The design, synthesis, biophysical and biochemical study of:
(i) dual action agents targeting DNA as intercalators and minor-groove binders with potential as more selective anticancer drugs (SFI). P.S. Nagle, C. McKeever, F. Rodriguez, B. Nguyen, W.D. Wilson, I. Rozas. J. Med. Chem. 7663-7672, 57 (2014)
(ii) chemical probes targeting Guanine-Quadruplexes in oncogenic precursors of Ras, B-Raf, or c-Myc. I. Rozas, M.O. Senge. Future Med. Chem. 609-612, 8 (2016)
(iii) Pt complexes of guanidinium based DNA minor-groove binders with potential as anticancer drugs (SFI). M. Marin-Luna, G. Sanchez-Sanz, P. O?Sullivan, I. Rozas. J. Phys. Chem. A 5540-5547, 118 (2014)
The design, synthesis and biochemical study of guanidinium derivatives as tyrosine or threonine/serine kinase inhibitors as anticancer activity (School of Chemistry ?TCD-, Ulysses award). E. Diez-Cecilia, B. Kelly, C. Perez, D.M. Zisterer, D.K. Nevin, D.G. Lloyd, I. Rozas. Eur. J. Med. Chem. 427-441, 81 (2014).
The design, synthesis and pharmacological study of antagonists of alpha2- or alpha2C-adrenoceptors as antidepressants or antipsychotics (IRC). (a) M. McMullan, A. Garcia-Bea, P. Miranda-Azpiazu, L.F. Callado, I. Rozas. Eur. J. Med. Chem. 48-57, 123 (2016). (b) B. Kelly, M. McMullan, C. Muguruza, J.E. Ortega, J.J. Meana, L.F. Callado I. Rozas. J. Med. Chem. 963?977, 58 (2015)
Clinicians often prescribe drugs based exclusively on the indications of pharmaceutical companies. However, in many occasions they are not aware of what entails the design, preparation and preclinical evaluation of a new therapeutic entity. In our lab, clinicians PhD students will be able to participate in this translational drug-discovery process being involved in one of the research lines that are presently developed: kinase inhibitors, antipsychotics or nucleic acid (DNA or Guanine-quadruplexes) targeting agents.
Molecular modelling techniques are regularly used in our group. Thus, using different programs we can represent in the computer the target macromolecule as well as the proposed potential drug. Then, we can virtually determine if this potential drug will be able to interact with the target and produce the biological effect that is pursued. The targets for the three research lines proposed are well-known (BRAF/MEK and other kinases; alpha2C-adrenoceptor; DNA and several G-quadruplexes) and therefore the design step can be properly performed in each case.
Preparation of biologically active compounds requires the use of organic syntheses, which involve complex methodologies suitable for students with knowledge of chemistry. However, some basic steps in the preparation of our proposed therapeutic agents could be carried out in conjunction with chemistry PhD students and postdoctoral researchers.
Finally, we performed the biological evaluation of the compounds prepared in association with different laboratories. We collaborate with the School of Medicine at the University of the Basque Country (Spain) where pharmacologist perform experiments that will indicate the validity of our compounds as antidepressants or antipsychotics using human brain tissue and different animal models. Regarding the projects that deal with compounds targeting kinases or nucleic acids, our final aim is to obtain anticancer agents and, thus, compounds are tested by the students in our lab in different cancer cell lines in collaboration with Prof. Zisterer from the School of Biochemistry and Immunology (TCD).