The Molecular Synthesis group integrates organic, inorganic, physical and biological chemists whose common interest is to create molecules. Molecules are synthesized because they are needed. Either as simple molecules, as units to produce complex structures or even to prove a scientific hypothesis – molecules are key players in everyday life.
Research is focused on the design of Molecules and Materials for biomedical, agricultural, environmental, energy and food applications, and improvement of Synthetic Methods granting the sustainable chemistry concept.
Several classes of molecular frameworks such as hydroxypyridinones, porphyrins, carbohydrates, amino acids, benzimidazoles and peptides are functionalized with several chemical groups to produce molecules whose physicochemical properties are fine-tuned according to the application in view. Examples are fluorescent chelators to monitor and sensing metal ions in body fluids and natural waters, anticancer, antimalarial, antimicrobial and novel anti-inflammatory drug candidates.
Peptides, carbohydrates, porphyrin, and dyes like coumarin and xanthene derivatives are preferential frameworks to produce innovative [Bio]materials with potential applications in Biomedical Engineering, [Bio]sensing, Catalysis, Separation and Cleaner Energies.
Chemical synthesis of a wide diversity of molecules for:
- Chelates and chelators to address iron imbalance-related diseases
- Membrane-active peptides as novel antimicrobial agents
- Modification of classical anti-malarials to bypass parasite resistance
- Bioactive ionic liquids derived from anti-infective drugs
- Synthetic analogues of vitamin D3 precursors
- Peptidomimetics to address neurodegenerative disorders
- Benzimidazole-based compounds as cyclooxygenase-inhibitors
- Nature-inspired molecules, from marine compounds, and xenobiotic metabolites, to bacterial cell wall disaccharide components, and sugar-based compounds with bactericidal and cytotoxic activities
- Oxygen heterocycles as potential antioxidant, anticancer and anti-diabetic agents
- Porphyrin derivatives as potential anticancer and antimicrobial agents
Agricultural, environmental and food applications
- Chelators for regulation of iron uptake and storage in plants
- Pyridinone chelators for iron speciation in waters
- Peptides and proteins of relevance in wine properties
- Ferrocene-based imine ligands as selective sensors for mercury(II)
- Organometallic molecules as catalysts for CO2 functionalization, and other chemical reactions
- Porphyrin derivatives as potential antimicrobial agents
- Porphyrin derivatives and analogues as chemosensors for anions
- Homogeneous and heterogeneous oxidation of alkenes, alkanes, catechol, organosulfur compounds
- Homogeneous oxidation of indole to afford indigo dye
Development of innovative methods for the chemical synthesis or computational design and study of relevant target molecules
- Innovative approaches for one-pot synthesis of oligopeptides, and heterocycles of interest in medicinal and process chemistry
- Solid-phase synthesis and grafting of peptides onto biomaterials
- New routes for enantioselective synthesis of chiral compounds with potential pharmaceutical interest
- Ohmic heating as an emerging concept in organic synthesis and their application in the synthesis of bioactive compounds
- Design and synthesis of efficient solid fluorophores with potential application in luminescent materials
- Cycloaddition reactions for creating improved porphyrin-based photosensitizers
- Aza-Michael addition reactions – unprecedented sapphyrin derivatives
- Design and synthesis
Use of molecular synthesis tools towards development of innovative [bio]materials with potential applications in Biomedical Engineering, Drug Delivery, Separation Techniques and Cleaner Energies.
- Peptide-tethered antimicrobial coatings for bone implants
- “click”-chemistry-coated microspheres for bacterial removal
- Sugar-based polymeric nano/microparticles and amino
- Acid-based surfactants for drug delivery and gene therapy
Separation and cleaner energies
- Drug-imprinted xerogels for chromatographic applications
- Coumarin-based chromophores for dye-sensitized solar cells
- Better Fe-shuttles to address crop Fe deficiency
Iron Deficiency Chlorosis (IDC) is a disorder that has consequence not only in plant growth but also in the Fe content of seeds and fruits. To solve the problem, Fe-chelates with properties that allow more efficient pathways for root uptake, root to shoot translocation and maintenance of metal homeostasis are needed. In a pilot study performed in soybean (Glycine max L.) we tested a family of Fe-chelates that permits to design compounds with a variety of chemical properties that can be fine-tuned according to the results obtained on plants. We found that the Fe-chelates have potential as new IDC correctors since plants were significantly greener and had increased biomass when compared to plants supplied with the commercial fertilizers. In particular, plants supplied with one of the compounds, were able to translocate more iron from the roots to the shoots.
