- Candida antarctica Lipase B in a chemoenzymatic route to cyclic α-quaternary α-amino acid enantiomers
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Kinetic resolution of three cyclic quaternary ethyl 1-amino-2,3-dihydro-1H- indene-1-carboxylates and both 1- and 2-amino-1,2,3,4-tetrahydronaphthalene analogues have been studied. Interesterification with butyl butanoate and Candida antarctica lipase B accomplished the task. The enantiomers of all 1-amino analogues reacted with excellent enantioselectivity (enantiomeric ratio er greater than 200), whereas the 2-amino analogue was not enantioselective (er = 4). Amino acid enantiomers were finally obtained as their respective hydrochlorides with almost maximum theoretical yields. For the first time, a lipase enzyme was effectively used in the kinetic resolution of cyclic α-quaternary α-amino esters. Copyright
- Li, Xiang-Guo,Rantapaju, Maria,Kanerva, Liisa T.
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p. 1755 - 1762
(2011/05/06)
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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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- Mitsunobu approach to the synthesis of optically active α,α-disubstituted amino acids
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Chiral tertiary α-hydroxy esters of known stereochemical configuration were transformed to α-azido esters by Mitsunobu reaction with HN3. Optimization of this reaction was shown to proceed at room temperature with high chemical yield using 1,1-(azodicarbonyl)dipiperidine (ADDP) and trimethylphosphine (PMe3). Complete inversion of configuration was observed at the α-carbon. Several α,α- disubstituted amino acids were synthesized in high overall chemical yield and optical purity.
- Green, Jonathan E.,Bender, David M.,Jackson, Stona,O'donnell, Martin J.,Mccarthy, James R.
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supporting information; experimental part
p. 807 - 810
(2009/08/08)
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- TETRALINE DERIVATIVES AS GHRELIN RECEPTOR MODULATORS
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The present invention is related to compounds of formula (I), or a therapeutically suitable salt or prodrug thereof, the preparation of the compounds, compositions containing the compounds and the use of the compounds in the prevention or treatment of disorders regulated by ghrelin including anorexia, cancer cachexia, eating disorders, age-related decline in body composition, weight gain, obesity, and diabetes mellitus.
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- Conformationally constrained deltorphin analogs with 2-aminotetralin-2- carboxylic acid in position 3
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Two approaches to the design of very active and highly selective δ opioid peptides were used to obtain new deltorphin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for δ receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltorphins exhibited similar K(i) values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the δ receptor, the side chain of residue 3 adopts the trans conformation at χ1.
- Tóth, Géza,Darula, Zsuzsa,Péter, Antal,Fül?p, Ferenc,Tourwé, Dirk,Jaspers, Hendrika,Verheyden, Patricia,B?cskey, Zsolt,Tóth, Zoltán,Borsodi, Anna
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p. 990 - 995
(2007/10/03)
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- Tritiated deltorphin analogues with high specific radioactivity and high affinity and selectivity for delta opioid receptors
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New conformationally constrained deltorphin I and II analogues were designed and synthesized, using a more lipophilic amino acid (Ile) instead of Val at positions 5 and 6, and 2-aminotetralin-2-carboxylic acid (Atc) at position 3. Two analogues (Tyr-D-Ala-(S)-Atc-Asp-Ile-Ile-Gly-NH2 and Tyr-D-Ala-(R)-Atc-Glu-Ile-Ile-Gly-NH2) with high potency and selectivity for δ opioid receptors were chosen for tritiation, with 3,5-I2-Tyr1-deltorphin analogues as precursors. Catalytic dehalotritiation of these precursors resulted in tritiated peptides with high specific radioactivity (1.28 TBq/mmol (34.5 Ci/mmol) and 1.33 TBq/mmol (36.0 Ci/mmol), respectively).
