Prodrugs of the Archetypal Dynamin Inhibitor Bis-T-22.
Bis-T-22
dynamin
endocytosis
prodrug
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
16 12 2022
16 12 2022
Historique:
revised:
06
10
2022
received:
21
07
2022
pubmed:
10
11
2022
medline:
21
12
2022
entrez:
9
11
2022
Statut:
ppublish
Résumé
The Bis-T series of compounds comprise some of the most potent inhibitors of dynamin GTPase activity yet reported, e. g., (2E,2'E)-N,N'-(propane-1,3-diyl)bis(2-cyano-3-(3,4-dihydroxyphenyl)acrylamide) (2), Bis-T-22. The catechol moieties are believed to limit cell permeability, rendering these compounds largely inactive in cells. To solve this problem, a prodrug strategy was envisaged and eight ester analogues were synthesised. The shortest and bulkiest esters (acetate and butyl/tert-butyl) were found to be insoluble under physiological conditions, whilst the remaining five were soluble and stable under these conditions. These five were analysed for plasma stability and half-lives ranged from ∼2.3 min (propionic ester 4), increasing with size and bulk, to greater than 24 hr (dimethyl carbamate 10). Similar profiles where observed with the rate of formation of Bis-T-22 with half-lives ranging from ∼25 mins (propionic ester 4). Propionic ester 4 was chosen to undergo further testing and was found to inhibit endocytosis in a dose-dependent manner with IC
Identifiants
pubmed: 36351775
doi: 10.1002/cmdc.202200400
doi:
Substances chimiques
Prodrugs
0
Dynamins
EC 3.6.5.5
Esters
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202200400Informations de copyright
© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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