2007 Project Descriptions

 

Chemistry

Multi-step synthesis of protected intermediates used in synthesis of combinatorial libraries.

Research plan for 3-month period includes multi-step synthesis of protected intermediates that could be used in synthesis of combinatorial libraries. Synthesis would start from commercially available synthons. The ultimate goal is to obtain 5-10g of novel and chemically stable intermediates that would be tested in ongoing chemistries and would become part of our new combinatorial libraries. Besides this major goal, a parallel research on design and synthesis of safety-catch linkers would be carried out. State-of-the art oxygen activated, water cleavable linker is proposed and all structural elements would be explored.

Development of Hydrazine linker and multiple heterocycle Library.

Intern will be involved into two projects:

1. Hydrazine-linker project: Intern will further develop the use of hydrazine base linker in library development and production. One objective of this research is to synthesize variety of stabilized analogues of the hydrazine linker and test them against various conditions of library development on solid phase.
2. Library development of multiple heterocycle: Intern will continue development of heterocyclic chemistry on solid-phase using microwave technology. Successful development will lead to library development of class of heterocycle.

Exploration of solid phase chemistry for libraries on solid support.

Exploration and development of solid phase chemistries for library synthesis. If successful exploration, the student will develop and optimize the chemistry up to library production.
The exploratory projects will include either of the following 1) optimization of Baylis-Hillman reactions on solid support and novel transformations of the Baylis-Hillman intermediates; 2) adaptation of novel 3-component reactions to solid support, or 3) solid phase Horner-Emmons reactions followed by (a to be optimized) cyclative cleavage step. All options include carbon-carbon bond forming reactions, and final products are novel.

Ring Closure Metathesis Investigation in Combinatorial Library Synthesis.

In the continuation of ongoing project "The Ring Closure Metathesis Library" we will explore and develop robust synthesis schemes for RCM on solid and solution phase and will investigate modifications of the resulting double bond to generate a combinatorial library targeting Aspartyl-Protease inhibitors.

 

Library Production

Synthesis of arrays of compounds and evaluation of SCF extraction.

The student will be asked to synthesize small arrays of compounds using established chemistries on solid support, and to evaluate the use of Liquid CO2 (SCF CO2) as a solvent replacement for solid phase chemistry. Experiments will have to be designed to access the efficiency of SCF CO2 washing steps in comparison with standard solid support washing procedures. Student will have an opportunity to work within the Library Production Group using unique state of the art instrumentation for library production and purification. He or she will have also an opportunity to use modern parallel analytical methods to assess library purity.

 

Analytical Department

Development and evaluation of pilot methods for solubility measurement.

As more awareness is gained of the correlation between the success of Lead Discovery efforts and solubility of the explored compound series, the need for assessing solubility on samples produced in Tucson is increasing. It is proposed that a student intern evaluate existing methods and tools for measuring solubility to determine the best fit for this environment according to sample throughput, operator efficiency, and precision and accuracy of results.

Optimization of parallel HPLC system MS detection.

Optimize Nanostream/MS. The proposed research would involve optimization of hardware and analytical lab protocols to increase the reliability of the parallel HPLC method. A requirement would be collaboration with Scientific Computing to make available and modify where needed the "Caterpillar" method for associating LC peaks with MS signals. Possible outcomes of this internship are a go/no go on further development of the Nanostream/MS interface, recommended changes to hardware or protocols, and/or improvements in Caterpillar.

Improvement of analytical deconvolution of complex samples from combinatorial libraries.

The intern could become involved in all aspects of deconvolution from sample preparation and handling, chromatographic separations, data processing, and possibly mass spectral analysis. The development of improved chromatographic methods would be an obvious area of concentration. The internship position offers an opportunity to learn elementary techniques of drug discovery in support of structure-bioactivity correlation.

 

Biology Department

Biological characterization of small molecules specifically targeting cancer cells.

We are characterizing small molecules to identify those that may be useful in specifically targeting cancer cells. We are interested in pathways that may be more vulnerable in cancer cells than in normal cells. We have used whole cell and biochemical approaches to identify interesting molecules and we have identified a class that appears to affect the ability of cancer cells to progress through the cell cycle. These compounds may induce apoptosis and appear be to be directed at pathways which are altered in many cancers. We are currently developing assays to gain further insight in the mechanism of action of our compounds and to help identify a structure activity relationship in some of our compound series. An intern will work in the modern industrial laboratory and gain experience in assay development and with equipment for and high-throughput screening.

Discovery of activity of small molecules through automated high-throughput screening of large combinatorial libraries.

Student intern will be involved in an adaptation and validation of cellular and molecular assays to the high-throughput screening, execution of screening campaigns on robotic stations and conformation and evaluation of activity of compounds in follow up assays. Student will work with state of the art robotic and screening equipment. Computer proficiency and capability and willingness to work with lab instrumentation is essential for this project.

Cellular responses to chemokines.

Chemokines are a large family of small proteins that help to coordinate inflammatory processes, and they constitute a class of target for modulating various diseases. The local research center of sanofi-aventis has discovered several classes of small molecule antagonists that affect different chemokines. An intern is sought to work on model systems of the biological responses to chemokine stimulation using both engineered and primary cell types.

 

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