2 research outputs found
Interrogation of the Active Sites of Protein Arginine Deiminases (PAD1, -2, and -4) Using Designer Probes
Protein arginine deiminases (PADs) are involved in a
number of
cellular pathways, and they catalyze the transformation of peptidyl
arginine residue into a citrulline as part of post-translational modifications.
To understand ligand preferences, a group of probe molecules were
investigated against PAD1, PAD2, and PAD4. These probe molecules carried
a well-known covalent modifier of the catalytic cysteine residue,
2-chloroacetamidine moiety, which was tethered to an α-amino
acid via a carbon linker. The chain length for the linker varied from
0 to 4. Time-dependent assays indicated that 2-chloroacetamidine (2CA)
with no linker inhibited all PAD enzymes with a similar trend in the
second-order rate constants, although with poor affinity. Among the
other three probe molecules, compound <b>3</b> with a three-carbon
linker exhibited the best second-order rate constants for optimal
ligand reactivity with the binding site. These analyses provide insights
into the relative patterns of covalent inactivation of PAD isozymes
and the design of novel inhibitors targeting PAD enzymes as potential
therapeutic targets
Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4
Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2<i>H</i>)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G<sub>2</sub>/M phase and bind to the colchicine-binding site on β-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds <b>36</b>, <b>44</b>, and <b>45</b> efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships