From Bacteria to Antineoplastic: Epothilones A Successful History
Samuel Kaiser, Joseane John Muller, Pedro Eduardo Froehlich, Simone Cristina Baggio Gnoatto and Ana Maria Bergold
Affiliation: Faculdade de Farmacia Programa de Pos Graduacao em Ciencias Farmaceuticas (PPGCF), Universidade Federal do Rio Grande do Sul (UFRGS), Avenida Ipiranga 2752, Sala 708, Porto Alegre, RS, Brazil.
Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of
the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first
choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of
cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and
tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six
new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase III
clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the
treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer,
respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for
clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) in
comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones
presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects
presented by some substances of this class of anticancer drugs.
Keywords: Anticancer agents, chemotherapy, ixabepilone, patupilone, sagopilone, structure-activity relationship, semi-syntetic analogs.
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