine, compound 6e shows promising anti-tuberculosis activity and much less mammalian cell cytotoxicity, compound 6e merits to be further explored as new anti-tuberculosis agents.
- He, Chun-Xian,Meng, Hui,Zhang, Xiang,Cui, Hua-Qing,Yin, Da-Li
-
supporting information
p. 951 - 954
(2015/08/18)
-
- Synthesis of pyrazoles based on functionalized allenoates
-
Regiospecific synthesis of pyrazole-3-carboxylate derivatives by 1,3-dipolar cycloaddition of diazomethane with allenoates in presence of triethylamine is demonstrated. Reaction of allenoates with stearic acid moiety containing diazoketone is explored under ultrasonic conditions. Novel derivatives of pyrazole were achieved in excellent yields.
- Sakhautdinov, Ilshat M.,Gumerov, Aynur M.,Batyrshin, Ilnur R.,Fatykhov, Akhnaf A.,Suponitsky, Kyrill Yu.,Yunusov, Marat S.
-
p. 641 - 651
(2014/04/03)
-
- A rhodamine-labeled citalopram analogue as a high-affinity fluorescent probe for the serotonin transporter
-
A novel fluorescent ligand was synthesized as a high-affinity, high specificity probe for visualizing the serotonin transporter (SERT). The rhodamine fluorophore was extended from an aniline substitution on the 5-position of the dihydroisobenzofuran ring of citalopram (2, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile), using an ethylamino linker. The resulting rhodamine-labeled ligand 8 inhibited [3H]5-HT uptake in COS-7 cells (Ki = 225 nM) with similar potency to the tropane-based JHC 1-064 (1), but with higher specificity towards the SERT relative to the transporters for dopamine and norepinephrine. Visualization of the SERT with compound 8 was demonstrated by confocal microscopy in HEK293 cells stably expressing EGFP-SERT.
- Zhang, Peng,Jorgensen, Trine Nygaard,Loland, Claus J.,Newman, Amy Hauck
-
supporting information
p. 323 - 326
(2013/02/23)
-
- Development of a practical and scalable synthesis of (R)- and (S)-3-amino-2-[(benzyloxy)methyl]propan-1-ol monohydrochloride: A useful C-4 Chiral Building Block
-
The development of a practical and scalable synthesis of a C-4 chiral amine building block (R)-1·HCl and (S)-1·HCl is described. This important chiral intermediate (R)-1·HCl is efficiently synthesized from the commercially available, inexpensive, and simple 2-(hydroxymethyl)-1,3- propanediol (31) using lipase-catalyzed enantioselective hydrolysis as a key reaction. Development resulted in a telescoped process that was operated successfully and reproducibly in a pilot-plant-scale synthesis, and 22 kg of chiral amine (R)-1·HCl was prepared in the first scale-up synthesis. This synthetic method is also useful for preparation of the important chiral building block (S)-1·HCl, which is the enantiomer of (R)-1·HCl.
- Yoshida, Shinya,Obitsu, Kazuyoshi,Hayashi, Yasumasa,Shibazaki, Mitsuyoshi,Kimura, Takenori,Takahashi, Takumi,Asano, Toru,Kubota, Hirokazu,Mukuta, Takashi
-
p. 1527 - 1537
(2013/02/23)
-
- Preparation of the β2-homoselenocysteine derivatives Fmoc-(S)-β2hSec(PMB)-OH and Boc-(S)-β2hSec(PMB)- OH for solution and solid-phase peptide synthesis
-
Fmoc-β2hSer(tBu)-OH was converted to Fmoc-β2hSec(PMB)-OH in five steps. To avoid elimination of HSeR, the selenyl group was introduced in the second last step (Fmoc- β2hSer(Ts)-OAll→Fmoc-β2hSec(PMB)-OAll). In a similar way, the N-Boc-protected compound was prepared. With the β2hSe-derivatives, 21 β2-amino-acid building blocks with proteinogenic side chains are now available for peptide synthesis. Copyright
- Patora-Komisarska, Krystyna,Jadwiga Podwysocka, Dominika,Seebach, Dieter
-
scheme or table
p. 1 - 17
(2011/03/17)
-
- Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses
-
An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103 N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.
- Kertesz, Denis J.,Brotherton-Pleiss, Christine,Yang, Minmin,Wang, Zhanguo,Lin, Xianfeng,Qiu, Zongxing,Hirschfeld, Donald R.,Gleason, Shelley,Mirzadegan, Taraneh,Dunten, Pete W.,Harris, Seth F.,Villasenor, Armando G.,Hang, Julie Qi,Heilek, Gabrielle M.,Klumpp, Klaus
-
scheme or table
p. 4215 - 4218
(2010/08/22)
-
- Trimethylsilyldiazomethane as a versatile stitching agent for the introduction of aziridines into functionalized organic molecules
-
A highly enantioselective route for the introduction of aziridines into functionalized organic molecules was developed via a tandem acylation and aziridination of TMSCHN2.
