New Synthetic Methodology for the Preparation of Bioactive Compounds

Our main aim is to develop new synthetic methodology for the preparation of bioactive compounds, in an efficient, reliable and simple manner.

We look for robust, versatile and diversifiable protocols, amenable to a variety of chemotypes, and ready to use in biological or medchem programs. Practicality is a first need. We tackle non-trivial structures, and standard chemistry involving for instance long stepwise synthetic sequences, is not contemplated. Apart of developing new methodology, we use our discoveries in the study of biological or pharmaceutical projects, usually in collaboration with different groups.

A central part of this project is the research on new chemical methodology. Our main focus is in the development of novel MultiComponent Reactions (MCRs), particularly dealing with heterocycles. Also we are interested in modern heterocyclic chemistry and in peptide chemistry, dealing with unmet chemical needs in these fields. As targets, we are interested in small drug-like molecules (ideal for classical MedChem programs), and also in medium-sized peptides and bigger biomolecules. The synthetic outcome of our projects is being used in MedChem and Chemical Biology projects, especially involving bioprobes.

Overall, the idea is to synthesize the required compounds in such a way that they will be produced in relevant amounts, suitable for biological testing and, importantly, through methods amenable to combinatorial diversification; this is, capable of a fast preparation of a second generation of compounds, after the initial biological screening.

Multicomponent Reactions

The goals in this field consist in the study of new reactivity pathways for nitrogen and oxygen heterocycles, and their use in efficient, preparative processes. In this respect, multicomponent reactions (MCRs, processes where 3 or more reactants form an adduct with meaningful parts of each component) display the most wanted features of an ideal synthesis (fast, convergent, atom-economy, bond forming efficiency, molecular diversity, etc.). Our main purpose is to develop new MCRs dealing with the participation of these heterocyclic systems, as they are the natural precursors of structural types frequently found in natural products and bioactive compounds (piperidines, pyrans, tetrahydrofurans, etc.). In this way we want to prepare new scaffolds, with many diversity points, which may be further manipulated, thus speeding the process of S.A.R. in the search of drug candidates, and eventually amenable for High Throughput Synthesis (automated solid-phase protocols).

We are implementing Povarov and Isocyanide MCRs using heterocyclic inputs to achieve the highest levels of structural diversity (see Figure aside). A productive line of research, involves reaction discovery, and we have described interrupted MCR processes, allowing the participation of extra-components, and also through scanning formally forbidden processes, we have disclosed an unexpected new MCR. Through collaborations with biology and medicine research groups, the activity profile of these structures is being determined. In this way, a number of interesting observations has led to the disclosure of anti-Alzheimer, antitumoral compounds, prolyl-oligopeptidase inhibitors, DNA labels, fluorescent probes, etc.

Heterocyclic Chemistry

In this section we aim for the description of novel reactivity pathways and for the use in biology of the compounds synthesized thereof. In this way, we have discovered a novel fluorination reaction of aromatic heterocyclic rings, namely indoles and thiazoles, leading to di- and trifluorinated derivatives. Systematic scanning of differently susbtitued substrates allowed the efficient preparation (2-3 steps) of a combiset of diaryl thiazoles and indoles. In a collaboration with Prof J Gil (UB. Medicine), the apoptotic features of these compounds were determined, and a p53-independent mode of action was described. This started a focused research on this topic, and the antitumoral activity of this new scaffold was tuned, its pharmacological profile and toxicity were established and finally the biological target was determined. This turned to be a mitochondrial protein (prohibitin), which adds renewed interest in this class of compounds. Furthermore, they are the most suitable and accessible prohibitin antagonists reported to date.

In a different project, we looked for the construction of heterocyclic building blocks to clasp peptides. This chemistry involved the preparation of oligo-thiazole amino acids, which were prepared through optimized iterative protocols. Then, they were used to close linear peptidic sequences and the cycloderivatives showed interesting biological properties. In a collaboration with BioLeitat, the antiangiogenic properties of these derivatives was determined, and they display interesting selectivities against integrins, different from the drug of choice (cilengitide). Its interaction with model integrin was analyzed computationally by Prof. F. J. Luque.

Peptide Chemistry

In this section, we apply modern reactivity methodology for the site-selective functionalization of peptides. We have focused on the arylation of the indole moiety of tryptophans, either suitably protected or directly in peptidic sequences. Also the process can be performed intermolecularly (arylatyion of peptides with external aromatic precursors) or intramolecularly, leading to staple peptides from iodoaromatic amino acids (iodo-phenylalanine or iodo-tyrosine).

