- Title
- Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins
- Creator
- Hill, Timothy; Odell, Luke; McCluskey, Adam; Edwards, Jennifer K.; Graham, Mark E.; McGeachie, Andrew B.; Rusak, Jenny; Quan, Annie; Abagyan, Ruben; Scott, Janet L.; Robinson, Phillip J.
- Relation
- Journal of Medicinal Chemistry Vol. 48, Issue 24, p. 7781-7788
- Publisher Link
- http://dx.doi.org/10.1021/jm040208l
- Publisher
- American Chemical Society Publications
- Resource Type
- journal article
- Date
- 2005
- Description
- Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a μM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC₅₀ 70 μM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low μM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC₅₀ = 5.1 ± 0.6 μM), its 3,4,5-trihydroxy congener (10) (IC₅₀ = 1.7 ± 0.2 μM), and the corresponding 3-methyl ether (11) (IC₅₀ = 9 ± 3 μM). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC₅₀'s of 1.7 ± 0.2, 1.7 ± 0.2, and 5 ± 1 μM, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC₅₀'s of 42 ± 3, 38 ± 2, and 61 ± 2 μM, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.
- Subject
- dynamin I; GTPase enzyme; endocytosis; tyrphostins; BisT; GTPase inhibitor
- Identifier
- uon:2267
- Identifier
- http://hdl.handle.net/1959.13/28860
- Identifier
- ISSN:1520-4804
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