Angewandte Chemie International Edition

Cover image for Vol. 54 Issue 41

Editor: Peter Gölitz, Deputy Editors: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

Press Release

For full article and contact information, see Angew. Chem. Int. Ed. 2003, 42 (39), 4762—4762

No. 39b/2003

Reknitting Molecules

Designed antitumor agent with a highly promising pharmacological profile

Modern methods of "high-throughput screening" make it possible to search for new pharmaceuticals in giant—though sometimes quite randomly compiled—substance libraries. In contrast, an interdisciplinary team at the Sloan-Kettering Institute for Cancer Research in New York is depending on quality rather than quantity. Starting with a pharmaceutically active natural substance, researchers working with chemist Samuel J. Danishefsky and pharmacologist Ting-Chao Chou "rework" the molecule very precisely, in order to give it, step by step, an improved pharmacological profile. The newly designed molecules are then built out of the simplest possible components in a "total synthesis". That this method of "chemical editing" can be highly successful is demonstrated by the team’s latest development: an epothilone with unusually promising antitumor activity. Derived from microorganisms, epothilones work similarly to the yew-derived taxoids (such as Taxol), which are used as cytostatics. Both types of drugs stabilize the microtubuli of the cells, locking them into one phase of the cell-division process, which leads to the death of the cell.

The basic structural framework of epothilones consists of a fifteen-membered carbon chain that is closed into a ring by an (oxygen-containing) lactone bond. The oxygen atom forms a bridge between carbon atoms twelve and thirteen. This bridge seems to be responsible for a large part of the non-tumor-specific cytotoxicity, a potential source of side effects in medicines. Danishefsky and his chemistry colleagues removed the bridge and replaced it with a double bond between the two carbon atoms. However, this disruption caused some of the agent’s effectiveness against tumor cells to be lost. The researchers were able to partially compensate for this loss by introducing an additional double bond between carbon atoms nine and ten. This had a positive side effect; the double bond significantly stabilizes the compound with regard to decomposition in the plasma. However, the researchers were still not completely satisfied. They replaced the three hydrogen atoms of a methyl group (CH3) with three fluorine atoms. This third modification to the molecule doesn’t just stabilize it even further; it apparently allows the agent to more easily enter into the tumor cells. These edited epothilones cause human tumors that have been transplanted into mice, to permanently disappear. Of course, the path from xenograft mice to human clinical applications is fraught with uncertainty but these results are quite exciting said Drs. Chou and Danishefsky. The second generation compounds are being developed in a collaborative effort embracing Memorial Sloan-Kettering Cancer Center, Kosan Biosciences and Hoffman LaRoche.