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|Clarke Science (CS) 202|
Academic BackgroundProfessor Williams graduated from Milsaps College in Jackson, MS with a BS in Chemistry in 1967 after spending his freshman and sophomore years at Vanderbilt University as an English major. He took a PhD. in organic chemistry from Tulane University in New Orleans in 1972 under the direction of Adam Aguiar and joined the RIC Physical Sciences Department as an Assistant Professor of Chemistry.
His interests have included synthesis, toxicity and electrochemistry of organophosphonium salts, synthesis of novel cephalosporins, photochemistry of aryl phosphines, and computational chemistry of chromogenic cepholosporins.
Sabbaticals in computational chemistry with Ken Houk at LSU, organometallic synthesis with Dwight Swigart at Brown, and solid state polypeptide synthesis with Chris Seto at Brown have informed his research at RIC.
Over thirty of his former undergraduate research students have successfully completed PhD's and pursued careers in industrial or academic chemistry. Others have become MD's, PharmDoc's Optometrists, or secondary school chemistry teachers.
Most recently, his undergraduate research group has been involved in research projects funded by RI-INBRE and EPSCoR and in collaboration with chemistry and biology faculty at the college on the toxicity of arylphospohnium salts to DNA in vitro and in vivo, and malignant cell lines. Funding for a new project to synthesize and screen selective estrogen receptor modulators has just been granted by the RI Science and Technology Advisory Council in a competitive grant competition for which twenty cent of the proposals were funded. This project includes researchers at RIC, URI and an industrial partner who is the CEO of Organomed, Ltd.
A couple of years after I arrived at RIC a guy with long hair and casual attire (even for a student in the early 70's) came to my office and said he wanted to major in chemistry and do research. I was dubious, but had just come back to my office from my lab where I was unsuccessful in completing what I thought was the very simple task of making a solution of electrolytes in a mixed solvent. So I showed him my lab and suggested he try his luck making the solution. I went back to my office and about twenty minutes later he came back and said he had solved the problem. It turned out that the order of addition of components is important; and the novice high school graduate, using empirical methods, solved a problem the Ph.D. couldn't quite figure out.
Jimmy Covill is now the NAFTA Area Director for Clarient Corporation's operations in the western hemisphere. He was one of the first RIC BA chemistry graduates. He started at the old Hoechst Chemical plant in Coventry as a pilot-plant chemist, using a wheel barrow and shovel to mix chemicals, and moved up from there as the company evolved into Clarient over the last thirty years. There are scores of similar stories about my students and those mentored by my colleagues in chemistry, physics and biology. Students not only can do basic research as part of their education, but, in the sciences, where it is essential, we actively recruit students to include research as part of their undergraduate program. Experimental science is one of the last surviving crafts where apprentices learn from masters, but, unlike the Medieval model, the "masters" also learn from the "apprentices" like I did many years ago from Jim Covill.
RIC BA and BS chemistry graduates are in the process or have taken Master's or Ph.D's in chemistry from Brown, Yale, Dartmouth, UNC at Chapel Hill, University of Florida, UC Berkeley, University of Connecticut, SUNY Stony Brook, U of Georgia, Brandeis, U of Wisconsin, and others. The much younger BA degree in Physics has sent students to Harvard, Princeton, the U. of Cincinnati and the University of Pittsburg for graduate degrees. Other graduates have gone to Brown or the New England College of Medicine for MD degrees.
RIC alumni are employed in industry and academia; DuPont, Glaxo-Welcome, Pfizer, Lily-Ponds, Paratek, Genentech, Clarient, Cal State at Northridge, University of Arkansas, University of San Diego, College of the Holy Cross, Woods-Hole Oceanographic Institute, Scripts Oceanographic Institute, to name a few. Others have entered middle and high school science teaching in various school districts all over Rhode Island and southern New England.
Professor of Chemistry
Courses TaughtBIOL 652 Adv Topics in Biology
CHEM 104 General Chemistry II
CHEM 205 Organic Chemistry I
CHEM 206 Organic Chemistry II
CHEM 250 Topics
CHEM 491 Research In Chemistry
CHEM 492 Research In Chemistry
CHEM 493 Research In Chemistry
HONR 150 Topics
Research ProjectsJohn Williams is a professor of Chemistry in the Physical Sciences department. His tireless and dedicated approach to undergraduate research and the promotion of ‘learning through doing’ has benefitted an untold number of undergraduate students in the sciences.
In John’s own words, “RIC BA and BS chemistry graduates are in the process or have taken Master’s or Ph.D’s in chemistry from Brown, Yale, Dartmouth, UNC at Chapel Hill, University of Florida, UC Berkeley, University of Connecticut, SUNY Stony Brook, U of Georgia, Brandeis, U of Wisconsin, and others. The much younger BA degree in Physics has sent students to Harvard, Princeton, the U of Cincinnati and the University of Pittsburg for graduate degrees. Other graduates have gone to Brown or the New England College of Medicine for MD degrees.”
This work is divided into three parts. It is intended to introduce undergraduate chemistry and biology majors to chemical synthesis, purification and analysis of compounds that have a spectrum of toxicities, to screen these compounds for in vitro activity against bacteria, proteins, DNA and normal and malignant cells, and to examine the interactions between these compounds (“small molecules”) and DNA and proteins (“large molecules”) using computational chemistry. These are some of the techniques employed in the search for new drugs by pharmaceutical companies.
