{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ly HM"],"funding":["Natural Sciences and Engineering Research Council of Canada","Universit? de Sherbrooke","Proteo"],"pagination":["3711-3726"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10946398"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["67(5)"],"pubmed_abstract":["Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure-permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH<sub>4</sub> and the aqueous reductive mono-<i>N</i>-alkylation of aldehydes using catalytic SmI<sub>2</sub> and stoichiometric Zn. The permeability of the macrocycles was evaluated through a parallel artificial membrane permeability assay (PAMPA), and the results indicated that macrocycles with a furan incorporated into the structure have better passive permeability than those with a pyrrole moiety. Compounds bearing a 2,5-disubstituted pyrrole (<i>endo</i> orientation) were shown to be implicated in intramolecular H-bonds, enhancing their permeability. This study highlighted the impact of heterocycles moieties in semipeptides, creating highly permeable macrocycles, thus showing promising avenues for passive diffusion of drugs beyond the rule-of-five chemical space."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Insights on Structure-Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles."],"pmcid":["PMC10946398"],"funding_grant_id":["RGPIN-2022-04028"],"pubmed_authors":["Desgagne M","Nguyen DT","Comeau C","Froehlich U","Marsault E","Ly HM","Boudreault PL"],"additional_accession":[]},"is_claimable":false,"name":"Insights on Structure-Passive Permeability Relationship in Pyrrole and Furan-Containing Macrocycles.","description":"Macrocycles have recognized therapeutic potential, but their limited cellular permeability can hinder their development as oral drugs. To better understand the structure-permeability relationship of heterocycle-containing, semipeptidic macrocycles, a library was synthesized. These compounds were created by developing two novel reactions described herein: the reduction of activated oximes by LiBH<sub>4</sub> and the aqueous reductive mono-<i>N</i>-alkylation of aldehydes using catalytic SmI<sub>2</sub> and stoichiometric Zn. The permeability of the macrocycles was evaluated through a parallel artificial membrane permeability assay (PAMPA), and the results indicated that macrocycles with a furan incorporated into the structure have better passive permeability than those with a pyrrole moiety. Compounds bearing a 2,5-disubstituted pyrrole (<i>endo</i> orientation) were shown to be implicated in intramolecular H-bonds, enhancing their permeability. This study highlighted the impact of heterocycles moieties in semipeptides, creating highly permeable macrocycles, thus showing promising avenues for passive diffusion of drugs beyond the rule-of-five chemical space.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-04-03T23:36:28.918Z","creation":"2025-04-03T23:36:28.918Z"},"accession":"S-EPMC10946398","cross_references":{"pubmed":["38417040"],"doi":["10.1021/acs.jmedchem.3c02162"]}}