Synthesis of pharmacologically important naphthoquinones and anticancer activity of 2-benzyllawsone through DNA topoisomerase-II inhibition

• Published in: Bioorganic & medicinal chemistry 2017-02, Vol.25 (4), p.1364-1373
• Main Authors: Kumar, Balagani Sathish, Ravi, Kusumoori, Verma, Amit Kumar, Fatima, Kaneez, Hasanain, Mohammad, Singh, Arjun, Sarkar, Jayanta, Luqman, Suaib, Chanda, Debabrata, Negi, Arvind S.
• Format: Article
• Language: English
• Subjects: Acute oral toxicity; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Naphthoquinones; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Regioselective; Structure-Activity Relationship; Synthesis; Topoisomerase; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Tumor Cells, Cultured
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.12.043

Simple, efficient and straight-forward syntheses of lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved. Lawsone derivative exhibited significant anticancer activity through induction of apoptosis through caspase pathway and topoisomerase-II inhibition. [Display omitted] Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to β-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50=5.2μM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose.