Pharmaceutical Chemistry Research Group (QO1).
Main lines of research:
- Design and synthesis of new Epi-drugs Based on Natural Products and Retinoids, for the modulation of the epigenetic changes in cancer. (SAF2007-63880 and VI PM: Epitron) LSCH-CT-2005-518417).It covers the design and synthesis of ligands modulators of retinoid receptors in particular antagonists of RAR subtypes, and also new epi-drug taking patterns inspired by the structure of natural products with demonstrated activity as enzymes modulators of chromatin remodeling: psammaplina A and ciclostellettaminas (HDACis) bisaprasine and peyssonenines (DNA methyl transferase inhibitors, DNMTis) and chaetocine (inhibitors of histone lysine methyl transferase KHMTs). The Project also addresses the analysis of potential sensitiveness and cross communication of epi-drugs, revealing the foundations of apoptosis of cancer cells via selective activation of ligand TRAIL.
- Development of New Adamantilic Retinoids kinase inhibitors for Cancer Treatment " (08CSA052383PR).In collaboration with Dr. F. Javier Piedrafita, researcher at the Torrey Pines Institute for Molecular Studies (La Jolla, USA), we are making new adamantilic arotinoids designed to act as multikinase inhibitors and analyzing its effect on cancer cell lines. We study the mechanism of antiproliferative action and induction of apoptosis of these compounds from the identification of receptor proteins by using immobilization some derivatives in a sepharose resin, then purification of the receptor complex by affinity chromatography and determination of their identity by MS. Most potent derivatives are evaluated in vitro and in vivo to determine their activity in cell culture of various cancers and in mice models.
- Development of laser-based technologies and prototyping tools for the genomic analysis by chromatin immunoprecipitation (ATLAS) VII PM-HEALTH-2007-B-221952.ATLAS is a consortium of molecular biologists, physicians, chemists, physicists, mathematicians and computer scientists to develop technology-based chromatin immunoprecipitation based on laser and applied to the entire genome (LChIP-Laser-based genome-wide Chromatin Immunoprecipitation) optimized for efficient and very selective protein-DNA interactions, by an adjustable femtosecond laser pulse, of high energy and very short duration. Some additional ATLAS aims include the adaptation of this technology to the global analysis of the genome (LChIP-chip) and unimolecular parallel and massive DNA sequencing (LChIP-seq).
- Stereo controlled synthesis of dietary carotenoids and cell signaling metabolites (Apocarotenoids and retinoids)" PGIDIT07PXIB314174PR).Using asymmetric synthesis techniques, we are preparing common dietary carotenoids also detected in plasma, of symmetrical structure (lycopene) and unsymmetrical ( -carotene), including oxygenated derivatives (xanthophylls, lutein and -cryptoxanthin) and metabolic products of acyclic ends of lycopene (2.6-ciclelycopen-1 ,5-diols). In addition to its antioxidant activity, antiproliferative capacity is studied and pro-apoptotic in human cancer cells, and is also complemented by mechanistic studies of the most active retinoids as modulators of cell signaling.
The highest priority of the research group lead by Prof. Angel Rodriguez de Lera is the chemistry underlying genetics, followed by the study of cellular and physiological functions of proteins through the interaction of small molecules -ligands- acting as modulators (activators or inhibitors) of their activity. After studies on modulators of gene transcription mediated by nuclear receptors, the group has recently started the design and synthesis of novel epi-drugs to define and validate the concept of cancer 'epigenetic treatment' adopting mold structure inspired by natural products with demonstrated activity as modulators of the enzymes related to chromatin remodeling.
The result of this work has been the development of a new drug that inhibits at least three epigenetic enzymes (HDAC, DNMT, and SIRT), whose potential as antitumor drug has been tested in animals. The structure has been patented (EU Patent: EP1964835 (A1), International Patent: WO2008125988 (A1)) and a drug is expected to be developed together with a pharmaceutical company.