D11, a novel glycosylated diphyllin derivative, exhibits potent anticancer activity by targeting topoisomerase IIα

Abstract

Glycosylated natural products are reliable platforms for the development of anticancer drugs, simply due to the important features added by sugar appendages to the shape and the stereoelectronic properties of natural scaffolds. Herein, we indentified D11, a novel diphyllin glycoside with acetylated D-quinovose sugar moiety, as a potent topoisomerase IIα (Topo IIα) inhibitior. This peculiar sugar moiety endows D11 an optimal conformation with a high binding affinity for Topo IIα via hydrogen bonding to the entrance of ATPase pocket, thereby helping achieve more potent Topo II inhibition activity compared to the aglycon diphyllin. Further biochemical insights manifested that D11 significantly inhibited Topo IIα ATPase-catalyzed ATP hydrolysis in an ATP-dependent, but a DNA-independent manner. All these underlie the consequent superiority of D11 in the in vitro proliferation inhibition, apoptosis induction and the in vivo remarkable antitumor potency in xenograft mouse model. Moreover, D11 treatment also displayed no obvious body weight loss and other apparent toxicities, indicative of the restricted side effects by the virtue of sugar attachment. Taken together, a defined glycosylated manipulation of diphyllin may be a promising alternative approach in the development of novel Topo II inhibitors.

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase

“…Fourth, daurinol did not inhibit the activity of human topo isomerase I, which does not contain an ATP-binding domain. These properties of daurinol are similar to those reported for D11, a novel glycosylated diphyllin derivative (22). Taken together, these data demonstrate that daurinol inhibits human topoisomerase IIα by targeting its ATP-binding domain.…”

Proposal of Dual Inhibitor Targeting ATPase Domains of Topoisomerase II and Heat Shock Protein 90

“…Diphyllin was extracted from Justicia procumbens , which showed tumoricidal effects. D11 is a novel acetylated D-quinovose diphyllin analogue exhibiting potent topo II inhibitory activity and binding to the ATPase domain (Gui et al ., 2011). When the compound binds to the ATP binding site it is not always a topo II catalytic inhibitor, as it is the case with salvicine and emodin.…”

Recent Advances in the Development of Catalytic Inhibitors of Human DNA Topoisomerase IIα As Novel Anticancer Agents

“…D11 was also tested against 18 different tumour cell lines from diverse tissues including breast, colon, liver, stomach, blood and ovary as well as normal lines. The average value of its inhibitory activity against all tested cell lines was 0.652 M [67].…”

“…The binding Fig. (B) of this compound was subsequently investigated by the surface plasmon resonance (SPR) technique, where it was demonstrated that compound 13 binds to the ATPase domain with a K D of 37.7 M [67]. A molecular docking study revealed a flat scaffold of D11 occupies a hydrophobic pocket, while the sugar moiety forms a hydrogen bond with Arg98 at the entrance of the ATP binding pocket.…”