- Design and Synthesis of Fsp3-Rich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening
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The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented.
- Stotani, Silvia,Lorenz, Christoph,Winkler, Matthias,Medda, Federico,Picazo, Edwige,Ortega Martinez, Raquel,Karawajczyk, Anna,Sanchez-Quesada, Jorge,Giordanetto, Fabrizio
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supporting information
p. 330 - 336
(2016/07/06)
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- Two methods for spirothiohydantoin synthesis
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Two methods for spirothiohydantoin synthesis are presented. The title compounds were prepared with reaction of the corresponding 1- aminocycloalkanecarboxylic acids and thiourea. These compounds were also prepared by a hydrolysis of the relevant spirodithiohydantoins with barium hydroxide. The structures of the compounds obtained were verified by comparison of 1H, and 13C NMR, IR and MS spectral data.
- Stoyanov, Neyko,Marinov, Marin
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p. 680 - 685,6
(2020/08/24)
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- Microwave-assisted synthesis of cycloalkanespirohydantoins and piperidinespirohydantoins as precursors of restricted α-amino acids
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Cycloalkanespirohydantoins 3 and piperidinespirohydantoins 4 were synthesized from cycloalkanones 9 and piperidones 10 under microwave-assisted conditions. Results are compared with those obtained under thermal conditions. Cycloalkanespirohydantoins 3 were N-protected with Boc group and hydrolyzed under basic conditions to obtain five, six and seven-membered ring restricted α-amino acids 12 in very good overall yields (76-94%). ARKAT USA, Inc.
- Rivero, Ignacio A.,Reynoso-Soto, Edgar A.,Ochoa-Teran, Adrian
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experimental part
p. 260 - 271
(2011/05/13)
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- PEPTIDES AND PEPTIDOMIMETIC COMPOUNDS, THE MANUFACTURING THEREOF AS WELL AS THEIR USE FOR PREPARING A THERAPEUTICALLY AND/OR PREVENTIVELY ACTIVE PHARMACEUTICAL COMPOSITION
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Peptides, peptidomimetics and derivatives thereof of the general formula I: H2N-GHRPX1-β-X4X5X6X7X8X9X10-X11 (I), in which X1-X10 denote one of the 20 genetically coded amino acids, wherein X8, X9 and X10 may also denote a single chemical bond;X11 denotes OR1 in which R1 equals hydrogen or (C1-C10) alkyl NR2R3 with R2 and R3 are equal or different and denote hydrogen, (C1-C10) alkyl, or a residue —W-PEG5-60K, in which the PEG residue is attached via a suitable spacer W to the N-atom, ora residue NH—Y-Z-PEG5-60K, in whichY denotes a chemical bond or a genetically coded amino acids from the group S, C, K or R andZ denotes a spacer, via which a polyethylene glycol (PEG)-residue can be attached, and their physiologically acceptable salts, andβ denotes an amino acid, or a peptidomimetic element, which induces a bend or turn in the peptide backbone.
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- Novel N-(phosphonomethyl) glycine derivatives: Design, characterization and biological activity
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A series of Cα,α-disubstituted cyclic derivatives of N-(phosphonomethyl) glycine have been synthesized and characterized. They exhibited moderate clastogenicity, low antiproliferative activity on mice bone marrow cells and well expressed cytotoxicity against human tumor cell lines. The 8- and 12-membered cyclic analogs proved superior to the remaining compounds and were found to trigger apoptotic cell death in DOHH-2 cells. The latter compound caused 50% inhibition of the viability of hemobastose-derived cell lines at concentrations ranging from 20 to 67 μM.
- Naydenova, Emilia D.,Todorov, Petar T.,Topashka-Ancheva, Margarita N.,Momekov, Georgi Ts.,Yordanova, Tsvetelina Z.,Konstantinov, Spiro M.,Troev, Kolio D.
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p. 1199 - 1205
(2008/09/20)
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- Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
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Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg-1, TD50 = 36.4 mg kg-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.
- Ho, Bin,Michael Crider,Stables, James P
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p. 265 - 286
(2007/10/03)
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- Synthesis and tumorinhibiting activity of lanthanum(III) complexes with some 1-aminocycloalkancarboxylic acids
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Complexes of La(III) with 1-aminocyclopentane-, -hexane, -heptane and -4-ethylcyclohexanecarboxylic acids were obtained. The compounds were characterized by elemental analyses, IR spectroscopy and conductivity measurements. The following general formula was derived: LaL3Cl3·5 H2O, where L is the corresponding 1-aminocycloalkanecarboxylic acid. The pharmacological studies showed that all complexes manifested higher cytostatic and cytotoxic effects in comparison with lanthanum chloride. Much higher cytotoxic (anti-P388/D1) and cytostatic (anti-L-1210 and antimelanoma-B16) activity was found for the lanthanum complex with 1-aminocyclopentanecarboxylic acid.
- Kovachev,Ivanov,Buyukliev,Konstantinov,Karaivanova
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- N-acyl amino acid derivative and process for production and use thereof
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N-halogenophenoxyacetyl amino acid or ester thereof and salt thereof, a process for production thereof comprising acylation of amino acid or derivative thereof, a herbicidal composition comprising the compound, and a method for killing or controlling plants using the compound. The compounds have a selective herbicidal effect.
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- Peptide Sweeteners. 6. Structural Studies on the C-Terminal Amino Acid of L-Aspartyl Dipeptide Sweeteners
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Stereochemical and structural aspects of the variations in the C-terminal residue of L-aspartyl-L-phenylalanine methyl ester have been investigated.Novel configurational analogues such as L-aspartyl-D-alanine benzyl ester and L-aspartyl-D-α-aminobutyric acid benzyl ester were found to be sweet.In addition, chiral and achiral α,α-dialkylglycine and α-aminocycloalkanecarboxylic acids were incorporated into the dipeptides.The L-aspartic acid based dipeptide derivatives of α-aminoisobutyric acid methyl ester, α-aminocyclopropanecarboxylic acid methyl ester, α-aminocyclobutanecarboxylic acid methyl ester, and α-aminocyclopentanecarboxylic acid methyl ester are sweet.Dipeptides with α-aminocyclohexanecarboxylic acid methyl ester and α-aminocycloheptanecarboxylic acid methyl ester are bitter, whereas the analogues with α-aminocyclooctanecarboxylic acid methyl ester, α,α-diethylglycine methyl ester, and α-aminoisobutyric acid benzyl ester are tasteless.Aspects on chirality and effective volume of the C-terminal residue are discussed and correlated with taste.
- Tsang, Joseph W.,Schmied, Bernhard,Nyfeler, Rolf,Goodman, Murray
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p. 1663 - 1668
(2007/10/02)
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