Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins.
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.
Hill
Timothy
T
Discipline of Chemistry, Chemistry Building, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
Odell
Luke R
LR
Edwards
Jennifer K
JK
Graham
Mark E
ME
McGeachie
Andrew B
AB
Rusak
Jenny
J
Quan
Annie
A
Abagyan
Ruben
R
Scott
Janet L
JL
Robinson
Phillip J
PJ
McCluskey
Adam
A
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
D020032:Tyrphostins; D034284:Dynamin I