title: Synthesis of novel naphthoquinone aliphatic amides and esters and their anticancer evaluation.
abstract: Fourteen new naphthoquinone aliphatic amides and seventeen naphthoquinone aliphatic esters were synthesized in nine to ten steps from 1-hydroxy-2-naphthoic acid with 9-25% overall yield for the amides, and 16-21% overall yield for the esters. The key step of the amide synthesis is a coupling reaction between amine and various aliphatic acids using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as a coupling agent while for the ester synthesis, DCC/DMAP or CDI was used as the coupling reagent between aliphatic acids and naphthoquinone alcohol. Both naphthoquinone amides and esters were evaluated for their anticancer activity against KB cells. It was found that naphthoquinone aliphatic amides showed stronger anticancer activity than those of the esters when the chains are longer than 7-carbon atoms. The optimum chain of amides is expected to be 16-carbon atoms. In addition, naphthoquinone aliphatic esters with α-methyl on the ester moiety possessed much stronger anticancer activity than the straight chains. Decatenation assay revealed that naphthoquinone amide with 16-carbon atoms chain at 15 μM and 20 μM can completely inhibit hTopoIIα activity while at 10 μM the enzyme activity was moderately inhibited. Molecular docking result also showed the same trend as the cytotoxicity and decatenation assay.
authors: Natural Products and Organic Synthesis Research Unit, Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, 50 Phahon Yothin Rd, Chatuchak, Bangkok 10900, Thailand.
authors: Boonsong
authors: B
authors: Kongkathip
authors: Sunisa
authors: S
authors: Akkarasamiyo
authors: Komkrit
authors: K
authors: Hasitapan
authors: Pichamon
authors: P
authors: Sittikul
authors: Nonlawat
authors: N
authors: Boonyalai
authors: Ngampong
authors: N
authors: Kongkathip
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007624:KB Cells; D008958:Models, Molecular; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004952:Esters; D009285:Naphthoquinones