Prodrugs of the Archetypal Dynamin Inhibitor Bis-T-22

Odell, Luke R. (author): Uppsala universitet,Preparativ läkemedelskemi,Univ Newcastle, Univ Dr, Callaghan, NSW 2308, Australia.

Robertson, Mark J. (author): Univ Newcastle, Univ Dr, Callaghan, NSW 2308, Australia.;James Cook Univ, Coll Sci & Engn, Chem, Townsville, Qld 4814, Australia.

Young, Kelly A. (author): Univ Newcastle, Univ Dr, Callaghan, NSW 2308, Australia.

McGeachie, Andrew B. (author): Univ Sydney, Childrens Med Res Inst, Cell Signalling Unit, 214 Hawkesbury Rd, Westmead, NSW 2145, Australia.

Quan, Annie (author): Univ Sydney, Childrens Med Res Inst, Cell Signalling Unit, 214 Hawkesbury Rd, Westmead, NSW 2145, Australia.

Robinson, Phillip J. (author): Univ Sydney, Childrens Med Res Inst, Cell Signalling Unit, 214 Hawkesbury Rd, Westmead, NSW 2145, Australia.

McCluskey, Adam (author): Univ Newcastle, Univ Dr, Callaghan, NSW 2308, Australia.

(creator_code:org_t)

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Abstract Subject headings

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 similar to 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 similar to 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 similar to 8 mu M, suggesting this compound is able to effectively cross the cell membrane where it is rapidly hydrolysed to the desired Bis-T-22 parent compound.

By the author/editor: Odell, Luke R.; Robertson, Mark ...; Young, Kelly A.; McGeachie, Andre ...; Quan, Annie; Robinson, Philli ...; show more...; McCluskey, Adam; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Organic Chemistr ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.