Synthesis of symmetrical 1,5-bisacyloxyanthraquinone derivatives and their dual activity of cytotoxicity and lipid peroxidation.
Symmetrical bis-substituted anthraquinones were successfully prepared and demonstrated potent cytotoxicity against the growth of suspended murine and human tumors, i.e. rat glioma C6 cells and human hepatoma G2 cells.We report here a convenient synthetic pathway that leads to symmetrically substituted 1, 5-bisacyloxyanthraquinone derivatives. Acylation of the hydroxyl group of 1, 5-dihydroxyanthraquinone with the appropriate acyl chlorides in the presence of pyridine or sodium hydride, respectively, furnished this structural class of anthraquinones. The bis(butyryloxy) analog 2b, bis(2-chlorobenzoyl) analog 2f, and bisphenylpropionyloxy analog 2n exhibit potent cytotoxicity in inhibition of human hep G2 cell growth in culture, as determined by using XTT colorimetric assay, while their antiproliferative activity is markedly enhanced and is comparable to that of the anticancer agent mitoxantrone. In addition, redox properties of the compounds for the inhibition of lipid peroxidation in model membranes were determined. Compounds 2n also exhibited stronger antioxidant activity than ascorbic acid, (+)-alpha-tocopherol, and anthrarufin. Biological evaluation and SAR studies of these symmetrical anthraquinones have been performed and the results are discussed.
Huang
Hsu-Shan
HS
School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, ROC. huanghs@ndmctsgh.edu.tw
Chiu
Hui-Fen
HF
Chiou
Jeng-Fong
JF
Yeh
Pen-Fong
PF
Tao
Chi-Wei
CW
Jeng
Wei-Ren
WR
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents