- Design, synthesis and crystal structure determination of dinuclear copper-based potential chemotherapeutic drug entities; In vitro DNA binding, cleavage studies and an evaluation of genotoxicity by micronucleus test and comet assay
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Copper-based potential chemotherapeutic complexes 1 and 2 were designed, synthesized and evaluated for in vitro DNA binding, cleaving capability and in vivo genotoxicity. The structural elucidation of complexes was done using elemental and spectroscopic data while the (R)-enantiomer of Cu(ii) complex 1 was studied by single crystal diffraction. In vitro DNA binding profiling of both (R)- and (S)-enantiomers of complexes 1 and 2 was carried out to evaluate their enantioselectivity, exhibiting a remarkable degree of enantioselectivity in their interaction with DNA, with the (R)-enantiomer exhibiting greater DNA binding propensity. Interaction between complexes and pBR322 DNA was evaluated by agarose gel electrophoresis assay; both the (R)-enantiomeric complexes exhibit effective DNA cleavage and proceed via an oxidative pathway. Furthermore, the in vivo genotoxicity of the (R)-enantiomer of complex 1 was evaluated by micronucleus testing on bone marrow cells and comet assay in peripheral blood lymphocytes. These results support our contention that the (R)-enantiomer of complex 1 is a suitable chemotherapeutic drug candidate showing reduced toxic effects on normal cells as compared to cisplatin and an antioxidant (EVOO). The Royal Society of Chemistry.
- Arjmand, Farukh,Muddassir, Mohd,Zaidi, Yusra,Ray, Debashis
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Read Online
- Microwave-Assisted CuCl-Catalyzed Three-Component Reactions of Alkynes, Aldehydes, and Amino Alcohols
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A microwave (MW)-assisted three-component coupling of amino alcohols, aldehydes, and alkynes is developed under catalysis by CuCl. Compared with thermal conditions, MW irradiation greatly increases the reaction efficiency. The reactions of various primary N -alkyl/arylamino alcohols, aliphatic/aromatic aldehydes, and alkynes are systematically investigated, affording the desired products in moderate to good yields. Notably, acetylene is also an effective reactant under the current MW-assisted conditions.
- Chen, Ning,Li, Xiang,Xu, Jiaxi
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supporting information
p. 3336 - 3344
(2019/08/28)
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- Substrate-Controlled Diastereoselectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using N-Boc-N-Bn-Protected α-Amino Aldehydes
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The effectiveness of utilizing N-Bn-N-Boc-α-amino aldehydes in cross-benzoin reactions with heteroaromatic aldehydes is demonstrated. The reaction is both chemoselective and syn-selective, making it complementary to the anti-selective cross-benzoin reaction of NHBoc-α-amino aldehydes. Good diastereoselectivity is obtained for a variety of amino aldehydes, including nonhindered ones. A Felkin-Anh model can be used to rationalize the observed diastereoselectivity.
- Haghshenas, Pouyan,Quail, J. Wilson,Gravel, Michel
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p. 12075 - 12083
(2016/12/23)
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- NITROGEN-CONTAINING SPIROCYCLIC COMPOUNDS AND PHARMACEUTICAL USES THEREOF
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A compound of the following general formula [I]: wherein each symbol has the same meaning as defined herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical use of the same in treating organ transplant rejection, graft versus host reaction after transplantation, autoimmune disease, allergic disease and chronic myeloproliferative disease.
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Page/Page column 47-48
(2011/06/24)
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- Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors
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Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
- Medina, Jesús R.,Becker, Christopher J.,Blackledge, Charles W.,Duquenne, Celine,Feng, Yanhong,Grant, Seth W.,Heerding, Dirk,Li, William H.,Miller, William H.,Romeril, Stuart P.,Scherzer, Daryl,Shu, Arthur,Bobko, Mark A.,Chadderton, Antony R.,Dumble, Melissa,Gardiner, Christine M.,Gilbert, Seth,Liu, Qi,Rabindran, Sridhar K.,Sudakin, Valery,Xiang, Hong,Brady, Pat G.,Campobasso, Nino,Ward, Paris,Axten, Jeffrey M.
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p. 1871 - 1895
(2011/05/30)
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- SUBSTITUTED PIPERAZINES AS CB1 ANTAGONISTS
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Compounds of Formula (I) or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB1receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.
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Page/Page column 219-220
(2009/03/07)
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- Facile synthesis of β-amino disulfides, cystines, and their direct incorporation into peptides
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Herein, we report a simple and efficient methodology for the synthesis of β-amino disulfides by regioselective ring opening of sulfamidates with benzyltriethylammonium tetrathiomolybdate [BnNEt3] 2MoS4. Stability and reactivity of different protecting groups under the reaction conditions have been discussed. This methodology has also been extended to serine and threonine derived sulfamidates to furnish cystine and 3,3′-dimethyl cystine derivatives. Georg Thieme Verlag.
