Synthesis of Epothilone Analogs: Toward the Development of Potent Anticancer Drugs
Abstract
Having accomplished total syntheses of epoithilone A and B, we have been engaged in a new stage of investigation that involves development of efficient strategies for a large scale epothilone preparation and search for more potent analogues. Efficient and processable syntheses of key building blocks of 12,1 3-desoxyepothilone B (dEpoB) by catalytic asymmetric induction has been achieved. dEpoB is a potent anticancer agent, showing a highly promising therapeutic potential in the currently undergoing phase I study. The syntheses of two epothilone analogues, 15(S)-aza-12,13-desoxyepothilone B and the epimeric 15(R)-aza-12,13- -desoxyepothilone B have been accomplished. Tubulin binding and cytotoxicity profiles of these analogues have also been investigated. Another epothilone, 12,13-desoxyepothilone F (dEpoF), was synthesized and evaluated for antitumor potential. The results from an in vitro assay reveal that this new analogue is highly active against various tumor cell lines with a potency comparable to that of dEpoB. In particular, the growth of resistant tumor cells is inhibited by dEpoF at concentrations where paclitaxel (Taxol) is basically ineffective. A preliminary assessment of its in vivo activity is also promising. The new analogue, containing an additional hydroxyl group at C21, provides advantages over other epothilones in terms of water solubility and can serve as a readily functionalizable handle to produce other useful compounds for pertinent biological studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2000
- Accession Number
- ADA387649
Entities
People
- Chul B. Lee
- Samuel J. Danieshefsky
Organizations
- Memorial Sloan Kettering Cancer Center