Abstract 1623: 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone as a potential anticancer agent: its synthesis, characterization and anticancer properties

Abstract

Abstract A number of compounds based on the base compound 1,4,5,8 tetrahydroxyanthraquinone have anticancer properties. One compound of this class mitoxantrone bis-5,8 hydroxyethylaminoethylamino 1,4 dihydroxy anthraquinone has been on the market a number of years and is approved by the FDA for the treatment of: acute myelogenous leukemia, various lymphomas, breast cancer, sarcoma and the non-malignant condition multiple sclerosis. However this drug has a number of drawbacks: (1) for most cancer therapies is considered less effective than the anthracyclines, (2) although it has less cardiotoxicity than anthracyclines it does still has significant cardiotoxicity, (3) it is known to rapidly induce multi-drug resistance factors, and (4) has significant bone marrow toxicity. The class of compounds of 1,4-Bis aminoalkylamino class work against cancer cells by intercalating DNA in the major groove and inhibition of topoisomerase II enzyme. There have been a number of attempts to improve the class of drugs by adding different functional groups. However no compound of this class has exceeded the utility of mitoxantrone. Attempts to make derivatives of leuco 1,4,5,8-tetrahydroxyanthraquinone utilizing the replacement of all four hydroxyl groups for the purpose additional DNA binding or alkylation has been unsuccessful. It was discovered that 1,4,5,8-tetrachloroanthraquinone can be used as a base compound for production of compounds with potential anticancer activity. The compound 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone was synthesized and highly purified. It was found to have greater cytotoxicity in the screening assay than mitoxantrone or adriamycin. The cytotoxicity screening was done using the BOT-2 human breast cancer cell line. This compounds may have an advantage over the Bis-derivatives with: 1) greater cytotoxicity in screening assay, 2) cheap intermediates, 3) high yields, 4) increased number of potential active groups sites and 7) removal of the para dihydroxyl groups from the cytotoxic 1,4 bisaminoalkylaminoanthraquinone. This might result in reducing the potential for cardiotoxicity. The 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone was purified to 97.8 purity by HPLC. Initial screening in vivo mouse model B16 melanoma was done. The response was the same for mitoxantrone with considerably less toxicity. Citation Format: Don R. Ishmael, Orn Adelsteinsson. 1,4,5,8-Tetrakis-[(2-N,N-dimethylaminoethyl)amino]anthraquinone as a potential anticancer agent: its synthesis, characterization and anticancer properties. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1623. doi:10.1158/1538-7445.AM2014-1623