Structure basis for the inhibitory mechanism of a novel DNase γ-specific inhibitor, DR396 was written by Sunaga, Satoshi;Yoshimori, Atsushi;Shiokawa, Daisuke;Tanuma, Sei-ichi. And the article was included in Bioorganic & Medicinal Chemistry in 2006.Electric Literature of C9H6Cl2N4 The following contents are mentioned in the article:
DNase γ, a member of the DNase I family, has been suggested to cause DNA fragmentation during apoptosis. The authors recently identified 4-(4,6-dichloro-[1,3,5]-triazine-2-ylamino)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoic acid (DR396) as a novel specific inhibitor for human DNase γ. However, the binding mode (coordinate) of DR396 to DNase γ has not yet been defined. Here, the authors examined the mol. basis for the inhibitory activity of DR396 to DNase γ by structure-based computational docking studies. In the blind-docking study using a human DNase γ homol. model, a unique binding site of DR396 was predicted, which is tentatively named the DNA trapping site because of the binding domain of the unhydrolyzed DNA strand, but not the active site. Targeting the DNA trapping site as a hot spot, new human DNase γ inhibitors were obtained from our diverse chem. library in silico. These inhibitors showed high correlations between their predicted binding-free energies (ΔGs) and observed IC50 values in the DNA trapping site but not the active site. The IC50 of a regioisomer of DR396, 5-(4,6-dichloro-[1,3,5]-triazine-2-ylamino)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoic acid (DF365), was 73 μM (ΔG = -9.75 kcal/mol), a 20-fold weaker inhibitory ability than that of DR396 (IC50 = 3.2 μM, ΔG = -11.22 kcal/mol). Fluorescein and triazine derivatives, partial structures of DR396, had little inhibitory activity for DNase γ. Docking analyses of the interaction between DR396 and DNase γ revealed that DR396 binds tightly to three subsites (S1, S2, and S3) in the trapping site of DNase γ by forming six hydrogen bonds, whereas DF365 and the partial structures are unable to form hydrogen bonds at all three subsites. These findings suggest that the specificity and potency of the inhibitory activity of DR396 for DNase γ is due to the specific interaction of DR396 with three subsites in the DNA trapping site of DNase γ. This study involved multiple reactions and reactants, such as 4,6-Dichloro-N-phenyl-1,3,5-triazin-2-amine (cas: 2272-40-4Electric Literature of C9H6Cl2N4).
4,6-Dichloro-N-phenyl-1,3,5-triazin-2-amine (cas: 2272-40-4) belongs to organic chlorides. Organic chlorides can cause corrosion in pipelines, valves and condensers, and cause catalyst poisoning. The hydrocarbon processing industry (HPI) and others are affected by damage caused by these substances.While alkyl bromides and iodides are more reactive, alkyl chlorides tend to be less expensive and more readily available. Alkyl chlorides readily undergo attack by nucleophiles.Electric Literature of C9H6Cl2N4
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Chloride – Wikipedia,
Chlorides – an overview | ScienceDirect Topics