- Nasir Baig,Kanimozhi, Catherine K.,Sudhir, V. Sai,Chandrasekaran, Srinivasan
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scheme or table
p. 1227 - 1232
(2009/09/06)
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- New pseudonucleosides containing chiral oxazolidin-2-ones and Cyclosulfamides as aglycones: Synthesis and antiviral evaluation
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A series of chiral cyclosulfamides and oxazolidinon-2-ones have been synthesized starting from aminoacids. Regioselective substitution of these pseudopyrimidic heterocyles was carried out under Mitsunobu conditions. Best substitution results were obtained by preliminary deprotection of cyclosulfamides and their condensation with β -D-ribofuranose. Chiral oxazolidin-2-ones were coupled directly with D-ribofuranose. All compounds were tested against HSV-2, VV and SV viruses. Two compounds 6b and 6e showed significant activities against HSV-type 1. Copyright Taylor & Francis Group, LLC.
- Bouleghlem, Hocine,Berredjem, Malika,Lecouvey, Marc,Aouf, Nour-Eddine
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p. 1539 - 1542
(2008/09/20)
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- Piperazine derivatives
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This invention relates to piperazine derivatives of the formula: wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or preventing Tachykinin-mediated diseases in human being or animals.
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Page/Page column 11
(2010/02/15)
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- Stereocontrolled synthesis of 3-substituted azetidinic amino acids
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A set of enantiomerically pure N-disubstituted β-amino alcohols was chlorinated by treatment with thionyl chloride. This reaction gave a mixture of regioisomeric chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The chlorides thus obtained were engaged in an intramolecular anionic ring-closure and gave access to fully protected enantio- and diastereomerically pure 2,3-cis-disubstituted azetidinic amino acids. One of the latter was deprotected and included in a short peptide sequence. Georg Thieme Verlag Stuttgart.
- Sivaprakasam, Mangaleswaran,Couty, Fran?ois,Evano, Gwilherm,Srinivas,Sridhar,Rao, K. Rama
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p. 781 - 785
(2007/10/03)
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- Azetidinic amino acids: Stereocontrolled synthesis and pharmacological characterization as ligands for glutamate receptors and transporters
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A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have been synthesized in a diastereo- and enantiomerically pure form from ss-amino alcohols through a straightforward five step sequence. The key step of this synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine ring upon an intramolecular Michael addition. This reaction was proven to be reversible and to lead to a thermodynamic distribution of two diastereoisomers that were easily separated and converted in two steps into azetidinic amino acids. Azetidines 35-44 were characterized in binding studies on native ionotropic Glu receptors and in functional assays at cloned metabotropic receptors mGluR1, 2 and 4, representing group I, II and III mGlu receptors, respectively. Furthermore, azetidine analogues 35, 36 and 40 were also characterized as potential ligands at the glutamate transporter subtypes EAAT1-3 in the FLIPR Membrane Potential (FMP) assay. The (2R)-azetidines 35, 37, 39, 41 and 43 were inactive in iGlu, mGlu and EAAT assays, whereas a marked change in the pharmacological profile at the iGlu receptors was observed when a methyl group was introduced in the C-4 position, compound 36 versus t-CAA. At EAAT1-3, compound 35 was inactive, whereas azetidines 36 and 40 were both identified as inhibitors and showed selectivity for the EAAT2 subtype. The Royal Society of Chemistry 2005.
- Braeuner-Osborne, Hans,Bunch, Lennart,Chopin, Nathalie,Couty, Francois,Evano, Gwilherm,Jensen, Anders A.,Kusk, Mie,Nielsen, Birgitte,Rabasso, Nicolas
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p. 3926 - 3936
(2007/10/03)
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- Simple and Efficient Cleavage Reaction of the Boc Group in Heterocyclic Compounds
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A series of chiral cyclosulfamides have been synthesized by alkaline cyclisation starting from N-benzoylamino acids (Ala, Val, Leu, Phe) derivatives and chlorosulfonyl isocyanate. A simplified and regioselective deprotection of the cyclic compounds (cyclosulfamides) containing the tert-butyloxycarbonyl group (Boc) has been achieved in good yield by fusion under reduced pressure.
