First synthesis and anticancer activity of novel naphthoquinone amides

Sixteen novel naphthoquinone aromatic amides were synthesized by a new route starting from 1-hydroxy-2-naphthoic acid in nine or ten steps with good to excellent yield. Amide formation reaction was carried out by using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as an efficient condensing agent leading to carboxamides in high yield. The key step for converting naphthol to 3-hydroxynaphthoquinone was the Fremy’s salt oxidation followed by hydroxylation with tert-butyl hydroperoxide and triton B. Anticancer activity of these new naphthoquinone amides were evaluated and benzamide 22 showed potent inhibition against NCI-H187 cell lines while naphthamides 23 and 43 were the most potent inhibition against KB cells. The decatenation assay revealed that compounds 24 and 43 at 20 μM can inhibit hTopoIIα activity while three other compounds, namely compounds 22, 23, and 45, exhibited hTopoIIα inhibitory activity at final concentration of 50 μM. Docking experiment revealed the same trend as the cytotoxicity and decatenation assay. Therefore, naphthamides 24 and 43 can be promising target molecules for anticancer drug development.

Graphical abstractNovel naphthoquinone aromatic amides were synthesized in nine or ten steps and evaluated for their anticancer activity against KB, NCI-H187, and MCF-7 cell lines. Decatenation assay was also carried out. Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Sixteen novel naphthoquinone aromatic amides were synthesized in excellent yield. ► They were investigated for anticancer activity against three cancer cell lines. ► The decatenation assay was carried out against hTopoIIα activity. ► Molecular docking between naphthoquinone amides and hTopoIIα was performed.