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Synthesis, structural characterization and biological application of aminoarylthiazoles for the correction of chloride transport in cystic fibrosis
Universita degli Studi di Genova
University of Genova - Center of Excellence for Biomedical Research via De Toni, 2 ? 16132 ? Genova (Italy)
Prof. Antonio Uccelli
Proff. Enrico Millo e Gianluca Damonte
Type of Research Project
- Basic science
What is the background of the project?
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Cystic fibrosis (CF) is a severe multi organ disease caused by the mutations of the CFTR gene. The most common CF mutation, DF508, impairs the processing and activity of CFTR protein. These defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. The specific aim of the project is to design and synthesize library of Aminoarylthiazoles (AATs) to define, also through a structure activity relationship (SAR) approach, which chemical groups could be beneficial or detrimental for rescue the activity of the chloride channel. After synthesis, characterization and purification, the obtained molecules will be used for the
What is the aim of the project?
The specific aim of the project is to design and synthesize library of Aminoarylthiazoles (AATs) to define, also through a structure activity relationship (SAR) approach, which chemical groups could be beneficial or detrimental for rescue the activity of the chloride channel. After synthesis, characterization and purification, the obtained molecules will be used for the “in vitro” biological evaluation in order to obtain lead molecules to be tested in “in vivo” experiments.
What techniques and methods are used?
For the synthesis of the aminoarylthiazoles compounds a versatile, solution-phase procedure will be exploited. In this approach the aminoarylthiazoles derivatives were synthesized by nucleophilic substitution of aminoheterocycle and substituted 2- halothiazole, to obtain a quite wide library of potential hits. Various structural modification involving the position of different functional groups could be attempted. Structural characterisation will be performed, both on the synthetic intermediates and on finally raw products, by means of analytical HPLC techniques coupled with electrospray mass spectrometry (API-ESI-MS). This phase will be followed by preparative high-pressure liquid chromatography that permits to work with hundreds milligrams of crude powder.
What is the role of the student?
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
During the period of attending the laboratory, students will be theoretically and practically trained on techniques and approaches used for the research. Day by day students will follow the activity of laboratory personnel, learning the scientific methodology through the planning of experiments and the critical discussion of the obtained results. In detail she/he will be practically involved in chemical synthesis and instrumental analysis.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
No specific skill are required
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months)
- Dual activity of aminoarylthiazoles on the trafficking and gating defects of the cystic fibrosis transmembrane conductance regulator chloride channel caused by cystic fibrosis mutations. J Biol Chem. 2011 29;286(17):15215-26
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