Mitoxantrone, an anthraquinone derivative bearing polyamine side chains, can be considered as a partial analog of the anthracyclines including the hydroxyquinone function. This compound was obtained as an analog of ametantrone, which was initially prepared as a ballpoint pen ink, but a routine screening by NCI led to recognition of its antitumor activity. The reasoning that led to its design54 was based on the observation that a large number of antileukemic agents shared a common N-O-O triangular pharmacophore, which was also present in the anthra-cyclines and involved the daunosamine amino group (Fig. 4.21). The introduction of the two phenolic hydroxy groups in ametantrone allowed to envision two sets of N-O-O triangles, and had the advantage of eliminating the daunosamine amino group, which was considered to have some influence in the cardiotoxicity of the anthracyclines.55
Mitoxantrone is active in breast cancer, acute promyelocitic or myelogenous leukemias, and androgen-independent prostate cancer. Although early reports seemed to indicate that its cardiotoxicity was lower than that of the anthracy-clines,56 this claim has been subsequently challenged.57 Mitoxantrone has been recently approved for treatment of secondary progressive multiple sclerosis (MS).58 The rationale for this application stems from the fact that MS is considered to be an autoimmune disease where a heightened immune action results in the destruction of the myelin of the central nervous system, causing nerve impulses to be slowed or halted and leading to the symptoms of MS. Since chemotherapeutic
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