The process involves a C-H activation reaction, inspired in recent transformations dealing with naked indoles. We have found that tryptophans allow the reaction in comparatively milder conditions and that the process is general and reliable. In this way, we managed to accomplish the development of a modern and facile methodology for the modification of Trp peptides, the reaction being useful for a wide variety of sequences (only the presence of cysteine is not compatible with the arylation protocol).

The cyclization constitutes a new stapling method, which complements the few synthetic methodologies available for the preparation of this type of interesting peptides, suitably addressed to MedChem programs. Also the process is capable of delivering drug conjugates and stapled bicyclopeptides both bridged and fused, thus enabling a convenient access to novel peptidic architectures.

Finally, we have applied this technique for the selective modification of anifungal peptides to build a theragnostic agent, capable of detecting lung infections of Aspergillus. In this way, we have performed the arylation of a protected Trp derivative to link a fluorophore (Bodipy), then the desired tagged peptide was prepared through standard Solid Phase Peptide Synthesis, and the arylated peptide displayed the expected bioimaging features. This research was done in collaboration with Prof. M. Vendrell (U. Edinburgh), and this project is currently progressing, showing many possibilities for new applications of this chemistry.

• - Lorena Mendive-Tapia, Sara Preciado, Jesús García, Rosario Ramón, Nicola Kielland, Fernando Albericio, Rodolfo Lavilla “New Peptide Architectures through C-H Activation Stapling between Tryptophan -Phenylalanine/Tyrosine Residues” Nature Commun. 2015; 6: 7160. DOI: 10.1038/ncomms8160.

  - Alba Pérez-Perarnau, Sara Preciado, Claudia Mariela Palmeri, Cristina Moncunill-Massaguer, Daniel Iglesias-Serret, Diana M. González-Gironès, Miriam Miguel, Satoki Karasawa, Satoshi Sakamoto, Ana M. Cosialls, Camila Rubio-Patiño, José Saura-Esteller, Rosario Ramón, Laia Caja, Isabel Fabregat, Gabriel Pons, Hiroshi Handa, Fernando Albericio, Joan Gil and Rodolfo Lavilla “Novel trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins” Angew. Chem. Int. Ed. 2014, 53, 10150 – 10154.

  - Javier Ruiz-Rodríguez, Sara Preciado, Miriam Miguel, Gerardo Acosta, Jaume Adan, Axel Bidon-Chanal, F. Javier Luque, Francesc Mitjans, Rodolfo Lavilla, Fernando Albericio. “Polythiazole Linkers as Functional Rigid Connectors. A new RGD Cyclopeptide with Enhanced Integrin Selectivity” Chem. Sci. 2014, 5, 3929-3935;

  - Ana M. Vázquez, Nicola Kielland, María José Arévalo, Sara Preciado, Richard Mellanby, Yi Feng, Rodolfo Lavilla, Marc Vendrell  “Multicomponent Reactions for De Novo Synthesis of BODIPY Probes: in vivo Imaging of Phagocytic Macrophages” J. Am. Chem. Soc. 2013, 135, 16018 – 16201.

  - Nicola Kielland, Esther Vicente-García, Marc Revés, Nicolas Isambert, María José Arévalo, Rodolfo Lavilla “Scope and Post-Transformations for the Borane-Isocyanide Multicomponent Reactions: Concise Access to Structurally Diverse Heterocyclic Compounds” Adv. Synth. Catal. 2013, 355, 3273 – 3284.

  - Salomé Llabrés, Esther Vicente-García, Sara Preciado, Cristina Guiu, Ramon Pouplana, Rodolfo Lavilla, F. Javier Luque “Evolution of a Multicomponent System: Computational and Mechanistic Studies on the Chemo- and Stereoselectivity of a Divergent Process” Chem. Eur. J. 2013, 19, 13355 – 13361.

  - Sara Preciado, Esther Vicente-García, Salomé Llabrés, F. Javier Luque, Rodolfo Lavilla

   “Exploration of Forbidden Povarov Processes as a Source of Unexpected Reactivity: a New Multicomponent Mannich-Ritter Transformation” Angew. Chem. Int. Ed. 2012, 51, 6874  –6877.

