William L. Scott Ph.D.

Research

Dr. Scott has extensive experience in both the pharmaceutical and academic environments. He is building on this experience through a project called Distributed Drug Discovery (D3) in collaboration with Dr. Marty O'Donnell. At the center of this project is the belief that student learning is more effective when students clearly see the direct application of acquired knowledge to an important challenge.

Distributed Drug Discovery provides this organizing and motivating context as we teach the theory and practice of organic, computational and biological chemistry, and students apply one or more of these skills to the search for drug leads for neglected diseases. D3 proposes that if simple, inexpensive equipment and procedures are developed for each of the core disciplines of drug lead discovery - computational chemistry, synthetic chemistry, and biological characterization - a large problem can be divided into manageable smaller units and carried out by students, in parallel, at multiple academic sites throughout the world. The coordinated and recombined results of these distributed resources can accelerate the identification of leads in the early stages of the drug discovery process. Simultaneously, this effort provides educational opportunities in both the developed and developing worlds, while building cultural bridges for the common good.

D3 creates an opportunity for students to learn synthetic organic chemistry, computational chemistry and biology in a setting that incorporates key elements of the research environment normally absent in traditional lab courses. It engages beginning students with a research challenge that is scientifically important and socially relevant. A small subset of these students may choose to pursue scientific research and become actively involved with faculty in the development of future undergraduate laboratories. Some of them go further to teach (as teaching assistants in the undergraduate lab), relaying their in-depth expertise to their peers and serving as role models. Because drug discovery is the premier example of a challenge requiring integrated scientific expertise, students participating in these contextualized laboratories, whatever their ultimate role in society, will come away with a deeper understanding and appreciation of the integral place science plays in their lives.

D3 requires powerful yet student accessible tools to permit them to learn and participate in a meaningful way in all aspects of drug lead discovery. We want them to learn skills that can have a direct and major impact. This is a key challenge for the program. All the disciplines required of D3 share this same imperative. Our synthetic chemistry component is most developed. It has been implemented at sites in Russia, Spain and Poland, along with a number of academic institutions in the United States.

The focus of Dr. Scott’s basic research is the development of simple and inexpensive equipment and combinatorial synthetic methodologies to quickly make large numbers of “drug-like” molecules that facilitate the Distributed Drug Discovery project. These compounds can be screened in biological assays to generate leads for drug discovery. His synthetic focus is on the solid-phase synthesis of conformationally constrained peptidomimetic molecules, other general classes of biomimetic molecules, and unnatural amino acids.

Education

• B.A., Williams College, 1967
• Ph.D., University of California, Los Angeles, 1972
• NIH Postdoctoral Fellow, Rockefeller University, 1972-73
• NIH Postdoctoral Fellow, California Institute of Technology, 1974
• Research Scientist in Drug Discovery at Eli Lilly 1974-2001

Publications & Professional Activity

P. Zajdel, J. Krol, K. Grychowska, M. Pawlowski, G. Subra, G. Nomezine, J. Martinez, G. Satala, A. J. Bojarski, Z. Zhou, M. J. O’Donnell and W. L. Scott "Solid-phase synthesis of arylpiperazine derivatives and implementation of the Distributed Drug Discovery (D3) project in the search for CNS agents" Molecules 2011, 16, 4104-4121.

W. L. Scott, Z. Zhou, P. Zajdel, M. Pawlowski and M. J. O’Donnell "Solid-phase synthetic route to multiple derivatives of a fundamental peptide unit" Molecules 2010, 15, 4961-4983.

W. L. Scott and M. J. O’Donnell “Distributed Drug Discovery, Part 1: Linking academics and combinatorial chemistry to find drugs for developing world diseases” Journal of Combinatorial Chemistry 2009, 11, 3-13.

W. L. Scott, J. Alsina, C. O. Audu, J. L. Dage, E. Babaev, L. Cook, L. A. Goodwin, J. G. Martynow, D. Matosiuk, M. Royo, J. G. Smith, A. T. Strong, K. Wickizer, E. M. Woerly, Z. Zhou and M. J. O’Donnell “Distributed Drug Discovery, Part 2: Global rehearsal of alkylating agents for the synthesis of resin-bound unnatural amino acids and virtual D3 catalog construction” Journal of Combinatorial Chemistry2009, 11, 14-33.

W. L. Scott, C. O. Audu, J. L. Dage, L. A. Goodwin, J. G. Martynow, L. K. Platt, J. G. Smith, A. T. Strong, K. Wickizer, E. M. Woerly and M. J. O’Donnell “Distributed Drug Discovery, Part 3: Using D3 methodology to synthesize analogs of an anti-melanoma compound” Journal of Combinatorial Chemistry 2009, 11, 34-43.

W. L. Scott, Z. Zhou, J. G. Martynow and M. J. O’Donnell "Solid-Phase Synthesis of Amino- and Carboxyl-Functionalized Unnatural α-Amino Acid Amides" Organic Letters 2009, 11, 3558-3561.

W. L. Scott, J. G. Martynow, J. C. Huffman and M. J. O'Donnell "Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates" Journal of the American Chemical Society 2007, 129, 7077-7088.

J. Alsina, W. L. Scott and M. J. O'Donnell "Solid-phase synthesis of α-substituted proline hydantoins and analogs" Tetrahedron Letters 2005, 46, 3131-3135.

W. L. Scott, J. Alsina, J. H. Kennedy and M. J. O'Donnell "Solid-phase synthesis of constrained terminal and internal lactam peptidomimetics" Organic Letters 2004, 6, 1629-1632.

M. J. O'Donnell, J. Alsina and W. L. Scott "Solid-phase synthesis and utilization of side-chain reactive unnatural amino acids" Tetrahedron Letters 2003, 44, 8403-8406.

W. L. Scott, J. Alsina and M. J. O'Donnell "The manual and automated solid-phase synthesis of α-substituted prolines and homologues" Journal of Combinatorial Chemistry 2003, 5, 684-692.

W. L. Scott, M. J. O'Donnell, F. Delgado and J. Alsina "A solid-phase route to unnatural amino acids with diverse side-chain substitutions" Journal of Organic Chemistry 2002, 67, 2960-2969.

W. L. Scott, F. Delgado, K. Lobb, R. S. Pottorf and M. J. O'Donnell "Solid-phase synthesis of amino amides and peptide amides with unnatural side chains" Tetrahedron Letters 2001, 42, 2073-2076.

M. J. O'Donnell, F. Delgado, E. Dominguez, J. de Blas and W. L. Scott "Enantioselective solution- and solid-phase synthesis of glutamic acid derivatives via Michael addition reactions" Tetrahedron: Asymmetry 2001, 12, 821-828.

M. J. O'Donnell and W. L. Scott "Unnatural amino acid and peptide synthesis" In: Peptides 2000, J. Martinez and J.-A. Fehrentz, Eds., EDK: Paris, 2001, pp. 31-36.

M. J. O'Donnell, M. D. Drew, R. S. Pottorf and W. L. Scott "UPS on Weinreb resin: A facile solid-phase route to aldehyde and ketone derivatives of "unnatural" amino acids and peptides" Journal of Combinatorial Chemistry 2000, 2, 172-181.