Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
RANDOX LABORATORIES

Drug Development Cooperation Yields Synthetic Route for Anti-Skin Cancer Compounds

By BiotechDaily International staff writers
Posted on 12 Aug 2013
Print article
Image: Investigators at The Scripps Research Institute have achieved the first efficient chemical synthesis of ingenol, a highly complex, anticancer substance found in the Euphorbia genus of plant, whose milky sap has long been used in traditional medicine (Photo courtesy of the Scripps Research Institute).
Image: Investigators at The Scripps Research Institute have achieved the first efficient chemical synthesis of ingenol, a highly complex, anticancer substance found in the Euphorbia genus of plant, whose milky sap has long been used in traditional medicine (Photo courtesy of the Scripps Research Institute).
Cooperation between a Danish pharmaceutical company and a renowned American research institute has resulted in development of a method for chemical synthesis of the anticancer drug ingenol, which up to now could only be inefficiently extracted from plant materials.

Ingenol is a diterpenoid with unique architecture and has derivatives possessing important anticancer activity, including the recently [US] Food and Drug Administration–approved Picato (ingenol mebutate), a first-in-class drug for the treatment of the precancerous skin condition actinic keratosis. Ingenol mebutate, which is applied topically, can destroy precancerous skin cells with unusual swiftness, while sparing healthy skin cells. The treatment has a direct cancer-cell-killing effect, and also induces an inflammatory reaction. Currently, the compound is extracted inefficiently from the plant Euphorbia peplus.

Investigators at the Danish pharmaceutical company LEO Pharma (Ballerup Denmark), the manufacturer of Picato, recently collaborated with colleagues at The Scripps Research Institute (La Jolla, CA, USA) in an attempt to arrive at method for chemical synthesis of the drug.

They reported in the August 1, 2013, online edition of the journal Science Express that they had succeeded in developing a 14-step synthetic method beginning with inexpensive (+)-3-carene and employing a two-phase design (syntheses of ingenol had been described in the past, but they all required more than 37 steps). This newly described synthesis allowed for the creation of fully synthetic analogs of bioactive ingenol derivatives and provided a strategic blueprint for chemical production.

These results validated the concept of two-phase terpene total synthesis as not only an academic curiosity, but also a viable alternative to isolation or bioengineering for the efficient preparation of polyoxygenated terpenoids at the limits of chemical complexity.

“I think that most organic chemists had considered ingenol beyond the reach of scalable chemical synthesis,” said senior author Dr. Phil S. Baran, professor of chemistry at The Scripps Research Institute. “With this study we rebut that argument conclusively, and there are many other complex natural compounds waiting to be synthesized using a strategy like ours—this is really just a glimpse of the future of chemical synthesis.”

“At the time, the only way to get the product was by a relatively lengthy extraction process from the E. peplus plant,” said Michael Sierra, director of external discovery at LEO Pharma. “We were hoping to get a more efficient synthetic route for production, as well as a method that would allow us to make new derivatives. It is a pretty amazing feat: the total synthesis of ingenol within a year and a half of starting our collaboration. It is great to work with a research group like this.”

Related Links:
Leo Pharma
The Scripps Research Institute



Print article

Channels

Genomics/Proteomics

view channel
Image: Molecular model of E3 ubiquitin ligase (green), E2 ubiquitin enzyme (orange), \"activated ubiquitin\" (cyan), and \"allosteric ubiquitin\" (blue) (Photo courtesy of Dr. Bernhard Lechtenberg, Sanford Burnham Prebys Medical Discovery Institute).

Researchers Resolve Molecular Structure of Critical Ubiquitin-Binding Enzyme

The molecular structure of a protein complex critically involved in diverse cellular functions such as cell signaling, DNA repair, and mounting anti-inflammatory and immune responses has been elucidated... Read more

Business

view channel

Purchase Agreement to Boost Ebola Vaccine Development

A deal to help boost development of a vaccine to protect against Ebolavirus infection was finalized at the recent Davos Conference in Switzerland. Gavi (Geneva, Switzerland), the global alliance for vaccines and immunizations, announced that it would spend five million USD to purchase the Ebola vaccine under development... Read more
Copyright © 2000-2016 Globetech Media. All rights reserved.