  - Marc Vendrell, Nicola Kielland, Rodolfo Lavilla, Young-Tae Chang “Imaging Histamine in Live Basophils and Macrophages with a Fluorescent Mesoionic Acid Fluoride” Chem. Commun., 2012, 48, 7401–7403.

  - N. Kielland, F. Catti, D. Bello, N. Isambert, I. Soteras, F. J. Luque, Rodolfo Lavilla.  “New Multicomponent Access to Azomethine Ylides. Simple Generation of Substituted Aziridines, Oxazolidines and Pyrrolidines” Chem. Eur. J. 2010, 16, 7904-7915.

  - Sonia Pérez-Rentero, Nicola Kielland, Rodolfo Lavilla, Ramón Eritja “Synthesis and properties of oligonucleotides carrying isoquinoline imidazo[1,2-a]azine fluorescent units”.Bioconj. Chem.2010, 21, 1622-1628.

  - N. Isambert, R. Lavilla. “Heterocycles as key substrates in multicomponent reactions: the fast lane towards molecular complexity” Chem. Eur. J. 2008, 14, 8444-8454.

  - C. Masdeu, E. Gómez, N. A. O. Williams, R. Lavilla. “Double Insertion of Isocyanides into Dihydropyridines: Direct Access to Substituted Benzimidazolium Salts” Angew. Chem. Int. Ed. 2007,46, 3043-3046.

  - O. Jiménez, G. de la Rosa, R. Lavilla. “Straightforward access to a structurally diverse set of oxacyclic scaffolds through a four component reaction”, Angew. Chem. Int. Ed. 2005, 44, 6521-6525.

  - I. Carranco, J. L. Díaz, O. Jiménez, M. Vendrell, F. Albericio, M. Royo, R. Lavilla. “Multicomponent reactions with dihydroazines. Efficient synthesis of a diverse set of pyrido-fused tetrahydroquinolines” J. Comb. Chem. 2005, 7, 33-41.  

IP                                Prof. Rodolfo Lavilla

Postdocs                 

Dr. Nicola Kielland, Dr.Marc Revés

PhD students 

Lorena Mendive, Ouldouz Ghashgahie

Dr. Anna Alcaide, Prof. M. José Arévalo, Dr. Davide Bello, Sandra Bertran, Dr. M. Carmen Bernabeu, Dr. Inés Carranco, Dr. Federica Catti, Dr. Montse Cruz, Dr. José Luis Díaz, Dr. Elena Gómez, Cristina Guiu, Dr. Nicolas Isambert, Dr. Oscar Jiménez, Consiglia Manna, Dr. Carme Masdeu, M. Mar Mestre, Dr. Miriam Miguel, Cristina Monturiol, Dr. Sara Preciado, Dr. Rosario Ramón, Guillermo de la Rosa, Dr. Javier Ruiz, Prof. Ricardo Salazar, Helena Sayago, Miquel Sintes, Dr. Ana Vázquez, Dr Esther Vicente, Dr. Nana A. Williams.

Rodolfo studied pharmacy at the University of Barcelona, dis his Ms degree in Medicinal Chemistry and received his Ph. D (Total Synthesis of Natural Products) in 1987 under the guidance of Prof. Mercedes Alvarez also in U.B. After postdoctoral studies (1988-1990) with Prof. Ernest Wenkert at the University of California San Diego, he moved back to Barcelona and joined faculty as Assistant Professor. Later, he was promoted to Associate and Full Professor. His research interests deal with heterocyclic reactivity, multicomponent reactions and medicinal-biological chemistry. He has co-authored around 100 publications (articles, reviews, book chapters and patents), and collaborates with pharmaceutical companies.

Prof. F. Albericio (U. Barcelona, Chemistry), Prof. O. Cascone (U. Buenos Aires, Chemistry), Prof. Rocío Gámez-Montaño (U. Guanajuato, Chemistry), Prof. J. Gil (U. Barcelona, Medicine), Prof. R. Kumar (U. Delhi, Chemistry), Prof. F. J. Luque (UB, Pharmacy), Prof. D. Muñoz-Torrero (U. Barcelona, Pharmacy), Prof. Z. Orinska (U. Lübeck, Immunology). Prof. M. Vendrell (U. Edinburgh, Chemical Biology).

Adress:  Parc Científic de Barcelona. Baldiri Reixac 10-12, 08028 Barcelona (SPAIN)

Tel.: (+34)-93-4037106

E-mail: rlavilla@pcb.ub.es  or  rlavilla@ub.edu