The project design provides students the opportunity to be paid a stipend for doing work in preparation for a position in industry after earning a bachelor’s degree. If they are bound to graduate or medical school, it gives them the advantage of actual laboratory experience as undergraduates. In addition to the lab and computer work, students read the current literature to keep abreast of other work in the field and new aspects of APS biological activity. Finally, since the ultimate goal of any research project is to communicate the results to the larger scientific community, the students are each assigned a scientific journal for which to prepare a manuscript for submission. In the meantime, the INBRE project provides winter and summer all-day retreats where the projects are presented in a poster session and selected participating faculty present twenty-minute talks on their research.
In industry, the synthesis of new chemical entities (NCE’s) is done by medicinal chemists, toxicology screening by biologists and analytical chemists, and computation by scientists with backgrounds in chemistry, physics or mathematics. All of the research students are exposed to each of these aspects of drug research and development. Definite laboratory time is assigned to each participant through the week. We have one-hour group meetings every Friday in which I summarize progress since the last meeting and each student presents a brief PowerPoint talk on their projects.
We began with some known toxicology, biological activity data, physical chemical information, and chemical synthesis methods for the compounds of interest; arylphosphonium salts (APS). One class of these compounds, which were the basis for my PhD dissertation, showed significant activity against malignant cell cultures in NIH tests. Also, the activity was directly related to subtle changes in the molecular structure. That is, they showed a structure-activity relationship or SAR. The synthesis of these particular APS’s involved boiling acetic acid saturated with hydrogen chloride gas, which is a process that lends itself neither to undergraduate research, nor bulk industrial chemistry. For this work we are using APS that are more easily synthesized and modified that do not require such severe reaction conditions.
The activity of APS depends on their being soluble in both water and oil, because optimal solubility in both media is a goal of invention for all potential new drugs. Many cases of early failure in the physical screening of drug candidates are due to poor water solubility. After drugs are administered, they must be distributed in the blood stream, which is mostly water, to sites of action on or in the cells of target tissues, during which time they may also be metabolized and/or eliminated. Getting inside cells requires some affinity for the hydrophobic (“oily”) cell membrane interiors. The APS’s are positively charged, which renders them water-soluble. They also have large hydrocarbon attachments (the “aryl” parts) that render them “lipophilic” or oil loving. The APS with which we are working can be deliberately modified chemically to change the oil/water interaction dynamics and thus the spectrum and selectivity of biological activity. That is, they show predictable and potentially alterable structure-activity relationships (SAR’s). This chemical “tweaking” of a basic molecular structure is a standard strategy of medicinal chemists in the pharmaceutical industry.
Research SummaryOur lab is continuing work begun over 40 years ago and contributed to during the intervening time by many undergraduate and graduate students. Projects now involve synthesis and toxicology of antibiotic, anti cancer, antioxidant, and neuroprotective compounds and isolation and analysis of Hsp70 from G. demissa in Narragansett Bay. We now use microwave assisted organic synthesis, high pressure liquid chromatography and solid state polypeptide synthesis in addition to traditional benchtop methods. We have access to the INBRE Core Lab at URI for mass spectroscopy, protein sequencing and cellometry, and the EPSCoR lab at Brown for multi-laser cell isolation and counting. We maintain cell cultures of malignant and normal cells for screening. In recent years our projects have involved collaboration with other RIC science faculty and colleagues at URI and Brown.
Current work in my lab
1) Synthesis of small polypeptide recognition sequences to conjugate with arylphosphonium salts or co-administer with them to make targeting anticancer agents,
2) Collection of ribbed mussels (G. demissa) from four sites around Narragansett Bay for dissection and isolation of Hsp70 heat shock proteins for Western Blot separation and antibody staining to quantify the relationship of Hsp70 levels with the year-round climate of the Bay,
3) Maintaining cell cultures for anti-cancer screening by cellometry, FACS analysis and confocal microscopy of a variety of compounds synthesized in our labs. The cells are imaged by selective staining dyes or plasmids with fluorescent labels,
4) Synthesis of arylphosphonium salts (APS) for SAR’s from toxicology screening: as antibiotics, DNA binders, Estrogen receptor binding, anticancer screening and in vitro DNA binding.
5) The effects of metal cations (Na+, K+, Cs+, Ca
Work on hold and to be resumed in my lab
1) Synthesis of antibiotic polymers by grafting APS onto functionalized polymers or polymerization of monomers with covalently bound APS or their phosphine precursors,
2) SAR’s of DNA binding to a series of (X)APS (were X is an ortho or para substituent on the aryl group) by electrophoresis
3) SAR’s from computation of DNA-(X)APS interactions by HyperChem and AutoDock software
4) Synthesis of libraries of sets of “druglikely” compounds based upon six scaffolds for which one or more member has shown significant activity as Era+ and/or -, or against breast and/or liver cancer cells in culture.
5) Synthesis of APS ligands for G4-DNA binding studies
Collaborators: C. H. Leung, K. Almeida
[NB EPSCoR, INBRE, STAC, stipends, FRC and IS in AY]