Synthesis of novel naphthoquinone aliphatic amides and esters and their anticancer evaluation

• Published in: European journal of medicinal chemistry Vol. 60; pp. 271 - 284
• Main Authors: Kongkathip, Boonsong, Akkarasamiyo, Sunisa, Hasitapan, Komkrit, Sittikul, Pichamon, Boonyalai, Nonlawat, Kongkathip, Ngampong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.02.2013; Elsevier
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Proliferation - drug effects; Cercopithecus aethiops; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; Humans; KB Cells; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Naphthoquinone aliphatic amide; Naphthoquinone aliphatic ester; Naphthoquinones - chemistry; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Topoisomerase II; Vero Cells; Naphthoquinone aliphatic ester; Naphthoquinone aliphatic amide; Topoisomerase II; Anticancer activity; Cancer; APOPTOSIS; CELLS; RHINACANTHUS-NASUTUS; INDUCTION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.12.006

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. [Display omitted] ► Fourteen novel naphthoquinone aliphatic amides and seventeen naphthoquinone aliphatic esters were synthesized. ► They were evaluated for cytotoxicity against cancer cell lines. ► The decatenation assay and molecular docking of selected naphthoquinone aliphatic amides and esters were investigated.