KW-2170 (18) is a synthetic pyrazoloacridone derivative, prepared in a 13-step synthesis in 12% overall yield.103 KW-2170 is a topo II inhibitor with lower cardiotoxicity and lower cross-resistance to other topo II agents than doxorubicin. It was superior to doxorubicin against a variety of subcutaneous syngeneic and human tumor xenografts in mice (sarcoma 180, breast carcinoma MM102, fibrosarcoma Meth A, the doxorubicin-resistant human ovary carcinoma A2780/ADM, and nasopharynx carcinoma KB-A1).104 Several Phase I studies have been reported,105 with maximum tolerated dose suggested between 25 and 50 mg m _ 2. A recent Phase I study using a 30-min intravenous infusion every 4 weeks showed a maximum tolerated dose of 53 mg m _ 2, with the major toxicity being neutropenia. There were no objective responses, but no cardiotoxicity.106 Acridines and Related Intercalators

The acridines have been widely used as drugs, primarily as antibacterial and antiprotozoal agents, but increasing also as anticancer drugs. Amsacrine

The 9-anilinoacridine amsacrine (19) is a relatively weak DNA binder, with an association constant of 1.8 x 105M "1 for calf thymus DNA in 0.01 M salt, via reversible, enthalpy-driven108 intercalation of the acridine chromophore. It was one of the drugs first used to show that topo II was the target of most DNA intercalators,109 and has been widely used since then as a probe to study topoisomerase action. It is postulated to bind with the anilino ring lodged in the minor groove, with the 1'-substituent pointing tangentially away from the helix.110 Amsacrine appears unique among topo II poisons in that its ability to trap both topo IIa- and topo II^-induced lesions is only modestly reduced in ATP-depleted cells, implying that it produces mainly pre-strand passage DNA lesions, whereas other topo II poisons stabilize poststrand passage DNA lesions in intact cells.111 It was one of the first synthetic topo II inhibitors to reach clinical trial. The clinical use of amsacrine is mainly in acute myeloid leukemia,113 although successful use in various adult leukemias has also been reported; a recent Phase II trial114 of amsacrine with ara-C and etoposide in refractory acute leukemia achieved a complete remission rate of 55%.


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