Biological Evaluations and Structure Activity Relationships of Anthracene and Anthraquinone Derivatives

• Main Authors: Rong-Fu Chen, 陳榮福
• Other Authors: Jyh-Fei Liao
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/64184651816850797122

碩士 === 國立陽明大學 === 藥理學研究所 === 93 === Emodin is a type of anthraquinone that is produced by plants. Free radical and reactive oxygene species (ROS) derived from it have the effects of immunity suppression, mutagenicity and cyto-toxicity. However, emodin is also an anti-oxidant and able to scavenger free radicals. Therefore it can be used as an anti-inflammatory agent or to suppress the lipid peroxidation. Sythesized anthraquinone such as doxorubicin is widely used to treat leukemia and breast cancer. But the semiquinone radical and ROS derived from doxorubicin, combined with nitric oxide (NO) generated from other action mechanisms, become factors which can cause toxicity in the heart. Previously Dr. Huang's laboratory has synthesized seven different categories of anthraquinone derivatives, including 9-alkoxy 1,5-dichloroanthracene (type I ), 9-acyloxy 1,5-dichloroanthracene (type II), 9-acyloxy 1,8-dichloroanthracene (type III), 1,5-bis-acyloxy-9,10-anthraquinones (type IV), 1,5-bis-thio- 9,10-anthraquinones (type V), 1,4-bis-amido- 9,10-anthraquinones (type VI ) and 1,5-diamino-9,10-anthraquinones (type VII ). Among these derivatives, some demonstrate good suppressing effects on both tumor cell proliferation and lipid peroxidation. Because superoxide anion (O2-•) and reactive oxygene species (ROS) generated from polymorphonuclear neutrophils (PMN) as well as nitric oxide (NO) generated from inducible NO synthases (iNOS) play a very important role in inflammation, this study further investigates the effect by these seven categories of anthraquinone derivatives on phorbol-12-myristate-13-acetate (PMA)-induced O2-• and ROS production by PMN, lipopolysaccharides (LPS)-induced NO release by RAW 264.7 cells and the proliferation of human oral epidermoid carcinoma cells (KB) and human hepatoma cells (Hepa 59T/VGH). The results showed that among sixty-seven different derivatives from five categories, six of them have stronger suppression than emodin upon the O2-• production by PMN. 2I and 2H are the strongest among these five derivatives. In addition, five compounds among twenty-one derivatives from category VI to VII, including 7E, 7BE, 7BF, 7DG and 7DH, have better suppressing effect than emodin upon ROS production by PMN. There is a relationship between the chemical structures of the derivatives, especially the length of the main chain and substituent groups, and the suppression activity of O2-• or ROS production. Six derivatives are chosen for the evaluation of their influences on LPS-induced NO release by RAW 264.7 cells. The results showed that five derivatives such as 2H, 6C, 6L, 7BF and 7DH have suppressing effects, with 7BF being the strongest one, wherease 7DJ promotes the NO production. The proliferation of KB and Hepa 59T/VGH cells are not significantly affected by the derivatives of VI category. Derivatives of VII category such as 7BF, 7DG and 7DH have suppressing effect. The strongest 7DH can suppress the growth with the ED50 values of 6.77 and 7.77 µg/mL respectively, which are twenty times and eighty-six times higher than those of doxorubicin. In summary, the derivative 7BF is found in this study to have better tumor suppressing effects and potentially better anti-inflammatory effects as well. It is worth exploring the detailed action mechanism and conducting further study on the in vivo bio-activity of 7BF.