Sotelo
Research themes
Combinatorial Chemistry in Biomedicine
Main researcher(s)
Group members
Prieto Díaz, Rubén |
Postdoctoral Researcher |
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Reza Ramos, David |
Postdoctoral Researcher |
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Selas Lanseros, Asier |
Postdoctoral Researcher |
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Andújar Arias, Antonio |
PhD Candidate |
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Campos Prieto, Lucía |
PhD Candidate |
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Fojo Carballo, Hugo |
PhD Candidate |
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García Rey, Aitor |
PhD Candidate |
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González Pico, Lucía |
PhD Candidate |
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Miranda Pastoriza, Darío |
PhD Candidate |
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Ortigueira Noya, Sandra |
PhD Candidate |
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Rodríguez García, Carlos |
PhD Candidate |
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Rodríguez Pampín, Iván |
PhD Candidate |
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Paleo Pillado, María Rita |
Inv. collaborator |
Research
RESEARCH OVERVIEW
The discovery and optimization of small bioactive molecules remains an active goal for chemists in both academic and industrial settings. Bioactive molecules provide essential insights into basic cellular function and they are critical to identify cellular targets implicated in human diseases. Research in the Sotelo laboratory focuses on organic synthesis, with a specific emphasis on developing new methods and molecules that will enhance our understanding of the basis of human diseases and the discovery of new small molecule treatments. Synthesis is a powerful tool in Medicinal Chemistry and Chemical Biology, we exploit Multicomponent reactions (MCR) to development novel therapeutic agents to address significant unmet medical needs and to tailor molecular probes to study complex biological systems. The Sotelo laboratory has also pioneered the use of 3D printing concepts in the development of novel environmentally friendly heterogeneous catalysts.
Our ongoing projects are split into four major areas:
- Medicinal Chemistry and Chemical Biology of GPCRs.
- Development of Novel Multicomponent-Based Synthetic Strategies.
- Design and Optimization of Heterogeneous Catalysts by 3D Printing.
- ComBioMed Platform for Collaborative Drug Discovery Programs.
MEDICINAL CHEMISTRY AND CHEMICAL BIOLOGY OF GPCR
G protein-coupled receptors (GPCRs) are the most common family of receptors in the genome. The 800 members of this family comprise >1% of the coding human genome and they are expressed within every organ system. GPCRs are sensors for a wide array of extracellular stimuli, including proteins, hormones, small molecules, neurotransmitters, ions and light. As they regulate virtually every aspect of physiology, it is not surprising that GPCRs are also the target of >30% of all prescription drug sales. All GPCRs share a common architecture that consists of an extracellular N-terminal sequence, seven transmembrane domains that are connected by three extracellular and three intracellular loops, and an intracellular C-terminal domain. Recent advances in different scientific branches have markedly changed our perception and knowledge of the physiology, physiopathology and structural biology of GPCRs. The consolidation of key concepts such as GPCR (homo/hetero) oligomerization, allosteric modulation or signaling bias provides promising and unexplored therapeutic approaches to address significant unmet medical needs. In this context, the medicinal chemist’s armamentarium to modulate these targets has expanded considerably. In addition to classical GPCR modulators [e.g., agonists (full, partial or inverse) and antagonists], contemporary drug hunters now also intensively pursue (positive/negative) allosteric modulators, (homo/hetero) bivalent ligands, bitopic ligands and biased (functionally selective) ligands.
Our group is focused on research programs aimed at discovering novel drug candidates for serious pathologies (e.g., Parkinson disease, cancer, glaucoma, diabetes, schizophrenia and neuropathic pain). In each case, the therapeutic hypothesis entails the modulation of diverse therapeutic approaches and GPCR families (adenosine, dopamine, histamine, serotonin, angiotensin and cannabinoid receptors). We are also engaged in the development and optimization of molecular probes for diverse chemical biology programs, as well as in the design and validation of synthetic methodologies that can accelerate the rational discovery of the emerging class of GPCR therapeutics.
DEVELOPMENT OF NOVEL MULTICOMPONENT-BASED SYNTHETIC STRATEGIES
All aspects of the drug discovery process have undergone radical changes in the past two decades. In response to the need to discover valuable, pharmacologically useful compounds and to shorten the time required for preclinical research, medicinal chemists have incorporated successful new concepts and methodologies into the laborious process of lead discovery and lead optimization. Selectivity, atom economy, time savings, environmental friendliness, cost-effectiveness, diversity, and drug-like properties, as well as the reconciliation of molecular complexity with experimental simplicity, are some of the key pieces of the puzzle that must be assembled by modern medicinal chemists to achieve the maximum efficiency during drug discovery programs.
Most of these characteristics are met by multicomponent reactions, which have emerged as powerful strategies in contemporary drug discovery since they constitute powerful tools for creating molecular diversity by matching the space of biological targets with relevant chemistry. MCRs allow the generation of a high level of structural and functional complexity in a few steps from simple starting materials without the need to isolate intermediates. Additionally, the absence of workup and purification steps and the minimization of waste promotes time-efficiency when a premium is placed on speed during the drug discovery process. During the last decade we have exploited the advantages of MCR in our synthetic and medicinal chemistry programs. In this context we have published conceptually novel multicomponent-based reactions to assemble diverse heterocyclic libraries. In parallel, our group has documented diverse MCR approaches in GPCR medicinal chemistry, with novel pharmacophores described for different targets and the reinterpretation and refinement of hit compounds.
DESIGN AND OPTIMIZATION OF HETEROGENEOUS CATALYSTS BY 3D PRINTING
The increasing environmental consciousness of modern society challenges the chemical community to develop catalytic systems that enable chemical processes with a reduced environmental impact (E-factor). Transition metal-catalyzed reactions (TMCR) occupy a prominent position among modern synthetic methods in industrial and academic laboratories. The excellent selectivity and functional group compatibility of TMCR offer robust and mild synthetic alternatives for the synthesis of natural products, pharmaceuticals, agrochemicals or polymers. Nevertheless, leaching of the metal into the reaction medium is a critical problem that hampers the application of TMCR in the pharmaceutical industry. The strict safety guidelines of regulatory agencies limit the acceptable levels of most transition metals within drugs to the low ppb range. In this context, catalyst immobilization is an appealing strategy that, in addition to facilitating catalyst recovery and operation in a continuous-flow format, has proven to give higher catalytic performance, since the solid support usually imparts chemical, thermal, and mechanical stability to the catalytic species.
The emergence of 3D printing methods has impacted almost all areas of research and industry. This revolutionary technology stands out due to the key advantage of the fabrication of three-dimensional physical objects from a digital model by taking a virtual design from computer-aided design (CAD) software and reproducing it layer by layer until the physical definition of the layers gives the designed product. The 3D printing technique enables the fabrication of monoliths with different cross sections, pore sizes, and wall thicknesses, thus maximizing the catalytic surface. More importantly, the fabrication parameters can be tuned to obtain parts with excellent mechanical properties. In the context of catalysis, 3D printing offers plentiful unexplored avenues in the field of heterogeneous catalysts. In addition to the possibility of exquisite modulation of shape, size and metal loading of the catalytic system, 3D printing enables fine tuning of other critical parameters that influence both the macro- and microscopic aspects of catalysts.
The Sotelo laboratory, in collaboration with the Galician Ceramic Institute, pioneered the use of 3D printing concepts in the development of environmentally friendly heterogenous catalysts based on ceramic materials. These efforts provided the first 3D printed heterogeneous (copper) catalyst on an alumina support, new catalytic systems obtained by surface functionalization and metal (palladium or copper) heterogenization on a 3D printed silica support.