- Resolution of tert-butyl-1-(2-methylnaphthyl)phosphine oxide using selectors identified from a chemical combinatorial library
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Resolution of racemic tert-butyl-1-(2-methylnaphthyl)phosphine oxide 1, a chiral phosphorus compound, was achieved using selectors developed from a small peptide library. Separation factors as high as 3.2 were observed. The library consists of 81 peptide-based potential chiral selectors on polymeric synthesis resins. The linker needed to immobilize the identified chiral selectors onto silica gel proved important in the chiral separation; a longer linker provided a significantly higher separation factor in this study.
- Blodgett, Jordan,Wang, Yan,Li, Tingyu,Polavarapu, Prasad L.,Drabowicz, Jozef,Pietrusiewicz, K. Michal,Zygo, Krystyna
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- A new class of pseudopeptide antagonists of the kinin B1 receptor containing alkyl spacers
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Four previously reported kinin receptor peptide antagonists, including the B1 receptor-selective peptides desArg10-HOE 140 (H-D-Arg-Arg-Pro-Hyp- Gly-Thi-Ser-D-Tic-Oic-OH) and B-9858 (H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D- Igl-Oic-OH), have been modified by replacement of the central tetrapeptide Pro-Hyp-Gly-Xaa with linear alkyl spacers of variable length. The analogue of desArg10-HOE 140 containing the 11-aminoundecanoic acid as spacer, MEN 11575 [H-D-Arg-Arg-NH-(CH2)10-CO-Ser-D-Tic-Oic-OH], was found to be slightly more potent than the unmodified peptide (pA2 = 7.1) as a kinin B1 receptor antagonist in the rat ileum longitudinal smooth muscle assay. Moreover, MEN 11575 is devoid of residual agonist activity at the kinin B1 receptor (rat ileum) and antagonist activity at the kinin B2 receptor (guinea pig ileum longitudinal smooth muscle). Both these activities are displayed by the parent peptide desArg10-HOE 140. Therefore, despite its greatly simplified chemical structure, MEN 11575 shows an improved pharmacological profile in terms of both potency and selectivity, and it represents a good template for the development of new peptidomimetic kinin B1 receptor antagonists. We also report an attempt to investigate the conformational role of the flexible, linear spacer of MEN 11575 and to design more constrained analogues, possibly locked in the bioactive conformation, using semirigid spacers based on C(α)-tetrasubstituted α-amino acids of the family of 1-aminocycloalkane-1-carboxylic acids (Ac(n)c).
- Galoppini, Claudia,Meini, Stefania,Tancredi, Mariella,Di Fenza, Armida,Triolo, Antonio,Quartara, Laura,Maggi, Carlo A.,Formaggio, Fernando,Toniolo, Claudio,Mazzucco, Silvia,Papini, Annamaria,Rovero, Paolo
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p. 409 - 414
(2007/10/03)
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- Spacer molecules in peptide sequences: Incorporation into analogues of atrial natriuretic factor
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In the present study, 10 modified human atrial natriuretic factor (hANF) analogues were designed using solid phase synthesis. This was carried out by replacing 'alkyl or glycol' spacer with octapeptide sequence within die cyclic portion of hANF in each annlogue synthesised. The unnatural amino acid spacers (1b) and (2d) have been synthesised using solution chemistry. The latter spacers were successfully incorporated into the peptide structure, using solid phase synthesis assembly. Amongst the ten analogues, thus prepared, two in which the alkyl spacer was used to substitute amino acid residues Gly15 to Gly21 and Arg14 to Leu21 to give 4a and 4b, successively. In the purification process of the latter analogues (4a, 4b), problems of their severe solubility were encountered. The eight glycol-spaced analogues (5a-5h) were successfully synthesised and purified using HPLC. The structure of (5a-5h) was confirmed by the presence of mass ion peaks in the atom bombardment mass spectroscopy (FAB MS) and by NMR. The latter analogues were tested, in vivo, for their ability to bind to specific hANF receptors, as agonists or antagonists. The biological results have showed that none of these analogues (5a-5h) were active.
- Boumrah, Derradji,Campbell, Malcolm M.,Fenner, Simon,Kinsman, Richard G.
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p. 6977 - 6992
(2007/10/03)
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- Spacer molecules in peptide sequences: Incorporation into analogues of atrial natriuretic factor
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The spacer reagents FmocHN(CH2CH2CH2)3CH 2COOPfp (1b) and FmocHN(CH2CH2O) 3CH2COOPfp (2d) have been prepared and used to substitute for tetra-residue sequences in the cyclic portion of Atrial Natriuretic Factor (ANF) by solid phase peptide assembly.
- Boumrah, Deradji,Campbell, Malcolm M.,Fenner, Simon,Kinsman, Richard G.
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p. 7735 - 7738
(2007/10/02)
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