- Darula, Zsuzsa,Peter, Antal,Toth, Geza
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p. 817 - 826
(2007/10/03)
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- Design, synthesis, and structure-activity relationships of a new series of α-adrenergic agonists: Spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)]
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The contractions induced by a partial α1-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial α1- adrenoceptor agonist incr
- Cordi,Lacoste,Descombes,Courchay,Vanhoutte,Laubie,Verbeuren
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p. 4056 - 4069
(2007/10/03)
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- BENZOSPIROALKENE HETEROCYCLIC COMPOUNDS
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Compounds of formula (I): STR1 in which: X represents--CH. sub.2--,--(CH 2) 2--,--CH=CH--,--O--CH 2--,--S--CH 2--,--SO--CH 2--or--SO 2--CH 2--,Y represents oxygen or sulfur or--NR 6--,R. sub.1 represents hydrogen or linear or branched (C 1-C 6) alkyl, R 2 represents hydrogen or halogen, linear or branched (C 1-C 6) alkyl, (substituted or unsubstituted), hydroxyl, linear or branched (C 1-C 6) alkoxy or linear or branched (C 1-C 6) alkylthio,R 3 represents hydrogen or halogen, linear or branched (C 1-C 6) alkyl (substituted or unsubstituted), hydroxyl, linear or branched (C 1-C 6) alkoxy or linear or branched (C. sub.1-C 6)alkylthio,R 4 represents hydrogen (on condition that, in this case, R 1 represents hydrogen), halogen, linear or branched (C 1-C 6) alkyl (substituted or unsubstituted) or hydroxyl, or alternativelyR 1 and R 2, R 2 and R 3, R 3 and R 4 or R. sub.4 and X, together with the carbon atoms which bear them, form a benzene ring, on condition that, in the case where R. sub.1 and R 2 form a benzene ring, X is other than--CH 2--or--(CH 2) 2--,R 5 represents hydrogen or amino (substituted or unsubstituted),R 6 has the same meaning as R 1, their isomers and also their. addition salts with a pharmaceutically acceptable acid and medicinal product containing the sarne are useful as partial α 1 and α 2 adrenergic agonist in the treatment of venous disease and migraine.
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- Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue: Effects on receptor selectivity and stereospecificity
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In an effort to determine the effect of side chain conformational restriction on opioid receptor selectivity, the cyclic phenylalanine analogues 2-aminoindan-2-carboxylic acid (Aic), 2-aminotetralin-2-carboxylic acid (Atc), and tetrahydroisoquinoline-3-carboxylic acid (Tic) were substituted for Phe in the potent cyclic opioid peptide analogue H-Tyr-D-Orn-Phe-Glu-NH2, which lacks significant opioid receptor selectivity. Compounds were tested in μ- and δ-opioid receptor representative binding assays and bioassays in vitro. The analogue H-Tyr-D-Orn-Aic-Glu-NH2 was found to be a potent agonist with high preference of μ receptors over δ receptors. Opening of the five-membered ring of Aic in the latter peptide, as achieved through substitution of C(α)-methylphenylalanine or o-methylphenylalanine, resulted in only slightly selective compounds, indicating that the high μ selectivity of the Aic analogue is exclusively the consequence of the imposed side chain conformational restriction. Both diastereoisomers of H-Tyr-D-Orn-(D,L)-Atc-Glu-NH2 were highly μ-selective and, in contrast to the weak affinity observed with the D-Phe3 analogue as compared to the L-Phe3 analogue, both had similar potency. Thus, stereospecificity was lost as a consequence of side chain conformational restriction. Further structure-activity data obtained with analogues containing L- or D-homophenylalanine (Hfe) or 3-(1'-naphthyl)alanine (Nap) in place of Phe3 and consideration of geometric interrelationships between Nap and the L and D isomers of Atc, Hfe, and Phe led to the proposal that the D-Phe3 and the D-Atc3 analogue may have different modes of binding to the receptor. The very low potency observed with H-Tyr-D-Orn-N(α)MePhe-Glu-NH2 (N(α)MePhe = N(α)-methylphenylalanine) and H-Tyr-D-Orn-Tic-Glu-NH2 indicated that N(α)-alkylation at the 3-position is detrimental to activity.
- Schiller,Weltrowska,Nguyen,Lemieux,Chung,Marsden,Wilkes
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p. 3125 - 3132
(2007/10/02)
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- Modified phenylalanine peptidylaminodiols
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The invention relates to renin inhibiting compounds of the formula: STR1 wherein R2 is loweralkyl or arylalkyl; R3 is loweralkyl; X is STR2 wherein A is hydrogen or an N-protecting group, R1 is loweralkyl or arylalkyl, m is 1-3, n is 1-3, p is 1-3, q is 1-3, s is 1-3, and t is 0-2.
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