Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/28860

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Title
Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins
Author/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.
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.
Relation
Journal of Medicinal Chemistry Vol. 48, Issue 24, p. 7781-7788
Publisher Link
http://dx.doi.org/10.1021/jm040208l
Date
2005
Publisher
American Chemical Society Publications
Keyword(s)
dynamin I;  GTPase enzyme;  endocytosis;  tyrphostins;  BisT;  GTPase inhibitor
Resource Type
journal article
Identifier
http://hdl.handle.net/1959.13/28860
Identifier
ISSN:1520-4804
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Subject
"Journal of Medicinal Chemistry"
 
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