Synthesis and pharmacological activity evaluation of arctigenin monoester derivatives.
Arctigenin (ARG), a nature medicine with many pharmacological activities, was poorly soluble in water and placed restriction on practical usage. Six novel arctigenin monoester derivatives were obtained from the reflux reaction with arctigenin, carboxylic acids (crotonic acid, furoic acid, 2-naphthalene acid and indol-3-acetic acid), EDCI and DMAP in dichloromethane at 60°C for 4-6h and their properties on nitrite scavenging assay were investigated in vitro. Based on the results, the one of the most effective derivatives, arctigenin β-indolylacetate (ARG6), was selected to study anti-tumor activity in vivo at doses of 20 and 40mg/kg. The results showed that comparison with ARG group, ARG6 exhibited more anti-tumor activity in H22 tumor-bearing mice. Furthermore, ARG6 exhibited less damage to the liver, kidney, spleen and thymus when compared with those in positive group. Biochemical parameters of ALT, AST, BUN and Cre showed ARG6 had little toxicity to mice as well. ARG6 significantly improved serum cytokine levels of IL-2, IL-6, IFN-γ and TNF-α, and decreased VEGF compared with ARG. Moreover, H & E staining, TUNEL assay and immunohistochemical of tumor issues also indicated that ARG6 exhibited anti-tumor activity in vivo. In brief, the present study provide a method to improve ARG anti-tumor activity and provide a reference for new anti-tumor agent.
College of Chinese Medicinal Material, Jilin Agricultural University, NO. 2888 Xincheng Street, Nanguan District, Changchun, Jilin Province,130118, China.
Qiulian
Q
Chen
College of Chinese Medicinal Material, Jilin Agricultural University, NO. 2888 Xincheng Street, Nanguan District, Changchun, Jilin Province,130118, China. Electronic address: ylmh777@126.com.
Limin
L
Yang
College of Chinese Medicinal Material, Jilin Agricultural University, NO. 2888 Xincheng Street, Nanguan District, Changchun, Jilin Province,130118, China.
Mei
M
Han
College of Chinese Medicinal Material, Jilin Agricultural University, NO. 2888 Xincheng Street, Nanguan District, Changchun, Jilin Province,130118, China.
Enbo
E
Cai
College of Chinese Medicinal Material, Jilin Agricultural University, NO. 2888 Xincheng Street, Nanguan District, Changchun, Jilin Province,130118, China.
Yan
Y
Zhao
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D018836:Inflammation Mediators / Q000097:blood; D017705:Lignans / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009573:Nitrites / Q000737:chemistry; D013329:Structure-Activity Relationship; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D016207:Cytokines; D004952:Esters; D005663:Furans; D018836:Inflammation Mediators; D017705:Lignans; D009573:Nitrites; C071942:arctigenin
Anti-tumor activity in vivo; Aretigenin; H & E; Immunohistochemistry; Monoester derivatives; Nitrite scavenging assay in vitro; TUNEL