Design and synthesis of gambogic acid analogs as potent cytotoxic and anti-inflammatory agents

• Published in: Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (12), p.4018-4022
• Main Authors: Yen, Chiao-Ting, Nakagawa-Goto, Kyoko, Hwang, Tsong-Long, Morris-Natschke, Susan L., Bastow, Kenneth F., Wu, Yang-Chang, Lee, Kuo-Hsiung
• Format: Article
• Language: English
• Subjects: 1,3,6-Trihydroxy-9H-xanthen-9-one; Anti-inflammatory activity; anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antiinflammatory agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cancer; Cell Line, Tumor; Cell Survival - drug effects; chemistry; Cytotoxicity; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Elastase; formyl peptides; Ggambogic acid (GA); Humans; Inflammation; Inhibitory Concentration 50; Leukocytes (neutrophilic); Medical sciences; Multidrug resistance; multiple drug resistance; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Pancreatic Elastase - antagonists & inhibitors; Pancreatic Elastase - metabolism; Pharmacology. Drug treatments; phenylmethylsulfonyl fluoride; Prenylation; Prenylxanthones; Pyranoxanthones; Structure-Activity Relationship; superoxide anion; superoxide anions; Superoxides - metabolism; Tumor cell lines; Xanthones - chemical synthesis; Xanthones - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.04.084

Two pyranoxanthones (16 and 20) showed the greatest activity against the KBvin multidrug resistant (MDR) cell line with IC50 values of 0.9 and 0.8μg/mL, respectively. An angular 3-methyl-3-prenyl pyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than PMSF, the positive control. Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7–13 were generally less active than pyranoxanthones 14–21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC50 values of 0.9 and 0.8μg/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control.