Featured Research

from universities, journals, and other organizations

Long-sought method to efficiently make complex anticancer compound developed

Date:
August 1, 2013
Source:
The Scripps Research Institute
Summary:
Scientists have achieved the first efficient chemical synthesis of ingenol, a highly complex, plant-derived compound that has long been of interest to drug developers for its anticancer potential. The achievement will enable scientists to synthesize a wide variety of ingenol derivatives and investigate their therapeutic properties. The achievement also sets the stage for the efficient commercial production of ingenol mebutate, a treatment for actinic keratosis (a common precursor to non-melanoma skin cancer), that at present must be extracted and refined inefficiently from plants.

Scientists 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.
Credit: Photo courtesy of The Scripps Research Institute

Scientists at The Scripps Research Institute (TSRI) have achieved the first efficient chemical synthesis of ingenol, a highly complex, plant-derived compound that has long been of interest to drug developers for its anticancer potential. The achievement will enable scientists to synthesize a wide variety of ingenol derivatives and investigate their therapeutic properties. The achievement also sets the stage for the efficient commercial production of ingenol mebutate, a treatment for actinic keratosis (a common precursor to non-melanoma skin cancer), that at present must be extracted and refined inefficiently from plants.

"I think that most organic chemists had considered ingenol beyond the reach of scalable chemical synthesis," said TSRI Professor Phil S. Baran.

Baran and his laboratory report their achievement in this week's issue of Science Express, the early online edition of the journal Science.

An Anticancer Substance from Nature

Ingenol and its derivatives are found in the widely distributed Euphorbia genus of plant, whose milky sap has long been used in traditional medicine to treat skin lesions. Ingenol mebutate, extracted from the common "petty spurge" plant (E. peplus), was recently approved by the U.S. FDA, European Medicines Agency, Medicines Australia and Health Canada to treat actinic keratosis, a common type of precancerous lesion associated with cumulative sun exposure. Formulated and marketed as Picato®, the drug has also shown effects in models and in early trials of non-melanoma skin cancers.

In late 2011, the drug's manufacturer, Denmark-based LEO Pharma, collaborated with Baran's laboratory to find an efficient way to synthesize ingenol mebutate using organic chemistry -- the usual method for producing modern drugs. "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, LEO Pharma's director of external discovery. "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."

Studies have shown that ingenol mebutate, which is applied topically, can treat 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. Researchers suspect that derivatives of ingenol mebutate may be useful in treating other types of cancer, if they can be delivered properly.

Until now, it was debatable whether such derivatives could ever be synthesized. Some prominent researchers have suggested recently that the efficient chemical synthesis of structurally unusual "terpenoid" compounds such as ingenol is an unreachable goal -- and that drug developers should seek biotechnology solutions instead. Even leading scientists of LEO Pharma initially had their doubts. "It was initially hard for me to sell this project to the company," said Sierra. "But I knew Phil, and I knew that his lab could do this."

Achieving the 'Unreachable' Goal

Baran and his team started by examining what is known about ingenol's natural synthesis in plant cells. "A key feature of the natural synthesis is that the basic framework of the molecule is built first, and then in a second phase the important oxygenated functional groups are added," said Steven J. McKerrall, a graduate student in the laboratory who was one of the two first authors of the study.

Following that basic strategy of mimicking nature, McKerrall, Baran and their colleagues began designing the synthesis. They were eventually able to hone the process to 14 steps, starting from a common and inexpensive chemical, carene, and ending with long-sought ingenol. "Syntheses of ingenol have been described in the past, but they all require more than 37 steps," said co-lead author Lars Jørgensen, a postdoctoral fellow in the Baran Laboratory.

The new and concise synthesis turned out to yield relatively large quantities of ingenol, making it an efficient approach to the production of ingenol mebutate and other ingenol derivatives. The two-phase design also provides a significant amount of a key intermediate compound, which enables the efficient preparation of various ingenol derivatives. "We won't have to go through the entire synthesis every time we need to make a new ingenol derivative; we can start synthesizing from this intermediate compound," said Jørgensen.

Sierra and others at LEO Pharma were pleased with the project's outcome. "It's a pretty amazing feat: the total synthesis of ingenol within a year and a half of starting our collaboration," he said. "It's great to work with a research group like this."

To Baran, the achievement serves also as an emphatic rejoinder to those who had declared chemical synthesis a dead-end technique for making such complex natural compounds. "With this study we rebut that argument conclusively," he said. "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."


Story Source:

The above story is based on materials provided by The Scripps Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Lars Jørgensen, Steven J. McKerrall, Christian A. Kuttruff, Felix Ungeheuer, Jakob Felding, and Phil S. Baran. 14-step synthesis of ( )-ingenol from ( )-3-carene. Science, 1 August 2013 DOI: 10.1126/science.1241606

Cite This Page:

The Scripps Research Institute. "Long-sought method to efficiently make complex anticancer compound developed." ScienceDaily. ScienceDaily, 1 August 2013. <www.sciencedaily.com/releases/2013/08/130801142242.htm>.
The Scripps Research Institute. (2013, August 1). Long-sought method to efficiently make complex anticancer compound developed. ScienceDaily. Retrieved July 26, 2014 from www.sciencedaily.com/releases/2013/08/130801142242.htm
The Scripps Research Institute. "Long-sought method to efficiently make complex anticancer compound developed." ScienceDaily. www.sciencedaily.com/releases/2013/08/130801142242.htm (accessed July 26, 2014).

Share This




More Health & Medicine News

Saturday, July 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Beatings and Addiction: Pakistan Drug 'clinic' Tortures Patients

Beatings and Addiction: Pakistan Drug 'clinic' Tortures Patients

AFP (July 24, 2014) — A so-called drugs rehab 'clinic' is closed down in Pakistan after police find scores of ‘patients’ chained up alleging serial abuse. Duration 03:05 Video provided by AFP
Powered by NewsLook.com
Too Few Teens Receiving HPV Vaccination, CDC Says

Too Few Teens Receiving HPV Vaccination, CDC Says

Newsy (July 24, 2014) — The Centers for Disease Control and Prevention is blaming doctors for the low number of children being vaccinated for HPV. Video provided by Newsy
Powered by NewsLook.com
New Painkiller Designed To Discourage Abuse: Will It Work?

New Painkiller Designed To Discourage Abuse: Will It Work?

Newsy (July 24, 2014) — The FDA approved Targiniq ER on Wednesday, a painkiller designed to keep users from abusing it. Like any new medication, however, it has doubters. Video provided by Newsy
Powered by NewsLook.com
Doctor At Forefront Of Fighting Ebola Outbreak Gets Ebola

Doctor At Forefront Of Fighting Ebola Outbreak Gets Ebola

Newsy (July 24, 2014) — Sheik Umar Khan has treated many of the people infected in the Ebola outbreak, and now he's become one of them. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins