Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New paclitaxel analog kills more cancer cells than natural product

30.03.2004


A multi-university research team led by Virginia Tech University Distinguished Professor of Chemistry David G.I. Kingston has succeeded in enhancing the structure of paclitaxel (Taxol™) to make it more effective in killing cancer cells.




Having determined how paclitaxel fits into a cancer cell’s reproductive machinery, the team is optimistic that simpler molecules can be designed as future medicines.

Kingston will present the research that brought the team to this point at the 227th Annual Meeting of the American Chemical Society, being held in Anaheim, Calif., March 28 through April 1, 2004.


Paclitaxel, a natural compound from yew trees, is a relatively scarce resource, but synthetic forms and analogs have, so far, been less effective. So scientists have continued to study how the paclitaxel molecule works in order to develop more effective products.

Kingston explains that paclitaxel binds to tubulin, a protein molecule that forms the backbone of microtubules. Microtubules are a cell component whose duties include allowing chromosomes to move into the correct position for the cell to divide into two daughter cells.

"When paclitaxel binds to tubulin, it stabilizes the microtubules and messes up the equilibrium between tubulin and microtubule," says Kingston. "A cell with stable microtubules proceeds to programmed cell death without dividing,"

How does paclitaxel bind to tubulin? There is a binding pocket in the protein into which part of the paclitaxel molecule fits. This binding pocket has been visualized by some elegant electron crystallography experiments carried out by scientists at the Lawrence Berkeley National Laboratory (Nogales et al., Cell, 1999, 96, 79). Paclitaxel consists of a rigid ring system attached to a flexible side chain, but the exact arrangement of the side chain in space is not known. Kingston explains, "The issue has been, what is the shape or orientation of the side chain when paclitaxel is sitting on the microtubule? If we could figure that out, we could design a molecule that would plug in better than paclitaxel for better binding and possibly better activity against cancer. What is the right conformation of the side chain?"

One hypothesis was put forward by Jim Snyder of Emory University. Based on a computer model of the paclitaxel binding site, he proposed a particular orientation of the side chain. Kingston, his colleagues, and Snyder then designed molecules with bridges between the ring and the side chain. "We thought that if we linked the bridge in the right position, maybe it would hold the side chain in the right place," Kingston says.

It wasn’t a new idea. Gunda Georg of the University of Kansas and Iwao Ojima of the State University of New York (SUNY) Stony Brook both made bridged paclitaxel derivatives, but these were all less effective than natural paclitaxel.

Kingston collaborated with Snyder and Susan Bane of SUNY Binghamton to design a paclitaxel analog that linked in a new way. "We synthesized a number of the compounds and refined the details of how the link is formed until, last summer, we were able to get activity as good as paclitaxel."

Presently, their best compound is about 20 times more active in one assay, or biological test measuring the analog’s ability to kill cancer cells. In another assay, the compound is one and a half times more active; and in a third assay, it is three times more deadly to cancer cells. "In measurements of interaction with tubulin, it is two to three times more active than paclitaxel," Kingston says.

The research is significant because it has validated Snyder’s model, provided a more exact picture of the shape that paclitaxel takes in order to bind to tubulin, and "it offers the exciting possibility that now that we know that shape, we can design simpler molecules with a similar shape, which is what we are doing now," Kingston says.

He will present the paper, " Taxol Pharmacophore: Experimental evidence from a highly constrained analog and REDOR NMR (MEDI 192)" at 11.30 a.m., Tuesday, March 30, in Ballroom D at the Anaheim Convention Center. Co-authors of the paper are Kingston, Research Scientist Thota Ganesh, Graduate Student Rebecca C. Guza, and laboratory technicianJennifer K. Schilling, all at Virginia Tech; Susan Bane, Natasha Shanker, and Rudravajhala Ravindra of SUNY Binghamton, James P. Snyder and Ami Lakdawala of Emory, and Lynette Cegelski, Robert D. O’Connor, and Jacob Schaefer of Washington University, Saint Louis, all with the chemistry departments of their respective institutions. The material also will be presented as a poster during the SciMix from 8 to 10 p.m., Monday, March 29.

Susan Trulove | EurekAlert!
Further information:
http://www.technews.vt.edu/

More articles from Life Sciences:

nachricht To proliferate or not to proliferate
21.03.2019 | Max-Planck-Institut für molekulare Zellbiologie und Genetik

nachricht Discovery of a Primordial Metabolism in Microbes
21.03.2019 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Magnetic micro-boats

Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.

The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...

Im Focus: Self-healing coating made of corn starch makes small scratches disappear through heat

Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.

Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...

Im Focus: Stellar cartography

The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.

A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...

Im Focus: Heading towards a tsunami of light

Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.

"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...

Im Focus: Revealing the secret of the vacuum for the first time

New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum

For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Modelica Conference with 330 visitors from 21 countries at OTH Regensburg

11.03.2019 | Event News

Selection Completed: 580 Young Scientists from 88 Countries at the Lindau Nobel Laureate Meeting

01.03.2019 | Event News

LightMAT 2019 – 3rd International Conference on Light Materials – Science and Technology

28.02.2019 | Event News

 
Latest News

To proliferate or not to proliferate

21.03.2019 | Life Sciences

Magnetic micro-boats

21.03.2019 | Physics and Astronomy

Motorless pumps and self-regulating valves made from ultrathin film

21.03.2019 | HANNOVER MESSE

VideoLinks
Science & Research
Overview of more VideoLinks >>>