- Nadia, Klai,Malika, Berredjem,Nawel, Khettache,MedYazid, Belghit,Zine, Regainia,Aouf, Nour-Eddine
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- Combining Magnetic Resonance Spectroscopies, Mass Spectrometry, and Molecular Dynamics: Investigation of Chiral Recognition by 2,6-di-O-Methyl-β-cyclodextrin
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EPR spectroscopy has been employed to investigate the formation of complexes between heptakis-(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) and different enantiomeric pairs of chiral nitroxides of general structure PhCH2N(O·)CH(R)R′. Accurate equilibrium measurements of the concentrations of free and included radicals afforded the binding constant values for these nitroxides. The relationship between the stereochemistry of the DM-β-CD complexes and the thermodynamics of complexation was elucidated by correlating EPR data with 1H-1H NOE measurements carried out on the complexes between DM-β-CD and the structurally related amine precursors of nitroxides. NOE data suggested that inclusion of the stereogenic center in the DM-β-CD cavity occurs only when the R substituent linked to the chiral carbon contains an aromatic ring. For these types of complexes, molecular dynamics simulation indicated that the depth of penetration of the stereogenic center into the cyclodextrin cavity is determined by the nature of the second substituent (R′) at the asymmetric carbon and is responsible for the observed chiral selectivity. Analysis of mass spectra showed that, for the presently investigated amines, electrostatic external adducts of CDs with protonated amines are detected by ESI-MS.
- Franchi, Paola,Lucarini, Marco,Mezzina, Elisabetta,Pedulli, Gian Franco
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p. 4343 - 4354
(2007/10/03)
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- Properties and Reactions of Substituted 1,2-Thiazetidine 1,1-Dioxides: Chiral Mono- and Bicyclic 1,2-Thiazetidine 1,1-Dioxides from α-Amino Acids
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New chiral mono- and bicyclic β-sultams, valuable building blocks for drug synthesis, have been prepared from L-Ala, L-Val, L-Leu, L-Ile, L-Phe, L-Cys, L-Ser, L-Thr, and D-penicillamine by transformation of the COOH group into a methylsulfonyl chloride function, followed by cyclization under basic conditions. Selected properties, derivatives, and reactions of the β-sultams are described.
- Meinzer, Alexandra,Breckel, Andrea,Thaher, Bassam Abu,Manicone, Nico,Otto, Hans-Hartwig
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- Asymmetric synthesis of functionalized azetidines through intramolecular Michael additions
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Enantiopure 2-cyano azetidines were prepared in good yields from β-amino alcohols. This synthesis is based on two important steps: (i) Wittig olefination of a transient amino aldehyde derived from a N-cyanomethylated β-amino alcohol and (ii) a 4-exotet ring closure through the intramolecular Michael addition of a lithiated α-amino nitrile. The former step is stereoselective. The thus produced functionalized azetidines were transformed into conformationnally constrained analogues of glutamic acid.
- Carlin-Sinclair, Abel,Couty, Fran?ois,Rabasso, Nicolas
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p. 726 - 728
(2007/10/03)
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- Fluoroamines via chiral cyclic sulfamidates
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N-benzyl [1,2,3]-oxathiazolidine 2,2-dioxides (cyclic sulfamidates) were synthesized from their corresponding β-amino alcohols and used as substrates in fluorination reactions with tetrabutylammonium fluoride (TBAF). After desulfonation of the intermediates, the N-benzyl fluoroamines were debenzylated by transfer hydrogenolysis with Pd/C to yield (S) and (R)-2-amino-1-fluoropropanes (2b and 3b, respectively, both with 95% ee). The reactions were carried out on multi-gram scale without the need for chromatographic purification of the intermediates. In the presence of carbonate, the (S)- and (R)-N-benzylfluoroamines underwent intramolecular cyclizations in which fluoride was displaced to yield cyclic carbamates 13 and 14.
- Posakony, Jeffrey J.,Tewson, Timothy J.
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p. 766 - 770
(2007/10/03)
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- Synthesis of 1,2,5-thiadiazolidines 1,1-dioxides (Cyclosulfamides) starting from amino acids and chlorosulfonyl isocyanate
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We report here a practical access to a series of five-membered cyclosulfamides (1,2,5-thiadiazolidines 1,1-dioxides) N2 substituted by the BOC group. These compounds are synthesized starting from chlorosulfonyl isocyanate and nitrogen mustards or amino acids. The derivatization of amino acids can lead to an alkyl group on C-4 with a well-defined configuration; in this case the N5 position was protected by a benzyl group. These compounds are valuable tools for asymmetric synthesis. (C) 2000 Elsevier Science Ltd.
