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Biology-Oriented Synthesis (BIOS): From Natural Product To New Therapeutics

Date:
July 5, 2006
Source:
Max-Planck-Gesellschaft
Summary:
Phosphatases are key regulators of various life processes. As a result, many different scientists are looking at them to find treatments for diseases like diabetes and cancer. Researchers still have only a basic knowledge of phosphatases, but are continuing the search for inhibitors to their activity. Scientists from the Max Planck Institute of Molecular Physiology in Dortmund, Germany, have now developed a principle called "biology-oriented synthesis" (BIOS).

Simplification of the structure of the yohimbine alkaloid into indoles, thanks to the SCONP principle.
Credit: Image : Max Planck Institute of Molecular Physiology

Phosphatases are key regulators of various life processes. As a result, many different scientists are looking at them to find treatments for diseases like diabetes and cancer. Researchers still have only a basic knowledge of phosphatases, but are continuing the search for inhibitors to their activity.

Scientists from the Max Planck Institute of Molecular Physiology in Dortmund, Germany, have now developed a principle called "biology-oriented synthesis" (BIOS). Guided by this principle, they have discovered, at one time, four fully different classes of phosphatase inhibitors. This has opened the door to research into these enzymes, and could lead to new active ingredients in medications (PNAS, Early Edition, June 26-30, 2006).

Natural products have been evaluated in living organisms and therefore are a good place to start looking for medical therapies. These materials are created during biosynthesis. They have evolved to contain chemical structures which serve their functions, usually via interaction with various proteins.

Under the "BIOS" principle, natural products act as a starting point for the search of active agents in new medicines. In order to match the natural material to its corresponding enzyme, scientists mimic nature by either introducing chemical residues into areas of biological relevance (natural product-derived synthesis)".

The Max Planck researchers have demonstrated how effective the BIOS principle is by applying it to phosphatases. These are enzymes which dephosphorylate tyrosine or serin residues in enzymes. In the last few years, this enzyme class has increasingly been targeted by pharmaceutical researchers, due to work on cancer and diabetes. What we know about phosphatases is still incomplete. In order to identify new phosphatase-inhibitor classes with the aid of BIOS concepts, the scientists used "natural product-derived synthesis" to test two natural product libraries - as well as 354 isolated natural products from the company AnalytiCon Discovery - in a biochemical screen, against seven phosphatases: VE-PTP, Cdc25A, PTP1b, VHR, Shp-2, MptpA und MptpB:

- VE-TPT inhibition is very promising in the development of antiangiogenesis inhibitors in cancer therapy
- Cdc25A influences cell cycle regulation and may also be a target of interest in cancer therapy
- The phosphatase MptpB, from Mycobacterium tuberculosis, influences the host's immune reaction in a tuberculosis infection
- VHR dephosphorylates MAP kinases in the activation loop THX, which plays an important role in signal transduction processes
- Inhibiting MptpB and Shp-2 opens up new directions in the search for antibiotics
- The Ptp1B enzyme plays an important role in developing a medicine against type 2 diabetes and the metabolic syndrome

Central to choosing natural products and compound libraries is using a structurally diverse screening set. The natural product library 1 is made of 1,271 different compounds, based on the alkaloid cytisine, and delivers VE-PTP inhibitors in the low, micromolar range. These were the first inhibitors ever for VE-PTP, which comes from Dietmar Vestweber's working group at the Max Planck Institute of Molecular Biomedicine. Natural product library 2, which stems structurally from furanodictines, has proven to be a new inhibitor class for the enzyme PTP1b and Shp-2. The best inhibitors were in the low, micromolar range and were at least 20 times more selective for Shp-2 than for other tested phosphatases.

In the screening of the 354 isolated natural products, three out of seven isolated yohimbine alkaloids proved to be weak inhibitors of Cdc25A. Looking at the results of investigations of the first two libraries, we can also use structural variations to find compounds of increasing activity.

Because this alkaloid is so structurally complex, the researchers applied a second principle - and used it for structural simplification. It is the SCONP principle, which organizes and classifies natural products in a tree structure. It was into the indole branch of the SCONP tree that the scientists placed the basic structure of the yohimbine alkaloid 1.

Further brachiation in the SCONP-tree led to the tetracyclic Indoloquinolizidine-scaffold and over tricyclic -carbolines to indoles 4.

Following the principle of "natural product-inspired synthesis", 450 indoles were built on polymer supports. One screening of these connections yielded two weak Cdc25A inhibitors. This suggests that in spite of structural SCONP simplifications from pentacyclical alkaloids to indoles, the activity of the same enzyme continues.

In addition, it also shows that the collection of compounds also contains 11 inhibitors in the low, micromolar range. For MptpB - which originates from the working group of Harald Schwalbe at the University of Frankfurt - the scientists discovered again the very first inhibitors ever, in fact, unusually selective ones. Out of these 11 compounds, 9 inhibited MptpB exclusively. The library of 188 structurally even simpler indole 4 also showed these characteristics. Two of the compounds were weak Cdc25A inhibitors - similar to natural product 1. Interestingly, seven of the 188 indoles were even nanomolar MptpB inhibitors.

The results show how useful the concept of Biology-Oriented Synthesis can be applied for targeting new compound classes, and developing new kinds of therapeutics.


Story Source:

The above story is based on materials provided by Max-Planck-Gesellschaft. Note: Materials may be edited for content and length.


Cite This Page:

Max-Planck-Gesellschaft. "Biology-Oriented Synthesis (BIOS): From Natural Product To New Therapeutics." ScienceDaily. ScienceDaily, 5 July 2006. <www.sciencedaily.com/releases/2006/07/060703205735.htm>.
Max-Planck-Gesellschaft. (2006, July 5). Biology-Oriented Synthesis (BIOS): From Natural Product To New Therapeutics. ScienceDaily. Retrieved August 30, 2014 from www.sciencedaily.com/releases/2006/07/060703205735.htm
Max-Planck-Gesellschaft. "Biology-Oriented Synthesis (BIOS): From Natural Product To New Therapeutics." ScienceDaily. www.sciencedaily.com/releases/2006/07/060703205735.htm (accessed August 30, 2014).

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