title: Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins.
abstract: 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.
authors.affiliation: Discipline of Chemistry, Chemistry Building, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hill
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Edwards
authors.forename: Mark E
authors.initials: ME
authors.lastname: Graham
authors.forename: Andrew B
authors.initials: AB
authors.lastname: McGeachie
authors.forename: Jenny
authors.initials: J
authors.lastname: Rusak
authors.forename: Annie
authors.initials: A
authors.lastname: Quan
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Janet L
authors.initials: JL
authors.lastname: Scott
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D019281:Dimerization; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012756:Sheep; D013329:Structure-Activity Relationship; D020032:Tyrphostins / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D020032:Tyrphostins; D034284:Dynamin I