- Ren, Hong,Wulff, William D.
-
supporting information; experimental part
p. 4908 - 4911
(2011/02/21)
-
- Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists
-
Hit optimization of the class of quinazoline containing histamine H 4 receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline4-amino)-N- phenylethanesulfonamide (54) (pki = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
- Smits, Rogier A.,Adami, Maristella,Istyastono, Enade P.,Zuiderveld, Obbe P.,Van Dam, Cindy M. E.,De Kanter, Frans J. J.,Jongejan, Aldo,Coruzzi, Gabriella,Leurs, Rob,De Esch, Iwan J. P.
-
experimental part
p. 2390 - 2400
(2010/09/11)
-
- Oligonucleotide analogues with integrated bases and backbone: Part 20 - Hydrazide- and amide-linked analogues. 1. Design and synthesis of monomeric building blocks
-
Hydrazide- and amide-linked oligonucleoside analogues with integrated bases and backbone were designed to allow for a rapid synthesis of long and water-soluble oligomers. The uracil-, cytosine-, and adenine-derived hydrazide building blocks 13-15 were synthesized by nucleophilic substitution with the hydrazine 23 of the halides 19, 28, and 34, derived from the alcohols 18, 27, and 33, respectively, while the uracil-, cytosine-, and adenine-derived amide building blocks 45-47 were synthesized by a Curtius degradation of the carboxylic acids 51, 56, and 61. These acids were obtained by Wittig reaction of the aldehydes 49, 53, and 58. The guanine-derived monomers 44 and 48 were synthesized by reductive cyclisation of the nitroso amides 38 and 63, respectively, resulting from acylation of the known 2,6-diamino-4-(benzyloxy)-5- nitrosopyrimidine (37).
- Peifer, Manuel,De Giacomo, Fabio,Schandl, Martin,Vasella, Andrea
-
experimental part
p. 1134 - 1166
(2009/10/17)
-
- Total synthesis and antiproliferative activity screening of (±)-aplicyanins A, B and E and related analogues
-
The first total synthesis of the indole alkaloids (±)-aplicyanins A, B, and E, plus 17 analogues, all in racemic form, is reported. Modifications to the parent compound included changing the number of bromine substituents on the indole, the nature of the substituents on the indole nitrogen (H, Me, or OMe), and/or the oxidation level of the heterocyclic core tetrahydropyrimidine. Each compound was screened against three human tumor cell lines, and 14 of the newly synthesized compounds showed considerable cytotoxicity. The assay results were used to establish structure-activity relationships. These results suggest that the presence of the bromine at position 5 of the indole is critical to activity, as well as the acetyl group on the imine nitrogen does in some compounds. 2009 American Chemical Society.
- ?í?a, Miroslav,Pla, Daniel,Altuna, Marta,Francesch, Andrés,Cuevas, Carmen,Albericio, Fernando,álvarez, Mercedes
-
body text
p. 6217 - 6223
(2010/03/24)
-
- Synthesis, cleavage, and antifungal activity of a number of novel, water-soluble ester prodrugs of antifungal triazole CS-758
-
In this study, the synthesis and evaluation of a number of esters of CS-758 as injectable prodrugs are described. Phosphoryl ester 1a was soluble in water (>30 mg/mL) and was converted to CS-758 in human liver microsome. It was also converted to CS-758 in rats after iv administration, wherein the bioavailability of CS-758 was 53%. Compound 1a (iv) reduced the viable cell counts in kidneys in a murine systemic Candida albicans infection model, wherein the effect was comparable to or slightly superior to that of CS-758 (po). The prodrug 1a proved to be a promising injectable antifungal agent whose further evaluation is warranted.
- Kagoshima, Yoshiko,Mori, Makoto,Suzuki, Eiko,Shibayama, Takahiro,Iida, Tamako,Kamai, Yasuki,Konosu, Toshiyuki
-
scheme or table
p. 3559 - 3563
(2010/03/31)
-
- Synthesis of phosphonodipeptide conjugates of ursolic acid and their homologs
-
To prepare novel derivatives of naturally bioactive 3β-hydroxy-urs-12- en-28-oic acid (ursolic acid) with unusual properties and broad spectrum of activities, a number of chemical reactions were conducted. First, a variety of a-aminophosphonates were prepared by a series of reactions involving the three-component Mannich type reaction as a key step. Second, an array of phosphonodipeptides and their homologs was synthesized through multistep reactions including condensation of phthalic anhydride with glycine or β-alanine, chlorination of N-blocked amino acids, coupling of acid chloride with α-aminophosphonates and sequential hydrazinolysis. Finally, new classes of phosphonodipeptide conjugates of ursolic acid and their homologs were obtained by condensation of 3β-acetoxy-urs-12-en-28-oyl chloride with phosphonodipeptides and their homologs.
