An efficient synthesis of 5‐organotellanyl‐1H‐1,2,3‐triazole compounds was accomplished through [3+2] cycloaddition reaction of organic azides and (organotellanyl)alkynes. Additionally, 5‐organotellanyl‐1H‐1,2,3‐triazoles were readily functionalized at the 5‐position by using a Sonogashira cross‐coupling reaction, leading to highly functionalised triazoles. The regiochemistry of the products was assessed by two‐dimensional NMR spectroscopic experiments and X‐ray crystallography.
Vaccinia-related
kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr
protein kinases associated with increased cell division and neurological
disorders. Nevertheless, the cellular functions of these proteins
are not fully understood. Despite their therapeutic potential, there
are no potent and specific inhibitors available for VRK1 or VRK2.
We report here the discovery and elaboration of an aminopyridine scaffold
as a basis for VRK1 and VRK2 inhibitors. The most potent compound
for VRK1 (26) displayed an IC50 value of 150
nM and was fairly selective in a panel of 48 human kinases (selectivity
score S(50%) of 0.04). Differences in compound binding mode and substituent
preferences between the two VRKs were identified by the structure−activity
relationship combined with the crystallographic analysis of key compounds.
We expect our results to serve as a starting point for the design
of more specific and potent inhibitors against each of the two VRKs.
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