Design and Synthesis of a Novel Series of Pyranonaphthoquinones as Topoisomerase II Catalytic Inhibitors

Abstract

On the basis of previous pharmacophore modeling studies of naphthoquinones derivatives, we have designed and synthesized a new set of pyranonaphthoquinones. These compounds were obtained through a direct and highly efficient approach based on an intramolecular domino Knoevenagel hetero Diels-Alder reaction from lawsone (2-hydroxynaphthoquinone) and a variety of aldehydes containing an alkene. The synthesized pyranonaphthoquinones were evaluated against the alpha isoform of human topoisomerase II (hTopoIIalpha). Among the 11 derivatives studied, we found that six of them act as catalytic inhibitors of the enzyme in vitro. These six derivatives strongly preclude the enzyme from decatenating or relaxing suitable substrates. Finally, we correlate their active/inactive status with docking studies of these novel compounds into the ATPase domain of hTopoIIalpha.

Yeast cytotoxic sensitivity to the antitumour agent β-lapachone depends mainly on oxidative stress and is largely independent of microtubule- or topoisomerase-mediated DNA damage

“…Although most quinones that show anti-Top2 in vitro activities are para-quinones from the anthra-and naphthoquinone families, some ortho-naphthoquinones inhibit Top2 as well. This later group includes salvicine, b-lap itself and other related pyranonaphthoquinones [31][32][33][34][35]. Top2 is a nuclear enzyme that relaxes, supercoils, decatenates and unknots DNA, all essential processes for cell survival.…”

“…Since Top2 is a well-established target in antitumour chemotherapy, we tested whether b-lap and 3-Br-b-lap interacted with Top2 both in vitro and in vivo. Interestingly, several naphthoquinones have already been shown to inhibit the whole Top2-catalysed reaction [32,34]. The first in vitro test we performed was a decatenation assay against kinetoplast DNA (kDNA) (Fig.…”

Synthesis and biological assessment of novel acylhydrazone derivatives of 2-methyl-1,4-naphthoquinone

“…[6][7][8][9][10][11][12] Thus, the naphthoquinone acylhydrazones 6a-m were assessed for their anticancer effects against MCF-7 and HCT116 cell lines using MTT viability assay. The results of the compounds after 24 h of treatment are summarized in Figure 6.…”

“…1 A multitude of naturally occurring naphthoquinones reportedly exhibit a diverse array of biological activities including fungicidal, 2 antibacterial, 3 antiviral, 4 antimalarial, 5 anticancer, 1,[6][7][8][9][10][11][12] in addition to effects that counter inflammation 13 and artherosclerosis.…”

Benzo[b]tryptanthrin Inhibits MDR1, Topoisomerase Activity, and Reverses Adriamycin Resistance in Breast Cancer Cells

“…The magnesium ion was assigned a charge of + 0.9. [44] The coordinate file for the structure of benzo [b]tryptanthrin was constructed by Sybyl 8.0 and minimized energetically using a Tripos force field with Gasteiger-Hückel charges. The receptor and ligand file were prepared according to the original publication protocols.…”