- Modulation of the Passive Permeability of Semipeptidic Macrocycles: N- And C-Methylations Fine-Tune Conformation and Properties
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Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.
- Boudreault, Pierre-Luc,Comeau, Christian,Derbali, Rabeb Mouna,Grandbois, Michel,Poulet, Sylvain,Ries, Benjamin,Riniker, Sereina,Sarret, Philippe,Stadelmann, Thomas,Tremblay, Jacob,C?té, Jér?me,Fr?hlich, Ulrike,Leclair, Grégoire,Marsault, éric
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p. 5365 - 5383
(2021/05/04)
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- Conjugates of modified cryptophycins and RGD-peptides enter target cells by endocytosis
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Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based homing devices. An array of functionalized β2-amino acids was synthesized and incorporated into cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the cryptophycin prodrug.
- Nahrwold, Markus,Wei?, Christine,Bogner, Tobias,Mertink, Felix,Conradi, Jens,Sammet, Benedikt,Palmisano, Ralf,Royo Gracia, Soledad,Preu?e, Thomas,Sewald, Norbert
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p. 1853 - 1864
(2013/05/09)
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- Synthesis of Cα methylated carboxylic acids: Isosteres of arginine and lysine for use as N-terminal capping residues in polypeptides
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Replacement of the N-terminal α-amine with the isosteric methyl functionality in bioactive peptides can influence various pharmacokinetic parameters, including hydrophobicity and stability. Cα methylated amino acid analogues are thus of great interest to expand the repertoire of nonnatural synthons available as N-terminal 'capping' residues for peptide-based drug design. Several novel arginine and lysine analogues stereoselectively modified in the Cα position with a methyl group in place of the α-amine were prepared.
- Orwig, Kevin S.,Dix, Thomas A.
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p. 7007 - 7009
(2007/10/03)
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