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Sulfonadyn Compounds: A Class of Aryl Sulfonamides That Inhibit Dynamin GTPase and Clathrin-Mediated Endocytosis and Are Antiepileptic in Animal Models
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DOI：10.1021/acschembio.6c00046.png)
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Abstract
En 中文
Synthetic modification of dansylcadaverine (1) and our previously identified dynamin I and clathrin-mediated endocytosis inhibitor S1–47 gave rise to new members of the sulfonadyns class of GTP-competitive dynamin inhibitors. Analogues in this class displayed high dynamin I, dynamin II, and clathrin-mediated endocytosis inhibition (inhibition of Tfn-A594 uptake in U2OS cells). Dynamin activity was typically low micromolar with modest to no dynamin I versus dynamin II selectivity. For all analogues excepting those with bulky biaryl-terminal substituents, CME inhibition was within 1 order of magnitude of the dynamin I/II inhibition values. Michaelis–Menten kinetic analysis confirmed the GTP-competitive nature of these compounds. Closer examination of one analogue, 13 (we call S1–178B2), showed no dose-limited off-target effects in a CEREP ExpresS profile panel (55 binding assays) screen at 10 μM. Moreover, S1–178B2 showed no protein kinase activity when examined against PKA, PKC2β, AurA/Aur2 kinase, and CaMK2α. Preliminary pharmacokinetic evaluation reveals that a 100 mg/kg IP injection gave a 17 μM blood and 32 μM brain concentration after 15 and 30 min, respectively. A pull-down bead based on S1–178B2 allowed the identification of both dynamin I and dynamin II, supporting on-target activity in cells. Examination of S1–178B2 in the 6 Hz psychomotor seizure test revealed a significant increase in seizure threshold at doses of 30 (p = 0.003) and 100 mg/kg ip (p < 0.0001), with the higher dose proving to be similarly effective as the first-line antiseizure medication, sodium valproate. Finally, S1–178B2 was examined in the rat kindling model of epilepsy, demonstrating a clear dose-dependent reduction in seizure duration (p = 0.012) and a reduction in severity (p = 0.09) at 100 and 300 mg/kg, comparable to another first-line antiseizure medication, carbamazepine. These results indicate that the sulfonadyns show promise as a novel class of antiseizure medication with a mechanism of action targeting CME.
Keywords:
Anatomy
Endocytosis
Inhibition
Inhibitors
Rodent models
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