Biology-Oriented Synthesis (BIOS): From natural product to new therapeutics

July 03, 2006

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 (see image 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 (see image 1), 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 (see image 1). 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 (see image 2).

Further brachiation in the SCONP-tree led to the tetracyclic Indoloquinolizidine-scaffold and over tricyclic ß-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.
-end-


Max-Planck-Gesellschaft

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.