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.

Synthesis of symmetrical 1,5-bis-thio-substituted anthraquinones for cytotoxicity in cultured tumor cells and lipid peroxidation.

The synthesis of a series of anthraquinone moieties bearing symmetrical sulfur-linked substituents in the 1 and 5 positions is described. These compounds were evaluated for their ability to inhibit the growth of suspended rat glioma C6 cells and human hepatoma G2 cells, respectively. In addition, the redox property of the compounds was determined based on the inhibition of lipid peroxidation in model membranes. Compounds 2a and 2h in this series compared favorably and exhibited the most potent cytotoxicity (0.02, 0.05 microM) against C6 cells in the XTT colorimetric assay. As far as redox properties are concerned, all bis-thio-anthraquinones show potential lipid peroxidation in model membranes very close to that of mitoxantrone (MX), and 2a, 2d, 2e, 2i, 2j, and 2k have more potential than that of MX. The lack of cytotoxicity of compound 2i cannot be related to lipid peroxidation, but the steric and electronic properties of the side-chain substituent maybe impair effective recognition of the cleavable complex. In contrast to MX, 2a and 2h are cytotoxic in rat glioma C6 cells and do not enhance lipid peroxidation in model membranes.