Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds
We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-06, Vol.59 (11), p.5368-5376 |
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| container_end_page | 5376 |
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| container_issue | 11 |
| container_start_page | 5368 |
| container_title | Journal of medicinal chemistry |
| container_volume | 59 |
| creator | Hickey, Jennifer L Zaretsky, Serge St. Denis, Megan A Kumar Chakka, Sai Morshed, M. Monzur Scully, Conor C. G Roughton, Andrew L Yudin, Andrei K |
| description | We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles. |
| doi_str_mv | 10.1021/acs.jmedchem.6b00222 |
| format | Article |
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This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. 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This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.</description><subject>Amides - chemical synthesis</subject><subject>Amides - chemistry</subject><subject>Macrocyclic Compounds - chemical synthesis</subject><subject>Macrocyclic Compounds - chemistry</subject><subject>Molecular Conformation</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMlOwzAURS0EoqXwBwh5ySbleUy6bKsySK3oAsQy8hSRKkOxW0T-HndiycrSe-c-6x6EbgkMCVDyoEwYrmpnzaerh1IDUErPUJ8ICgnPgJ-j_m6WUElZD12FsAIARii7RD2aEgoilX30sVQhlN8OL1ytvWocXjpfO6XLqtx0uC3wQhnfms5ULuCpavDE4WnbbHxbVc5i3eHZz35dGjyuS-vwpG1suEYXhaqCuzm-A_T-OHubPifz16eX6XieKMazTWI009pCQSVwEFnKRJpJSQnXdCSssFzHrpZZDUJoVgiZkZRSkCKC3BnGBuj-cHft26-tC5u8LoNxVRWrtNuQk3QkMplxTiPKD2jsE4J3Rb72Za18lxPId0rzqDQ_Kc2PSmPs7vjDVsfdX-jkMAJwAPbxduubWPj_m799VoPc</recordid><startdate>20160609</startdate><enddate>20160609</enddate><creator>Hickey, Jennifer L</creator><creator>Zaretsky, Serge</creator><creator>St. Denis, Megan A</creator><creator>Kumar Chakka, Sai</creator><creator>Morshed, M. 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Med. Chem</addtitle><date>2016-06-09</date><risdate>2016</risdate><volume>59</volume><issue>11</issue><spage>5368</spage><epage>5376</epage><pages>5368-5376</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27120576</pmid><doi>10.1021/acs.jmedchem.6b00222</doi><tpages>9</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2016-06, Vol.59 (11), p.5368-5376 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Amides - chemical synthesis Amides - chemistry Macrocyclic Compounds - chemical synthesis Macrocyclic Compounds - chemistry Molecular Conformation |
| title | Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds |
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