Green Approaches in Taxol Cancer Research

Kevin Walker, Ph.D.

Professor, Michigan State University, Lansing, Michigan

Taxol – generically known as paclitaxel – is a top-selling cancer-fighting drug, and in unmodified form, the pharmaceutical is used in cancer treatment, in preventing the re-closure of blood vessels after stent placement in post-heart surgery, and is showing promise in Alzheimer’s therapy. The compendium of literature describes new generation paclitaxel compounds that demonstrate increased potency against various cancer cell lines, and several of these are in current clinical trials. Nearly all of these new generation paclitaxels are derived from synthetic routes from a common naturally occurring precursor (baccatin III) isolated from Taxus plants (see below, for an example).

Presently, the knowledge gained in my laboratory, regarding the broad substrate specificity and the chemoselectivity of the enzyme catalysts on the paclitaxel biosynthetic pathway, brings us to a position where we can now conceivably assemble the end-product (above) through a completely biocatalytic route in fewer steps, as shown below. Markedly, the biocatalytic route removes all protecting group steps in the synthetic pathway (above) that are obligate in directing the reactivity to a certain regiocenter.

Furthermore, the ability to overcome inherent co-substrate/co-product ratios by enzymatically driving a reversible biosynthetic reaction towards complete conversion of substrate to products surmounts a significant challenge in biological systems. Our lab is working towards this end by employing broad specificity enzymes encoded by cDNA, such as acyl CoA ligases, obtained from other biological sources, which are coupled to the activity of enzymes in our library in order to drive reactions to completion. Furthermore, we anticipate that E. coli, tractable to genetic manipulation, can be engineered with the pertinent cDNA in natural- or genetically modified-form to express enzymes needed to make novel compounds in vivo via a ‘greener’ way to manufacture drugs.

Included in this effort is the less obvious goal of developing biosynthetic processes to assemble novel drug types to circumvent extensive use of organic solvent-based methods requiring considerable mandates surrounding waste management. The goal is to juxtapose our green chemistry approaches next to conventional synthetic organic chemistry strategies to produce more potent versions of a very important pharmaceutical.

Kevin Walker was born January 23, 1965 in Seattle, WA and earned his BS in Chemistry in June 1988 at the University of Washington, Seattle. Thereafter, Kevin worked at the Seattle District Laboratory, Food and Drug Administration where he worked with senior scientists to develop various analytical techniques that identified xenobiotic compounds in aquatic species from June 1988 to August 1990. He then earned a PhD in Organic Chemistry in 1997 working on various natural product biosynthetic pathways in the laboratory of Prof. Heinz Floss at the University of Washington. He continued his training in Chemistry, Biochemistry and Molecular Biology at Washington State University (Institute of Biological Chemistry) where he did postdoctoral research with Prof. Rodney Croteau from 1997-1999, and continued at the Institute as a Research Assistant Scientist until December 2003. Since January 2004, he has been an Assistant Professor at Michigan State University serving in both the Department of Chemistry and the Department of Biochemistry and Molecular Biology, where he is investigating biocatalysis and Green Chemistry approaches in the production of bioactive natural products.