BMS-310705

A review.Epothilones are a novel class of natural cytotoxic compounds, originally isolated from the myxobacterium Sorangium cellulosum in the early 1990s.They induce hyperstabilization of microtubules similar to the taxanes leading to cell cycle arrest and finally to apoptosis.The natural epothilones are characterized by the letters A - F.Their chem. structure consists of a 16-membered macrocyclic ring system with a common side chain that differs in its oxidation status.Currently, natural epothilones, such as epothilone B (patupilone) and D (KOS-862), semisynthetic (ixabepilone, BMS-310705) and fully synthetic epothilones (sagopilone and KOS-1584) are in clin. development.Whereas paclitaxel and docetaxel provide significant clin. benefit in the treatment of a number of tumor types, their use is often limited by the development of multidrug resistance.Preclin. results indicate that natural epothilones are not subject to multidrug resistance to the same extent as the taxanes.Whether this translates into addnl. clin. benefit is currently the objective of extensive investigations.Ixabepilone, like the taxanes a substrate for PgP, has recently been approved for the treatment of metastatic breast cancer in the USA.However, the European agency CHMP declined a pos. opinion due to an insufficient benefit /risk ratio.Other epothilones are in different stages of development, the most advanced being patupilone in Phase III in ovarian cancer and sagopilone in Phase II in a number of different tumor types.Although their mechanism of action is identical and their chem. structures are very similar, epothilones exhibit a highly differentiated picture of activity, safety and tolerability profiles.For ixabepilone, the major adverse event is hematol. toxicity followed by peripheral sensory neuropathy.Patupilone, is mainly characterized by gastrointestinal side effects, which require pretreatment and concomitant therapy.In the case of sagopilone, peripheral sensory neuropathy is the major clin. relevant side effect.This review summarizes both preclin. and clin. results for the epothilones currently in clin. development.

Efficient regioselective syntheses of conjugates of folic acid and cytotoxic agents derived from natural epothilones are described. These folate receptor (FR) targeting compounds are water soluble and incorporate a hydrophilic peptide-based spacer unit and a reducible self-immolative disulfide-based linker system between the FR-targeting ligand and the parent drug.