- Deng, Sheng-Lou,Baglin, Isabelle,Nour, Mohammed,Cave, Christian
-
-
- Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules
-
Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.
- Kánai, Károly,Arányi, Péter,B?cskei, Zsolt,Ferenczy, Gy?rgy,Harmat, Veronika,Simon, Kálmán,Bátori, Sándor,Náray-Szabó, Gábor,Hermecz, István
-
experimental part
p. 7514 - 7522
(2009/12/07)
-
- Syntheses of phosphonic esters of alendronate, pamidronate and neridronate
-
Several synthetic pathways for obtaining phosphonic esters of the amino bisphosphonic acids (NBPs) pamidronate, alendronate and neridronate were investigated. The general guideline was to react N-protected amino acids activated as phthalimide esters or as acyl chlorides. Succinimide esters were found less reactive and quickly abandoned. γ-Lactam formation arises when starting from Boc- or Cbz-protected amino acids. The phthalimide N-protecting group allowed access to alkyl or aryl mono-, di- (symmetric or not) and triesters of these three NBPs in high yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Guenin, Erwann,Monteil, Maelle,Bouchemal, Nadia,Prange, Thierry,Lecouvey, Marc
-
p. 3380 - 3391
(2008/02/10)
-
- Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity
-
An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the μ and δ opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected β-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure-activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-d-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both δ and μ opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).
- Petrov, Ravil R.,Vardanyan, Ruben S.,Lee, Yeon S.,Ma, Shou-wu,Davis, Peg,Begay, Lucinda J.,Lai, Josephine Y.,Porreca, Frank,Hruby, Victor J.
-
p. 4946 - 4950
(2007/10/03)
-
- Preparation of protected β2- and β3- homocysteine, β2- and β3-homohistidine, and β2-homoserine for solid-phase syntheses
-
The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of β-peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β3-homoamino acid derivatives were obtained by Arndt-Eistert methodology from Boc-His(Ts)-OH and Fmoc-Cys(PMB)-OH (Schemes 2-4), with the side-chain functional groups' reactivities requiring special precautions. The β2-homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti-enolates to formaldehyde (generated in situ from trioxane) and subsequent functional-group manipulations. These include OH → OtBu etherification (for β2hSer; Schemes 5 and 6), OH → STrt replacement (for β2hCys; Scheme 7), and CH 2OH → CH2N3 → CH2NH 2 transformations (for β2hHis; Schemes 9-11). Including protection/deprotection/re-protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (tR), melting points, optical rotations, HPLC on chiral columns, IR, 1H- and 13C-NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X-ray crystal-structure analysis.
- Lelais, Gerald,Micuch, Peter,Josien-Lefebvre, Delphine,Rossi, Francesco,Seebach, Dieter
-
p. 3131 - 3159
(2007/10/03)
-
- Structure-based de novo design of ligands using a three-dimensional model of the insulin receptor
-
For the first time, a three-dimensional model of the insulin receptor is used in the de novo design of novel ligands that potentially mimic interactions of insulin at its receptor. Compound 4 competed with insulin as seen in autophosphorylation assays and inhibited up to 68% of IR autophosphorylation at 300 μM of 4 in 3T3IR cells induced by 1 nM insulin. This model provides a basis for the design of potent insulin receptor ligands.
- Tan, Christopher,Wei, Lianhu,Ottensmeyer, F. Peter,Goldfine, Ira,Maddux, Betty A.,Yip, Cecil C.,Batey, Robert A.,Kotra, Lakshmi P.
