Author
Raphael Schiess
Other affiliations: ETH Zurich
Bio: Raphael Schiess is an academic researcher from École Polytechnique Fédérale de Lausanne. The author has contributed to research in topics: Epothilones & Wittig reaction. The author has an hindex of 3, co-authored 5 publications receiving 55 citations. Previous affiliations of Raphael Schiess include ETH Zurich.
Topics: Epothilones, Wittig reaction, Cyclopropanation, Epothilone, Ixabepilone
Papers
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TL;DR: The current review provides a comprehensive overview on the chemical transformations that have been investigated for the major epothilones A and B as starting materials, and it discusses the biological activity of the resulting products.
Abstract: Epothilones are myxobacterial natural products that inhibit human cancer cell growth through the stabil- ization of cellular microtubules (i.e., a "taxol-like" mech- anism 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 epothil- ones have included a large number of fully synthetic ana- logs and semisynthetic derivatives. Previous reviews on the chemistryandbiologyofepothiloneshavemostlyfocusedon analogs thatwereobtainedbydenovochemical synthesis.In contrast, the current review provides a comprehensive over- view on the chemical transformations that have been investi- gatedforthemajorepothilonesAandBasstartingmaterials, and it discusses the biological activity of the resulting prod- ucts. 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 clini-
34 citations
TL;DR: 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.
16 citations
21 Aug 2012
TL;DR: Drugs targeting cellular microtubules are an important element of the clinical armamentarium for cancer therapy, with applications in the treatment of a variety of cancer types, either as single agents or as part of different combination regimens.
Abstract: Drugs targeting cellular microtubules are an important element of our clinical armamentarium for cancer therapy,1 with applications in the treatment of a variety of cancer types, either as single agents or as part of different combination regimens.2,3 Microtubule-interacting agents can be grouped in...
3 citations
03 Oct 2014
TL;DR: This chapter will provide a brief summary of the in vitro and in vivo biological properties of epothilone B (Epo B) and the underlying synthetic chemistry and the most important preclinical features will be reviewed, together with some important related structures.
Abstract: Epothilones A and B are naturally occurring microtubule stabilizers with nanomolar or even sub-nanomolar activity against human cancer cells in vitro and potent in vivo antitumor activity against multidrug-resistant tumors. Over the last decade, ten epothilonetype agents have entered clinical trials in humans; of these, the epothilone B lactam ixabepilone (BMS-247550; Ixempra®) was approved by the FDA for breast cancer treatment in 2007. Numerous synthetic and semisynthetic analogs of epothilones have been prepared and their in vitro and (in selected cases) in vivo biological activity has been determined, producing a wealth of SAR information on this compound family. This chapter will provide a brief summary of the in vitro and in vivo biological properties of epothilone B (Epo B). The major part of the discussion will then be organized around those epothilone analogs that have entered clinical development. For each analog the underlying synthetic chemistry and the most important preclinical features will be reviewed, together with the properties of some important related structures.
3 citations
TL;DR: A comprehensive review on the chemical transformations that have been investi- gatedforthemajorepothilonesAandBasstartingmaterials, and the biological activity of the resulting prod- ucts can be found in this article.
Abstract: Epothilones are myxobacterial natural products that inhibit human cancer cell growth through the stabil- ization of cellular microtubules (i.e., a "taxol-like" mech- anism 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 epothil- ones have included a large number of fully synthetic ana- logs and semisynthetic derivatives. Previous reviews on the chemistryandbiologyofepothiloneshavemostlyfocusedon analogs thatwereobtainedbydenovochemical synthesis.In contrast, the current review provides a comprehensive over- view on the chemical transformations that have been investi- gatedforthemajorepothilonesAandBasstartingmaterials, and it discusses the biological activity of the resulting prod- ucts. 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 clini-
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TL;DR: This research presents a novel and scalable approaches called “Smart Gene Regulation” that allows for real-time annotation of the FISH signal in the Eindhoven–Borff–Seiden cellular automaton.
Abstract: Lech-Gustav Milroy,† Tom N. Grossmann,‡,§ Sven Hennig,‡ Luc Brunsveld,† and Christian Ottmann*,† †Laboratory of Chemical Biology and Institute of Complex Molecular Systems, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands ‡Chemical Genomics Centre of the Max Planck Society, Otto-Hahn Straße 15, 44227 Dortmund, Germany Department of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany
376 citations
TL;DR: The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.
Abstract: The recent uptake of molecular metathesis catalysts in specialty-chemicals and pharmaceutical manufacturing is reviewed.
210 citations
TL;DR: Strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples, which include diverted total synthesis (DTS), function-oriented synthesis (FOS), biology- oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis.
Abstract: In this article strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples. Proven strategies include diverted total synthesis (DTS), function-oriented synthesis (FOS), biology-oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis. The latter includes mutasynthesis, the synthesis of natural products encoded by silent genes, and propionate scanning. Most of the examples from our group fall in the quite general concept of DTS. Thus, in case an efficient strategy to a natural product is at hand, modifications are possible at almost any stage of a synthesis. However, even for compounds of moderate complexity, organic synthesis remains a bottle neck. Unless some method for predicting the biological activity of a designed molecule becomes available, the design and synthesis of natural product analogues will remain what it is now, namely it will largely rely on trial and error.
113 citations
TL;DR: Recent progress in the chemistry and biology of these diverse microtubule stabilizers focusing on the wide range of organisms that produce these compounds, their mechanisms of inhibiting microtubules-dependent processes, mechanisms of drug resistance, and their interactions with tubulin including their distinct binding sites and modes are covered.
113 citations
TL;DR: This review describes only a handful of exemplary natural products and their derivatives as well as those that have served as elegant blueprints for the development of novel synthetic structures that are either currently in use or in clinical or preclinical trials together with some of their earlier analogs in some cases whose failure to proceed aided in the derivation of later compounds.
Abstract: Microbes from two of the three domains of life, the Prokarya, and Eukarya, continue to serve as rich sources of structurally complex chemical scaffolds that have proven to be essential for the development of anticancer therapeutics. This review describes only a handful of exemplary natural products and their derivatives as well as those that have served as elegant blueprints for the development of novel synthetic structures that are either currently in use or in clinical or preclinical trials together with some of their earlier analogs in some cases whose failure to proceed aided in the derivation of later compounds. In every case, a microbe has been either identified as the producer of secondary metabolites or speculated to be involved in the production via symbiotic associations. Finally, rapidly evolving next-generation sequencing technologies have led to the increasing availability of microbial genomes. Relevant examples of genome mining and genetic manipulation are discussed, demonstrating that we have only barely scratched the surface with regards to harnessing the potential of microbes as sources of new pharmaceutical leads/agents or biological probes.
67 citations