Azido and diazarinyl analogues of bis-tyrphostin as asymmetrical inhibitors of dynamin GTPase.
Probing the dynamin binding site: Bis-tyrphostin (1, Bis-T), is a potent inhibitor of the phospholipid-stimulated GTPase activity of dynamin I. Analogues of Bis-T have significant potential as a biological probes for the dissection of endocytic pathways. Bis-T-derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues (23 and 24) represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibition.Two azidobenzyl amide (4 and 23) and one 3-trifluoromethyl-3H-diazirin-3-ylphenyl (24) analogues of bis-tyrphostin (1, Bis-T) were synthesised as potential photoaffinity labels for the elucidation of the binding site of compound 1 in dynamin I. Of the two azidobenzyl amide analogues (4 and 23), the terminally substituted 23 retained dynamin I GTPase inhibition (IC(50)=6.4+/-2.8 microM) whilst 4, which was substituted on the central carbon of the amide linker, displayed no activity. Analogue 24 also retained inhibitory activity (IC(50)=36+/-9 microM). Photoaffinity labelling experiments did not unequivocally elucidate the binding pocket of compound 1. However, compounds 23 and 24 represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibitory activity, providing a new direction for analogue synthesis.
Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Luke R
LR
Odell
Ngoc
N
Chau
Anna
A
Mariana
Mark E
ME
Graham
Phillip J
PJ
Robinson
Adam
A
McCluskey
D000818:Animals; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012756:Sheep; D020032:Tyrphostins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D020032:Tyrphostins; D034284:Dynamin I