Synthesis and Cytotoxicity Evaluation of 13-<em>n</em>-Alkyl Berberine and Palmatine Analogues as Anticancer Agents

Abstract

By introducing long carbon-chain alkyl groups at the C-13 position of berberine and palmatine, 13-<em>n</em>-hexyl/13-<em>n</em>-octyl berberine and palmatine chloride analogues <strong>4a</strong>–<strong>d </strong>were synthesized and examined by MTT assays for cytotoxic activity in seven human cancer cell lines (7701QGY, SMMC7721, HepG2, CEM, CEM/VCR, KIII, Lewis), yielding IC₅₀ values of 0.02 ± 0.01–13.58 ± 2.84 μM. 13-<em>n</em>-Octyl palmatine (compound <strong>4d</strong>) gave the most potent inhibitor activity, with an IC₅₀ of 0.02 ± 0.01 μM for SMMC7721. In all cases, the 13-<em>n</em>-alkyl berberine and palmatine analogues<strong> 4a</strong>–<strong>d</strong> were more cytotoxic than berberine and palmatine. In addition, compounds <strong>4a</strong>–<strong>d </strong>also exhibited more potent cytotoxicity than berberine and palmatine in mice with S180 sarcoma xenografted<em> in vivo</em>. The primary screening results indicated that the 13-<em>n</em>-hexyl/13-<em>n</em>-octyl berberine and palmatine analogues might be valuable source for new potent anticancer drug candidates.

Keywords

• berberine
• palmatine
• alkylation
• cytotoxicity
• antitumor