A. MAUREEN ROUHI, C&EN WASHINGTON

Chemists in the labs of AnalytiCon Discovery are discovering, isolating, and determining the structures of new natural products daily. The company delivers to its pharmaceutical industry clients isolated natural products of fully elucidated structures and at least 85% purity that can go directly into high-throughput biological screens, just like any synthetic compound. No more long and tedious bioassay-guided fractionation.

	TECHNOLOGY TREATED AnalytiCon simplifies natural products drug discovery with advanced technologies. MICHAEL HÜBNER/MÄRKISCHE ALLGEMEINE

"Natural products fell out of favor because they did not fit into the current in-house efforts of drug companies," says Lutz Müller-Kuhrt, the company's chief executive officer. "We are transforming natural products drug discovery so that, in terms of the internal logistics of pharmaceutical companies, screening natural products is no different from screening synthetic compounds."

The Potsdam, Germany-based company has completely turned around the traditional approach to natural products drug discovery. Instead of tracking active compounds, it ignores biological activity and concentrates on retrieving from a biological material as many chemically interesting compounds as possible, purifying them, and determining their structures rapidly. Robotics, automated determination of molecular weight, and advances in liquid chromatography have compressed the time for isolation and purification. To determine chemical relevance and structures, the key tool is a process called MEGAbolite, which is a combination of hardware, software, and brain power.

Chemical relevance is revealed by chemical profiling. Crude extracts are analyzed by high-performance liquid chromatography with mass spectrometric, light scattering, and ultraviolet detection. "Mass spectrometry gives us the molecular weight and structural information," Müller-Kuhrt explains. "Light scattering estimates the amount of material represented by each peak, because we need a minimum amount to build good libraries that can be used for years. UV gives us additional insight on the compound's structure."

Data are fed to internally developed software that compares all the peaks in an extract with all the peaks that the software has seen. At the end, the software ranks the extracts on the basis of the number of new peaks. The high-ranking extracts will very probably contain new compounds and will be taken further to purification and structure elucidation, Müller-Kuhrt says. The technique is useful in determining whether a collection of biological materials is chemically interesting. Typically, he adds, only 10 to 20% of the initially acquired biological samples qualify for further processing by this profiling step.

High-throughput structural elucidation is based on fragmentation patterns and molecular weights. The AnalytiCon software compares the information for a compound with those in databases of known natural products. The majority of the peaks are elucidated within one to five minutes this way, Müller-Kuhrt says. The rest are solved manually.

With novel compounds, AnalytiCon chemists usually take one to two hours to elucidate structures as complex as paclitaxel (Taxol), Müller-Kuhrt says--with two constraints. First, if the scaffold is novel, the stereochemistry is not solved at this point. Second, if the compound has sugar side chains, the sugars will be identified but not the precise connections within the sugar chain. "At this point, these pieces of information are not critical to deciding whether to develop the compound further," he explains.

Müller-Kuhrt attributes the speed of manual structural elucidation to the breadth of experience of the company's structure elucidation team, headed by Jasmin Jakupovic, AnalytiCon's chief scientific officer. "In the past five years, they have elucidated about 27,000 natural products, including about 15,000 that have never been reported," he says. "If you have seen so many different compounds, new ones become easier and easier to solve."

The technology has opened up two revenue-generating tracks. On the basis of its own acquisition of biological samples, AnalytiCon has assembled libraries of isolated and structurally elucidated natural products. AnalytiCon does not claim intellectual property rights to these structures, Müller-Kuhrt says. The company's contracts with clients who screen these libraries stipulate that the client must negotiate with the source country for resupply. In addition, the company has a program called NatDiverse for preparing libraries of natural-products-based synthetic compounds.

Half of the company's revenues at present come from the second track, in which clients supply biological samples and AnalytiCon delivers compounds typically in 85% purity and with full structures on a fee-for-service basis. Some companies with natural product collections are for the first time seeing the real value of these assets, Müller-Kuhrt says. "We are allowed to keep the chemoinformatics, but physically, the compounds are shipped to the client."

Bayer, Boehringer Ingelheim, Roche Vitamins, Schering-Plough, and Takeda are some of AnalytiCon's clients, Müller-Kuhrt says. "I think what they find attractive is that, for the first time, tens of thousands of natural products are available with structural information."

COVER STORY REDISCOVERING NATURAL PRODUCTS Cast aside for years, natural products drug discovery appears to be reclaiming attention and on the verge of a comeback SPEAKING OUT The Case For Natural Products Research IN HIGH GEAR Advanced Technologies Transform Natural Products Drug Discovery BETTING ON NATURAL PRODUCTS FOR CURES In natural products drug discovery, traditional, as well as novel, approaches are being applied MOVING BEYOND NATURAL PRODUCTS Organic synthetic chemistry amplifies the potential of natural products as drug leads CALENDAR Events of Interest to the Pharmaceutical Community

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