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Organic Lab Sparks Drug Discovery
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Total Synthesis Surprise
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Intricacies Of The Proteasome
[C&EN, Mar. 20, 2000]


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Samuel J. Danishefsky

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Robert Huber

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NEWS OF THE WEEK
RESEARCH
March 4, 2002
Volume 80, Number 9
CENEAR 80 9 p. 14
ISSN 0009-2347
[Previous Story] [Next Story]

ENAMIDE TRANSFORMATION
Novel construction procedure is key to proteasome inhibitor total syntheses

STU BORMAN

A useful new organic synthetic transformation has proven to be an essential element in the first total syntheses of two promising proteasome inhibitors.

The inhibitors are potential drug leads for cancer and other conditions. Clinical trials of a smaller proteasome inhibitor for treatment of cancer are currently being conducted by Millennium Pharmaceuticals.

The new procedure makes it possible to add a cis-enamide group to a structure that already contains delicate functional groups. The technique--devised by chemistry professor Samuel J. Danishefsky of Sloan-Kettering Institute for Cancer Research and Columbia University and postdoctoral colleague Songnian Lin--was developed to facilitate total syntheses of the cyclic peptide natural products TMC-95A and TMC-95B [Angew. Chem. Int. Ed., 41, 512 (2002)].

One of the most challenging problems the researchers encountered was the need to add, near the end of the synthesis, a cis-enamide to a substantially complete TMC-95 precursor. Conventional methods for adding such a group could have disrupted delicate groups that had already been assembled in other parts of the synthon.

The researchers solved the problem using an a-silylallyl amine reagent. The amine is attached via an amide bond to a protected TMC-95 precursor. After heating, the amide undergoes bond reorganization, and the imidate product is then hydrolyzed to form the desired cis-enamide moiety.

A German research team that had earlier determined a crystal structure of TMC-95A bound to the proteasome is now reporting structure-activity relationship data on proteasome inhibition by a TMC-95A analog. The study shows that a simplified version of TMC-95A still retains much of its inhibitory activity. It was carried out by grad student Markus Kaiser, postdocs Michael Groll and Christian Renner, chemist Luis Moroder, and Nobel Prize-winning crystallographer Robert Huber at Max Planck Institute for Biochemistry, Martinsried [Angew. Chem. Int. Ed., 41, 780 (2002)].

The Max Planck group's paper "invites the synthesis of smaller compounds," Danishefsky says. Most researchers in the field believe TMC-95's activity lies in the tripeptide side of the molecule, he says, but an asymmetric center there necessitates a difficult separation that "renders the synthesis impractical." He and Lin hope to create simplified TMC-95 analogs that dispense with the problematic asymmetric center and substantially simplify the biaryl scaffold. "If the biological activity holds up, we can be looking at something quite exciting," Danishefsky says.


Proteasome inhibitors "are absolutely essential in helping to understand the physiological role of proteasomes in cells."

Madeleine M. Joullié,
University of Pennsylvania


Chemistry professor Robert M. Williams and graduate student Brian Albrecht of Colorado State University are close to finishing a synthesis of TMC-95A and B, using what Williams describes as "a different and more concise approach" than the Danishefsky group's synthesis. "We were also the first to report a Stille-type coupling reaction to make the biaryl moiety," Williams notes. Other approaches to TMC-95 synthesis have been pursued by the groups of chemistry professor Masahiro Hirama of Tohoku University, Sendai, Japan, and research professor of chemistry Dawei Ma of the Chinese Academy of Sciences, Shanghai. Hirama's coworker, Tohoku assistant professor of chemistry Masayuki Inoue, notes that the group earlier developed a cis-enamide addition strategy that, like Danishefsky's, is "considered mild enough to be applied to total synthesis" [Org. Lett., 3, 2863 (2001)].

Chemistry professor Madeleine M. Joullié of the University of Pennsylvania calls the Danishefsky group's total synthesis "elegant and useful." In addition to playing a major role in cellular processes, she says, "the proteasome is a promising target for drug development. Screening of inhibitor intermediates and analogs may produce simpler compounds having the same or better inhibition activity. Therefore, I think the work has broad implications."


Chemical & Engineering News
Copyright © 2002 American Chemical Society


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