901586-52-5Relevant academic research and scientific papers
Pyrimidyn-Based Dynamin Inhibitors as Novel Cytotoxic Agents
Odell, Luke R.,Chau, Ngoc,Russell, Cecilia C.,Young, Kelly A.,Gilbert, Jayne,Robinson, Phillip J.,Sakoff, Jennette A.,McCluskey, Adam
, (2021/11/16)
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 mono-substituted 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 GI50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N2-(3-dimethylaminopropyl)-N4-dodecyl-6-methylpyrimidine-2,4-diamine (31 a) and N4-(3-dimethylaminopropyl)-N2-dodecyl-6-methylpyrimidine-2,4-diamine (31 b).
Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain
Odell, Luke R.,Abdel-Hamid, Mohammed K.,Hill, Timothy A.,Chau, Ngoc,Young, Kelly A.,Deane, Fiona M.,Sakoff, Jennette A.,Andersson, Sofia,Daniel, James A.,Robinson, Phillip J.,McCluskey, Adam
supporting information, p. 349 - 361 (2017/04/26)
The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 ± 1.3 to 1.6 ± 0.3 μM) and CME (IC50(CME) = 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors.
