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Small molecule inhi...
Small molecule inhibitors of dynamin I GTPase activity : development of dimeric tyrphostins.
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Hill, Timothy (author)
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Odell, Luke R (author)
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Edwards, Jennifer K (author)
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Graham, Mark E (author)
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McGeachie, Andrew B (author)
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Rusak, Jenny (author)
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Quan, Annie (author)
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Abagyan, Ruben (author)
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Scott, Janet L (author)
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Robinson, Phillip J (author)
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McCluskey, Adam (author)
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- 2005-10-29
- 2005
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:24
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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 microM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 microM). 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 microM 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 microM), its 3,4,5-trihydroxy congener (10) (IC50= 1.7 +/- 0.2 microM), and the corresponding 3-methyl ether (11) (IC50= 9 +/- 3 microM). 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 microM, 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 microM, 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 headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
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- ref (subject category)
- art (subject category)
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Hill, Timothy
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Odell, Luke R
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Edwards, Jennife ...
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Graham, Mark E
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McGeachie, Andre ...
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Rusak, Jenny
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show more...
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Quan, Annie
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Abagyan, Ruben
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Scott, Janet L
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Robinson, Philli ...
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McCluskey, Adam
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
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Journal of Medic ...
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Uppsala University