Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

Abstract

Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from monosubstituted to trisubstituted. The highest levels of dynamin inhibition were noted with di-and tri-substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1-10, 10-25 and 25-60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues (31 a,b) developed returned average GI 50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N 2 -(3-dimethylaminopropyl)-N 4 -dodecyl-6-methylpyrimidine-2,4-diamine (31 a) and N 4 -(3-dimethylaminopropyl)-N 2 -dodecyl-6-methylpyrimidine-2,4-diamine (31 b).

The sulfonadyns: a class of aryl sulfonamides inhibiting dynamin I GTPase and clathrin mediated endocytosis are anti-seizure in animal models

“…IC 50 values are determined as described by the software program manufacturer using the model: Y = bottom + (top − bottom)/(1 + 10((log IC 50 − X ) × hillslope)). 54,74,75 The curves were generated using the Michaelis–Menten equation v = V max [ S ]/( K m + [ S ]) where S = PS activator or GTP substrate. After the V max and K m values were determined, the data was transformed using the Lineweaver–Burk equation 1/ v = 1/ V max + ( K m / V max ) × (1/[ S ]).…”