Structural Modification Of R(+)XK469 And Preliminary Antitumor Evaluation

As a type of nuclear enzyme, DNA topoisomerase (Topo) is widely expressed in all kinds of biosome and modulates the topology of chromosomal DNA. Eukaryotic DNA topoisomerases include topoisomerase Ⅰ and Ⅱ. It has proved that Topo II is high expressed in various tumor cells. Thereby, Topo Ⅱ has been an ideal and important target for the development of potential antitumor drugs. At present, a variety of topoisomerase Ⅱ inhibitors, such as etoposide, doxorubicin and mitoxantrone, etc, have been approved in the treatment of various malignancies.In this article, a series of quinoxalinone derivatives have been designed and synthesized as Topo II inhibitors, based on several designing principles including fragment combination, pharmocophoric migration and, bioisosteric replacement. Consequently, the antitumor activities of the synthesized compounds were preliminary evaluated by MTT assay. Three tumor cell lines that are sensitive to Topo Ⅱ, MCF-7 (breast cancer cell), K562 (leukemia cells) and Hela (cervical cancer cell), were chosen in the assay. As a result, compounds 13a and 13b, which contain dodecyl group, show improved antitumor activity than the control doxorubicin in the MTT assay.The SAR study showed that introducing long chain alphalic substituents in the 3-position of quinoxalinone skeletone is beneficial for the enhancement of antitumor activity, as exemplified by the compounds 13a and 13b, which possess dodecyl substituent in the 3-quinoxalinone. Moreover, these two compounds showed better potency than the methyl (compound 6f) or terf-butylamine (compound 13f,13h) counterparts. As to the R2 substituents, both benzyl (compoundl3a) and methyl (compound 3b) are preferable, and hydroxyl group (compounds 13a,13b) seems to be the most suitable substituent for the R3 group.