-
p. 1407 - 1410
(2007/10/03)
-
- 2-Arylimino-2,3-dihydrothiazoles, and their use thereof as somatostatin receptor ligands
-
The invention concerns novel 2-arylimino-2,3-dihydrothiazole derivatives of general formula (I), their preparation methods and their use as medicines, in particular for treating pathological conditions or diseases wherein one (or several) somatostatin receptors is/are involved. Said pathological conditions include in particular acromegaly, pituitary adenoma or endocrine gastroenteropanceatic tumors including the carcinoid syndrome, and gastrointestinal bleeding. In general formula (I), R1 represents in particular an alkyl, aralkyl, cyclohexyl radical optionally substituted by an amino radical or R1 represents a —C(R11)(R12)—CO—R10 radical wherein R11 represents H, R12 represents in particular H, carbocyclic or heterocyclic alkyl, cycloalkyl or aralkyl and R10 represents in particular an aminoalkylamino radical; R2 represents a carcyclic or heterocyclic aryl radical optionally substituted; R3 represents in particular COR5 or a carbocyclic or heterocyclic alkyl, adamantyl, aryl radical optionally substituted, carbocyclic or heterocyclic aralkyl optionally substituted on the aryl group; and R5 represents a radical fixed by a nitrogen atom to the group CO.
- -
-
Page column 43-44
(2010/02/06)
-
- Sulfur ylides 10. Modified method for the synthesis of pyrrolizine- and indolizinediones
-
A modified method for the synthesis of derivatives of pyrrolizinedione and iridolizinedione was proposed. The method is based on the intramolecular cyclization of keto-stabilized sulfur ylides generated in situ from diazo ketones and Me2S in the presence of Rh2(OAc)4.
- Lakeev, S. N.,Mullagalin, I. Z.,Maidanova, O. O.,Galin, F. Z.,Tolstikov, G. A.
-
p. 189 - 190
(2007/10/03)
-
- Synthesis and anticonvulsant activity of N,N-phthaloyl derivatives of central nervous system inhibitory amino acids
-
In order to study the influence of the length of the amino acid chain of N,N-phthaloyl-amino acid amides as analogues of the former anticonvulsant taltrimide on the seizure-antagonizing activity glycine, β-alanine and γ-aminobutyric acid (GABA) derivatives were synthesized. The corresponding taurine derivatives were also included. Generally, the glycine-derived amides showed a higher activity than the β-alanine and GABA derivatives in the maximal electroshock seizure (MES) test in mice upon intraperitoneal administration. The activity was comparable to the respective taurine derivatives. The N,N-phthaloyl-glycine amides were also active in the MES test upon oral administration to rats. No significant activity was noted in the seizure threshold test with subcutaneous pentylene-tetrazole. The ED50 of N,N-phthaloyl-glycine ethyl amide (4b) in the MES test upon intraperitoneal administration to mice was 19.1 mg/kg. On a molar basis this activity is comparable to the activity of phenytoin with little toxicity in the rotorod test. In conclusion, N,N-phthaloyl-glycine amides might represent promising antiepileptic drugs.
- Usifoh, Cyril O.,Lambert, Didier M.,Wouters, Johan,Scriba, Gerhard K.E.
-
p. 323 - 331
(2007/10/03)
-
- Rhodium(II)-catalyzed cyclization of amido diazo carbonyl compounds
-
A series of acyclic diazo ketoamides were prepared from N-benzoyl-N-alkylaminopropanoic acids and were treated with a catalytic amount of rhodium(II) acetate. The resultant carbenoids underwent facile cyclization onto the neighboring amide carbonyl oxygen atom to generate seven-membered carbonyl ylide dipoles. Subsequent collapse of the dipoles with charge dissipation produce bicyclic epoxides which undergo further reorganization to give substituted 5-hydroxydihydropyridones in good yield. Depending on the nature of the substituent groups, it was possible to trap some of the initially formed carbonyl ylide dipoles with a reactive dipolarophile such as DMAD. In other cases, cyclization of the dipole to the epoxide is much faster than bimolecular trapping. A related cyclization/rearrangement sequence occurred when diazo ketoamides derived from the cyclic pyrrolidone and piperidone ring systems were subjected to catalytic quantities of Rh(II) acetate. With these systems, exclusive O-cyclization of the amido group onto the carbenoid center occurs to generate a seven-ring carbonyl ylide dipole. Starting materials are easily prepared, and the cascade sequence proceeds in good yield and does not require special precautions. The overall procedure represents an efficient one-pot approach toward the synthesis of various indolizidine and quinolizidine ring systems.
- Padwa,Hasegawa,Liu,Zhang
-
p. 7124 - 7133
(2007/10/03)
-
- 6-N-(N-methylanthranylamido)-4-oxo-hexanoic acid : A new fluorescent protecting group applicable to a new DNA sequencing method
-
6-Amino-4-oxo-hexanoic acid with a fluorescent probe attached to the amino function, derivative of the levulinic acid has been developed for protection of hydroxyl groups. It is introduced by reaction of its symetrical anhydride and rapidly removed under mild conditions using a hydrazine- pyridinium acetate buffer at near neutral pH and room temperature. It can be used within the scope of a new DNA sequencing method and as a sensitive detectable protecting group.
