news of the week AUGUST 5, 20 13 EDITED BY WILLIAM G. SCHULZ & SOPHIA L. CAI
JASO N HO L L IN GER /F L ICK R
INGENOL, NOW IN FEWER STEPS ORGANIC SYNTHESIS: Efficient
route may speed production of precancer treatment
I
N JUST 14 STEPS, chemists have synthesized
ingenol, a plant-derived member of a medicinally vital family of compounds—terpenes. A Danish pharmaceutical firm is applying the work to what may become a more efficient, scalable production of Picato (ingenol mebutate), which is FDA-approved to treat actinic ent pending. A contract research organization keratosis, a skin condition that affects 250 million people in India “has worked through half the syntheO worldwide and if left untreated can lead to skin cancer. sis,” Sierra says, and is providing intermediates The study’s authors claim this achievement in synon a scale of hundreds of grams. The contractor thesis proves that organic chemistry is essential as a is optimizing the final steps of Baran’s route, drug-making method, even as other technologies, such some of which require stoichiometric quantias bioengineering of microbes to manufacture valuable ties of toxic oxidants. It will then proceed to chemical compounds, emerge. Picato and to novel analogs that can be tested Today’s supply of Picato comes for safety and efficacy. from spurges, weeds found in many “This report is a creative consoliSHORTER ROUTE gardens. Extraction is tedious, says dation of earlier observations, with More efcient ingenol Michael Sierra, director of external disinnovative elements of its own,” synthesis includes cyclase covery at Leo Pharma, maker of Picato. says Stanford University’s Paul A. and oxidase phases. “You need nearly 800 kilos of plant to Wender, who has worked on related obtain 1 g of drug.” molecules. Chemists have synthesized ingenol Baran’s report also mounts a vigorbefore, notes Phil S. Baran, the Scripps ous defense of total synthesis. He writes Research Institute, California, chemist that there is “a widely held assumpwho led the new study (Science 2013, tion that bioengineering is superior to (+)-3-Carene DOI: 10.1126/science.1241606). “Those organic synthesis” for terpene producroutes are beautiful. I teach them in tion. But his lab’s new work refutes that class every year,” he says. They renotion, he adds. Last year, Baran particiquire upward of 37 steps, however, “so pated in a debate, published in Nature, 1 RO they’re not a blueprint for commercialwith University of California, Berkeley, scale production.” bioengineer Jay D. Keasling about the H HO OR2 Sierra’s team approached Baran in merits of molecule-making in their re2011 because Baran’s group had already spective fields (DOI: 10.1038/492188a). developed a general approach to the Wender thinks debates that pit synsynthesis of terpenes. The Scripps thesis techniques against one another researchers used that as a basis for a are misdirected. “They’re unfortunate shorter two-phase approach to contestimonials to the tight funding situaO struct ingenol. Phase one, which they tion we’re in today,” he says. “The disH call the “cyclase phase,” sets up a precussion needs context. It shouldn’t be cursor carbon skeleton. Then phase about whether chemistry or synthetic HO HO two, the “oxidase phase,” puts finishing biology is the best way to make inHO OH touches on the skeleton and installs hygenol,” he adds. “It should be about how Ingenol droxyl groups. The company provided to make better molecules than those we almost all of the funding for the work. have now, perhaps even by combining R = silyl protecting groups The Leo Pharma technology is patapproaches.”—CARMEN DRAHL CEN.ACS.ORG
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O H O HO HO
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Picato
Picato currently comes from plants such as Euphorbia peplus.