- Ionic liquids derived from active pharmaceutical ingredients
Ionic liquids derived from active pharmaceutical ingredients (API-ILs) may open new perspectives towards greener methods for the rescuing of classical drugs. Following our long track record in the recycling of classical antimalarial drugs currently in decline due to resistance and/or toxicity issues, we have recently unveiled novel ionic liquids derived from the antimalarial drug primaquine as triple-stage antimalarial leads. This unprecedented approach opens a new chapter concerning sustainable development of low-cost drugs, not exclusive to the arena of antiparasitic drug discovery.
- Sugar-based polymeric nanoparticles
Carbohydrates are very important in biology, and excellent targets for the development of therapeutics. Following recent progress in nanoscience, which disclosed the relevance of nanomaterials in healthcare, glycopolymers are gaining prominence for drug delivery, given their high affinity and binding specificity towards targeted receptors.
Our Research Unit has combined nanotechnology and polymer science to develop polymeric nanoparticles (PNPs), based on glycosylation of biocompatible biopolymers. Novel polymer-based materials prepared from monosaccharides obtained by enzyme-catalyzed synthesis, that were homo-polymerized and copolymerized with styrene by a free radical process. Thus, polymer materials with sugar moieties, attached to the polymer backbone via ester linkages were attained where the structural features of the monomers greatly affected the thermal and rheological properties of the polymers. We have further produced novel amphiphilic polymers composed of poly(ethylene glycol) (PEG), cholic acid and sucrose. Owing to their amphiphilic characteristics in aqueous media, these PNPs could be prepared via a greener surfactant-free nanoprecipitation method. The spherical shape and size of the PNPs thus produced were suitable for drug delivery applications.
- Coumarin-based chromophores for dye sensitized solar cells
Dye-sensitized solar cells (DSSCs) are low-cost thin film solar cells with many attractive features, such as their ease of preparation and multiple applications, owing to their flexibility and transparency features. Although still less efficient than the best thin-film cells, their price/performance ratio is expected to become good enough to make them competitive with fossil fuels for generation of electricity. Bearing this in mind, and in line with the European Union Photovoltaic Roadmap that targets a significant contribution of DSSCs to renewable electricity generation by 2020, we have produced highly fluorescent coumarin dyes with styryl and phenylethynyl π-bridge moieties, via Sonogashira and regioselective Heck arylation reactions, for application in DSSCs.
- Highly efficient one-pot synthetic routes towards bioactive compounds
The development of new chemical methodologies and greener approaches for the assembly of important scaffolds is one of the main goals of modern organic chemistry. Our Research Unit has been devoted to synthesis of challenging scaffolds, such as azaindoles - a very popular class of compounds for both medicinal and process chemists, and developed a practical and straightforward syntheses of substituted and 1,2-disubstituted azaindoles. Thus, one-pot approaches were developed, involving several Pd-catalyzed cross-coupling reactions, such as Heck, Sonogashira, Buchwald-Hartwig reactions, opening a fast and elegant access to this not always easy to make class of compounds.
Equally noteworthy, a methodological advancement in solution-phase peptide synthesis was achieved, through development of a protocol to synthesize oligopeptides in a one-pot three-step cascade method, in which two peptide bonds are introduced chemoselectively. Oligopeptides were obtained in high global yields with no observable epimerization, through a faster, easier and milder approach that operates at equimolar amounts, and is compatible with virtually all protection schemes relevant in the context of peptide synthesis.
- Ohmic heating: a new method in chemical synthesis
Ohmic heating (ΩH) is an advanced thermal processing method. In ΩH, the reaction mixture, which behaves as an electrical ohmic heater, is heated by passing an AC electrical current of high frequency through it. The heat is generated in situ and dissipated directly in the reaction, with high-energy efficiency, by Joule effect.
