SYNTHESIS
Improved routes to thapsigargin 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, comisms to make thapsigargin isn’t possible ments Krishna P. Kaliappan of the Indian because the biosynthetic pathway is not Institute of Technology Bombay. fully known, and the semisynthesis of the And Evans’s group achieved its imcompound in large proved efficiency in O O amounts from a readpart by establishing O O ily available natural thapsigargin’s poly4O H O product is possible but oxygenated core with O O HO unproven. correct stereochemThat leaves total istry relatively early OH synthesis. Steven Ley of in the synthesis—an O the University of Camapproach that could O bridge and coworkers make it easier to Thapsigargin developed the first apprepare analogs for proach in 2007. With 42 steps and less than structure-activity relationship studies, 1% yield, that synthesis isn’t practical for Christensen says. making large amounts. There has been debate over the relative Groups led by Phil S. Baran of Scripps yields and number of steps of the two new Research Institute California and P. Andrew syntheses, so it is hard to compare the Evans of Queen’s University have now indeefficiencies of the approaches. But both pendently developed more-efficient synthe- new syntheses “allow scaling to produce ses with far fewer steps (ACS Cent. Sci. 2016, thapsigargin and represent advances in the DOI: 10.1021/acscentsci.6b00313; J. Am. ability to supply practical quantities for Chem. Soc. 2017, DOI: 10.1021/jacs.7b01734). drug discovery,” says Javier Moreno-Dorado The improved practicality of Baran and of the University of Cádiz.—STU BORMAN
Two new syntheses could lead to scale-up of anticancer agent 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 organ-
Sketch chemistry
A comic collaboration between C&EN and ChemScrapes cartoonist Brendan Burkett
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Molecular status updates MAY 8, 2017 | CEN.ACS.ORG | C&EN
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