title: First synthesis and anticancer activity of novel naphthoquinone amides.
abstract: 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.
authors.affiliation: Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, Thailand.
authors.forename: Narathip
authors.initials: N
authors.lastname: Pradidphol
authors.forename: Ngampong
authors.initials: N
authors.lastname: Kongkathip
authors.forename: Pichamon
authors.initials: P
authors.lastname: Sittikul
authors.forename: Nonlawat
authors.initials: N
authors.lastname: Boonyalai
authors.forename: Boonsong
authors.initials: B
authors.lastname: Kongkathip
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009285:Naphthoquinones; D004250:DNA Topoisomerases, Type II