- Title
- Prodrugs of the Archetypal Dynamin Inhibitor Bis-T-22
- Creator
- Odell, Luke R.; Robertson, Mark J.; Young, Kelly A.; McGeachie, Andrew B.; Quan, Annie; Robinson, Phillip J.; McCluskey, Adam
- Relation
- ChemMedChem Vol. 17, Issue 24, no. e202200400
- Publisher Link
- http://dx.doi.org/10.1002/cmdc.202200400
- Publisher
- Wiley
- Resource Type
- journal article
- Date
- 2022
- Description
- 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 IC50 ∼8 μM, suggesting this compound is able to effectively cross the cell membrane where it is rapidly hydrolysed to the desired Bis-T-22 parent compound.
- Subject
- Bis-T-22; dynamin; endocytosis; prodrug
- Identifier
- http://hdl.handle.net/1959.13/1480799
- Identifier
- uon:50565
- Identifier
- ISSN:1860-7179
- Rights
- © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
- Language
- eng
- Full Text
- Reviewed
- Hits: 563
- Visitors: 612
- Downloads: 49
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT02 | Publisher version (open access) | 2 MB | Adobe Acrobat PDF | View Details Download |