Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents

Abstract

Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]-pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2-aminopyridine with 2,3-epoxyesters toward synthesis of 2-arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIα-selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIα inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research.

Quantitative Structure–Cytotoxicity Relationship of Aurones

“…When three OSCC cell lines and three normal oral cells were used, [7] showed the highest TS value (>9.7), followed by [2] (6.6) and [11] Table I). [7] showed the highest PSE value (>23.3), followed by [2] (21.5) and [11] (9.3) (D/B 2 ×100 in Table I). …”

Aurones: A Golden Resource for Active Compounds

“…Suzuki and co-workers demonstrated the anti-tumor efficacy of isoaurostatin 21 (Figure 7), the fungal metabolite of Thermomonospora alba, as the result of its inhibitory activity against Topoisomerase I [36], while Priyadarshani and co-workers reported on the ability of (Z)-2-(4-methoxybenzylidene)benzofuran-3(2H)-one 22 (Figure 7) to inhibit Topoisomerase II [37]. Overall, the benzofuran-3(2H)-one scaffold gave evidence these key enzymes regulating DNA replication and transcription, once decorated with appropriate Aurones and their derivatives have also been described as effective anti-inflammatory agents [6].…”

Silver‐Catalyzed Direct Regioselective C3 Phosphonation of 4H‐pyrido[1,2‐a]pyrimidin‐4‐ones With H‐phosphites

“…The 4 H ‐pyrido[1,2‐ a ]pyrimidin‐4‐ones are important nitrogen‐containing heterocycles and exhibit a wide range of remarkable biological properties (Figure 1), such as 5‐HT 6 antagonist, [9] anti‐cancer, [10] and antioxidant [11] . Among them, paliperidone as classics in chemical neuroscience is used for treatment of schizophrenia [12] .…”