- Rasolonjatovo, Isabelle,Sarfati, Simon R.
-
p. 2021 - 2025
(2007/10/03)
-
- Synthesis and neuropeptide Y Y1 receptor antagonistic activity of N,N-disubstituted ω-guanidino- and ω-aminoalkanoic acid amides
-
Patent arpromidine-type histamine H2 receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y1 receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr36 in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y1 antagonists in human erythroleukemia (HEL) cells (Ca2+ assay) achieving pK(B) values in the range of 6.3-6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H2 receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y1 antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably mere potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.
- Mueller, Manfred,Knieps, Sebastian,Gessele, Karin,Dove, Stefan,Bernhardt, Guenther,Buschauer, Armin
-
p. 333 - 342
(2007/10/03)
-
- Carbonic anhydrase activators. Part 14. Syntheses of mono and bis pyridinium salt derivatives of 2-amino-5-(2-aminoethyl)- and 2-amino-5-(3-aminopropyl)-1,3,4-thiadiazole and their interaction with isozyme II
-
Reaction of 2-amino-5-(2-aminoethyl)- and 2-amino-5-(3-aminopropyl)-1,3,4-thiadiazole with 2,4,6-trisubstituted pyrylium salts in molar ratios of 1:1 and 1:2 afforded three series of derivatives which were investigated for their abilities to activate the enzyme carbonic anhydrase (CA). Only compounds possessing free aminoalkyl moieties behaved as strong CA II activators, presumably via a mechanism involving the shuttling of protons between the enzyme active site and the environment.
- Supuran,Barboiu,Luca,Pop,Brewster,Dinculescu
-
p. 597 - 606
(2007/10/03)
-
- Synthesis and pharmacology of 2--1H-isoindole-1,3(2H)-diones
-
The potassium salt of 1H-isoindole-1,3(2H)-dione (1) on treatment with 1-chloro-2,3-epoxypropane furnishes 2-(oxiranylmethyl)-1H-isoindole-1,3(2H)-dione (2) which on reaction with 1-arylpiperazines (3) affords 2--1H-isoindole-1,3(2H)-diones (4).The later compounds (4) are also obtained by reacting 3 with 2-(3-chloro-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione (6) which in turn is obtained by treating 1H-isoindole-1,3(2H)-dione with 1-chloro-2,3-epoxypropane. 2-Acetyl-1H-isoindole-1,3(2H)-dione on reaction with 3 in the presence of formaldehyde gives 2--1H-isoindole-1,3(2H)-diones (9). 1,3-Isobenzofuranedione (12) on condensation with 3-aminopropanoic acid (13) furnishes 3-(1H-isoindole-1,3(2H)-dion-2-yl)propanoic acid (14) which on conversion into its acid chloride (15) followed by condensation with 3 afford 2--1H-isoindole-1,3(2H)-diones (16). 2-Hydroxy-1H-isoindole-1,3(2H)-dione (17) is reacted with 1,3-dibromopropane to obtain 2-(3-bromopropoxy)-1H-isoindole-1,3(2H)-dione (21) which on condensation with 3 affords 2--1H-isoindole-1,3(2H)-diones (23).Compounds 4, 16 and 23 show 50-80percent decrease in the blood pressure of anaesthetised cats at 1 mg/kg.Two of them show 50percent decrease in BP at 0.01 mg/kg and have LD50 200 mg/kg.All the compounds show mild CNS depressant activity.
- Khadilkar, B. M.,Samant, S. D.
-
p. 1137 - 1142
(2007/10/02)
-
- SULFUR YLIDES. 3. SYNTHESIS OF KETO-GROUP STABILIZED AMINO-CONTAINING SULFUR YLIDES FROM AMINO ACIDS
-
An effective path of synthesis was developed of new synthetic intermediates, the optically active, keto-group stabilized amino-substituted sulfur ylides.
- Tolstikov, G. A.,Galin, F. Z.,Lakeev, S. N.,Khalilov, L. M.,Sultanova, V. S.
-
p. 535 - 541
(2007/10/02)
-
- SYNTHESIS AND CHARACTERIZATION OF STABLE N-PHTHALIMIDYL-2,3-BUTADIENOATES
-
A variety of stable, crystalline N-phthalimidyl-2,3-butadienoates were synthesized via a Wittig reaction of the acid chloride with ethyl-2-(triphenyl-phosphoranylidene)-propionate.Both proton and (13)C-nmr are used to confirm the allene structure.
- Kathawala, F. G.,Schuster, H. F.,Shapiro, M. J.
-
p. 3703 - 3706
(2007/10/02)
-