The first ΩH reactor for chemical synthesis was constructed in our group in 2013. This reactor has been used to perform several reactions, including Diels–Alder reactions, nucleophilic substitutions, N-alkylations, C-C cross coupling reactions, sequential Knoevenagel condensations followed by a hetero-Diels–Alder reaction, indium (In)-promoted reductive dehalogenations and reductive eliminations. ΩH allows a rapid and uniform heating of the reaction medium and increases the dynamics/mobility of the charged particles in solution, leading in most cases to better yields, better selectivity and shorter reaction times than classical and microwave heating methods.
- Tuning antibacterial activity of 3,4-HPO chelators through fluorophores
Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully targeted by novel antibacterial drugs. By analysing the effect of a variety of 3-Hydroxy-4-Pyridinone Fe chelators in the inhibition of the intramacrophagic growth of Mycobacterium avium, we have gathered information regarding the chemical properties necessary for an efficient antimycobacterial chelator.
The results showed that the chelation of Fe is a determinant but not sufficient property for antimicrobial activity. The activity is strongly dependent on the presence of the xanthene fluorophore, its type and on the linker binding the fluorophore and the chelating unit. The more active compound is a rhodamine hexadentate chelator bearing N-ethyl substituents on the rhodamine framework and the thiourea linkage. Such a combination is also responsible for an enhanced uptake by macrophages, thus implying that the efficiency of rhodamine-labelled 3,4-HPO chelators as antimycobacterial agents is strongly determined by the structural features that provide a better permeation through membranes and consequently a superior ability to reach the infection target.
- Highly selective optical chemosensor for cyanide in aqueous medium
Starting from commercially available precursors, we developed cyanide selective chromogenic chemosensors based on metallophthalocyanines. The new compounds revealed high sensitivity for several anions (AcO−, F−,CN−, NO2−, H2PO4− and OH−) over other anions, such as Br−, Cl−, NO3− and HSO4−, both in DMSO and THF solutions. Surprisingly, in 1:2 DMSO:water mixtures an extremely high selectivity was observed for CN− anion. Interestingly, the host:guest complexes formed during the sensing event can be undo by acid treatment without loss of the sensing ability of the chemosensors allowing their reuse. The selectivity of the new phthalocyanines for CN− anion is preserved when they are adsorbed in filter paper. That allowed the preparation of a simple detection kit for monitoring cyanide anion in contaminated environments.
- Antimicrobial peptide-based coatings for biomedical application
Implant-associated infection (IAI) and chronic wound infections (CWI) are a considerable burden in medical care. IAI are amongst the most common problems of in vivo implantation of any material and involve bacterial colonization and biofilm formation on the implant surface. CWI occur in individuals with alterations in the complex process of wound healing such as patients with diabetes or poor vascular supply, whose incapacity to fight infection on its onset leads to bacterial growth and subsequent establishment of mixed-species biofilms, resistant to host defenses and existing antibiotics. Also, the growing prevalence of antibiotic-resistant bacteria compromises current antibiotherapy. Antimicrobial peptides (AMP) are well-known components of the innate immune system that can be used to overcome IAI and CWI, as their relevance as alternatives to conventional antibiotics is increasing. Chemical synthesis of AMP and their covalent immobilization onto chitosan-based materials is being addressed by us, with overall results showing that the AMP-tethered surfaces reduce bacterial adhesion, which holds promise towards development of novel antimicrobial coatings for biomedical applications.
- All-organic fluorophores with potential application in luminescent materials
The fluorophores were based on a difluoroboron diketonate core, decorated with peripheral substituents to fine tune the photo-physical properties. The synthesis of the dyes involved the selective complexation of boron in a diketonate pocket and not in another, and were obtained in good yields. The dyes present good photo-physical properties in dilute solutions, and more interestingly they are highly emissive in the solid state, due to their organization into J-dimers, which prevents their self-quenching. With this design, the best dye emits in the solid state at 700 nm with a quantum yield of 12%, this performance being rare for solid state all-organic dyes. These exceptional photo-physical properties make this family of dyes promising building blocks for the preparation of luminescent materials.