News

February 21, 2011

Stereoselective Synthesis of 12,13-Cyclopropyl-Epothilone B and Side-Chain-Modified Variants

A general strategy has been devised for the stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants thereof,
which relies on late stage introduction of the heterocycle through Wittig olefination of ketone 14. Formation of the macrocycle was achieved
through RCM-based ring closure and introduction of the cyclopropane moiety involved a highly selective Charette cyclopropanation of allylic
alcohol 7.

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1 January 2011

Diversity through semisynthesis: the chemistry and biological
activity of semisynthetic epothilone derivatives

Epothilones are myxobacterial natural products
that inhibit human cancer cell growth through the stabilization
of cellular microtubules (i.e., a “taxol-like” mechanism
of action). They have proven to be highly productive
lead structures for anticancer drug discovery, with at least
seven epothilone-type agents having entered clinical trials in
humans over the last several years. SAR studies on epothilones
have included a large number of fully synthetic analogs
and semisynthetic derivatives. Previous reviews on the
chemistry and biology of epothilones have mostly focused on
analogs that were obtained by de novo chemical synthesis. In
contrast, the current review provides a comprehensive overview
on the chemical transformations that have been investigated
for themajor epothilones A and B as startingmaterials,
and it discusses the biological activity of the resulting products.
Many semisynthetic epothilone derivatives have been
found to exhibit potent effects on human cancer cell growth
and several of these have been advanced to the stage of clinical
development. This includes the epothilone B lactam ixabepilone
(Ixempra), which has been approved by the FDA
for the treatment of advanced and metastatic breast cancer.

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October 20, 2010

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5′-deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4′- and the 5′-hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7′-C8′ double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.