Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

Abstract

A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choicebased change" in target-specific mode of action for rapid drug discovery.

The Groebke‐Blackburn‐Bienaymé Reaction

“…With the aid of molecular docking studies they predicted bicyclic N-fused aminoimidazoles as potential human topoisomerase IIα (hTopoIIα). [63,94] Based on the previous reported topo II inhibitors in combination with known drugs containing an imidazo[1,2-a] scaffold, a library was synthesized using the GBB-3CR. The result is a GBB-3CR scaffolds, by heating the corresponding heterocyclic amidine, aldehyde and isocyanide with a catalytic amount of ZrCl 4 at 50°C in PEG-400 or under MW conditions at 140°C in n-butanol.…”

Increasing the distance between two monomers of topoisomerase IIβ under the action of antitumor agent 4β-sulfur-(benzimidazole) 4′-demethylepipodophyllotoxin

“…2A . Topoisomerase IIβ poisons such as VP-16 were known to stabilize the topoisomerase IIβ-DNA complex that lead to DNA breaks and generate linear DNA 23 , 24 . In agarose gel, linear DNA (L) was difficult to enter and appeared at the top; whereas the relaxed DNA (R), and supercoiled DNA (S) move easily into the gel.…”

Progress on the Photocatalytic Organic Hydrogen-Evolution Coupling/Aromatization Reaction

“…图式 14 光催化偶联放氢合成芳基唑类化合物 Scheme 14 Photocatalytic hydrogen-evolution coupling synthesis of aryl azoles 咪唑并吡啶是重要的稠合双环 5～6 元杂环结构, 在药物化学中被广泛应用 [50,51] . 雷爱文课题组 [52] 由于金属与氧元素的 HOMO 和 LUMO 之间较高的 能垒, C-H 官能化形成 C-O 键在金属催化中受到的关 注较少 [59] .…”