Volume 95 Issue 19 | p. 7 | News of The Week
Issue Date: May 8, 2017 | Web Date: May 5, 2017

Improved routes to thapsigargin

Two new syntheses could lead to scale-up of anticancer agent
Department: Science & Technology
News Channels: Biological SCENE, JACS In C&EN, Organic SCENE
Keywords: Synthesis, thapsigargin, mipsagargin
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Thapsigargin
Line structure of thapsigargin
 
Thapsigargin

Two improved total syntheses of a hot anticancer agent, thapsigargin, could help lead to a commercially viable way to produce the compound.

Thapsigargin kills cells by inhibiting an enzyme that controls essential calcium gradients inside cells. Right now, the compound is isolated from a poisonous Mediterranean plant called “deadly carrot.” Søren Brøgger Christensen of the University of Copenhagen, John Isaacs and Samuel R. Denmeade of Johns Hopkins Medicine, and coworkers developed a prodrug version of the molecule called mipsagargin. An enzyme expressed selectively in some cancer cells converts mipsagargin to thapsigargin by cleaving off a peptide side chain.

Inspyr Therapeutics is believed to be close to starting Phase III human trials of mipsagargin. For future trials, companies may need a metric ton per year of thapsigargin, Christensen says. Isolating that amount of product from plants is not currently feasible, engineering organisms to make thapsigargin isn’t possible because the biosynthetic pathway is not fully known, and the semisynthesis of the compound in large amounts from a readily available natural product is possible but unproven.

That leaves total synthesis. Steven Ley of the University of Cambridge and coworkers developed the first approach in 2007. With 42 steps and less than 1% yield, that synthesis isn’t practical for making large amounts.

Groups led by Phil S. Baran of Scripps Research Institute California and P. Andrew Evans of Queen’s University have now independently developed more-efficient syntheses with far fewer steps (ACS Cent. Sci. 2016, DOI: 10.1021/acscentsci.6b00313; J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b01734).

The improved practicality of Baran and coworkers’ approach is based in part on using strategic oxidations and introducing stereocenters in a way that avoids the use of expensive chiral ligands or auxiliaries, comments Krishna P. Kaliappan of the Indian Institute of Technology Bombay.

And Evans’s group achieved its improved efficiency in part by establishing thapsigargin’s polyoxygenated core with correct stereochemistry relatively early in the synthesis—an approach that could make it easier to prepare analogs for structure-activity relationship studies, Christensen says.

There has been debate over the relative yields and number of steps of the two new syntheses, so it is hard to compare the efficiencies of the approaches. But both new syntheses “allow scaling to produce thapsigargin and represent advances in the ability to supply practical quantities for drug discovery,” says Javier Moreno-Dorado of the University of Cádiz.

 
Chemical & Engineering News
ISSN 0009-2347
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