- Rega?nia, Zine,Abdaoui, Mohamed,Aouf, Nour-Eddine,Dewynter, Georges,Montero, Jean-Louis
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p. 381 - 387
(2007/10/03)
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- Imidazo[1,5-g][1,4]diazepines, TIBO analogues lacking the phenyl ring: Synthesis and evaluation as Anti-HIV agents
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The imidazo[1,5-g][1,4]diazepine derivatives 7a and 7b, analogues of TIBO lacking the aromatic ring, were prepared as part of a research program to find compounds displaying antiviral activity against HIV-2 and resistant strains of HIV-1. Condensation of N-trityl and N-tosyl 4-(2-chloroethyl)imidazole with the appropriate amino alcohols gave compounds 10a-e and 16a-e. The hydroxyl group in these intermediates was activated toward closure of the [1,4]diazepine ring by either conversion to the corresponding chloro derivative, or by N → O transfer of the tosyl group. However, only cyclization to compounds 13a and 13b proved efficient. These products were converted to the target molecules 7 by reaction of their C-2 anion with Sg. In vitro evaluation of compounds 7a,b and 13a,b in cell culture (GEM SS/HIV-1-LAI and CEM SS/HIV 1 nevirapine resistant cells) revealed that only 13b displayed minimal activity.
- Janin, Yves L.,Aubertin, Anne-Marie,Chiaroni, Angele,Riche, Claude,Monneret, Claude,Bisagni, Emile,Grierson, David S.
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p. 15157 - 15170
(2007/10/03)
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- A practical stereoselective synthesis of (2S, 4S)-4-tert-butoxycarbonylamino-2-methylpyrrolidine
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Two practical syntheses of (2S, 4S)-4-tert-butoxycarbonylamino-2-methylpyrrolidine, an important intermediate for quinolone antibacterial agents, have been developed through the combination of diastereo and enantioselective reactions starting from ethyl crotonate and L-alanine, respectively.
- Qun, Li,Chu, Daniel T. W.,Raye, Kathleen,Claiborne, Akiyo,Seif, Louis,Macri, Bryan,Plattner, Jacob J.
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p. 8391 - 8394
(2007/10/02)
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- Stereoselective Synthesis of (2S,3S)-Norstatine Derivatives by Addition of Lithiated Methoxyallene to Amino Aldehydes and Subsequent Ozonolysis
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Addition of lithiated methoxyallene 2 to optically active N-benzyl-Boc-protected amino aldehydes 12-14 and to aldehyde 16 provides products 17-20 with good to excellent diastereoselectivity.These adducts are subsequently cleaved by ozonolysis to give α-hydroxy-β-amino acid derivatives 21-25 in good overall yield.By conversion into an oxazolidone derivative, the configuration of the major diastereomer was determined to be anti (2S,3S).Thus, the additions of 2 follow the course proposed by the Felkin-Anh model and are not ruled by chelation effects.The diastereoselective synthesis of 22 constitutes one of the simplest routes to a protected norstatine derivative. - Key Words: Methoxyallene / Allenes / Aldehydes, α-amino / Lithium compounds / Ozonolysis / Norstatine derivatives
- Hormuth, Stephan,Reissig, Hans-Ulrich,Dorsch, Dieter
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p. 121 - 128
(2007/10/02)
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- A new approach to the synthesis of N-arylakyl aminoalcohols
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N-arylmethyl substituted aminoalcohols were prepared by enantioselective reductive amination of different aromatic and heteroaromatic aldehydes using aminoalcohols and NaBH3CN as a catalyst. The reaction of optically active aminoalcohols afforded optically pure products.
- Leskovsek,Urleb
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p. 1415 - 1424
(2007/10/02)
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- Chiral quinolone intermediates
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Chiral compounds having the formulae STR1 useful in the synthesis of quinolone intermediates.
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- Synthesis of Homochiral 3-Oxa-2,7-diazabicyclooctanes from Amino Acids by Intramolecular 1,3-Dipolar Cycloaddition of Nitrones
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N-Allylamino alcohols 9 were prepared from amino acids by various methods.Swern oxidation of 9 afforded aldehydes 11.By reaction of 11 with N-alkylhydroxylamines nitrone intermediates 4 were formed which spontaneously underwent an intramolecular 1,3-dipolar cycloaddition to yield the bicyclic compounds 6.The cycloaddition proceeds diastereoselectively furnishing homochiral compounds 6 from homochiral starting materials.The structure of 6aA was confirmed by X-ray structural analysis. Key Words: Heterobicyclooctanes, homochiral / Amino acids / Nitrones / Cycloadditions, diastereoselective, intramolecular
- Aurich, Hans Guenter,Frenzen, Gerlinde,Gentes, Christian
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p. 787 - 796
(2007/10/02)
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- An improved, convenient procedure for reduction of amino acids to aminoalcohols: Use of NaBH4-H2so4
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The use of NaBH4-H2SO4, For the reduction of α-amino acids to the corresponding aminoalcohols offers definite advantages: i) operational simplicity, ii) ease of scaling up the reaction without risking explosion, and iii) use of the inexpensive reagents.
- Abiko, Atsushi,Masamune, Satoru
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p. 5517 - 5518
(2007/10/02)
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