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7. Regiochemical assignments were confirmed by 2D NMR
studies. Substitution of dichloropyrimidine
2 occurs
regioselectively at C-4 when X = Br. When X = CF3, a
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(3:1, in favor of the C-4 isomer), while couplings with
compound 7 occur specifically at the C-2 position.
8. CDK1 assay was performed according to the manufac-
turerÕs protocol (New England Biolabs) with the minor
modification of incubating the reaction for 2 h at room
temperature. Indurubin 3-monoxime (IC50 = 180 nM) was
used as a reference inhibitor of CDK1 activity.
9. The structure of human CDK1 was built through homo-
11
logy modeling using MODELLER
in INSIGHTII. The
template used for building the model was the structure
of CDK2 in complex with 4-[(6-amino-4-pyrimidi-
nyl)amino]benzene sulfonamide.12 The template has 65%
sequence identity, 78% sequence similarity and 3% gaps
when aligned with the CDK1 sequence. Compounds 10,
13, and 35 were docked into CDK1 using GLIDE.13 The
obtained protein–ligand complex was optimized using
500 ps molecular dynamics simulation using TIP3P water
14
for solvation. The simulation was done using CHARMM
with constant dielectric of 1, temperature of 300 K, and
1 fs time step.
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