Identification and study of new NF-κB-inducing kinase ligands derived from the imidazolone scaffold

Francisco Maqueda-Zelaya, Lara Valiño-Rivas, Ana Milián, Sara Gutiérrez, José Luis Aceña, Javier Garcia-Marin,* Mª Dolores Sánchez-Niño, Juan J. Vaquero, Alberto Ortiz*

Arch. Pharm. ASAP
DOI: 10.1021/ardp.20240061

Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology-derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB-inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF-κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF-κB activation pathway. The introduction of heterocyclic substituents in position 2 of the imidazolone core provides compounds with affinity against human NIK. Three candidates, with best affinity profile, were tested in phenotypic experiments of noncanonical NF-κB activation, confirming that the derivative bearing the 4-pyridyl ring can inhibit the processing of NFκB p100 to NFkB2 p52, which is NIK-dependent in cultured kidney tubular cells. Finally, exhaustive docking calculations combined with molecular dynamics studies led us to propose a theoretical binding mode and rationalize affinity measures, in which the aminopyridine motif is a key anchoring point to the hinge region thanks to several hydrogen bonds and the interaction of heterocyclic rings in position 2 with Ser476 and Lys482. Our result will pave the way for the development of potential drug candidates targeting NIK in the context of CKD.

Alkanes C1–C6 C–H Bond Activation via a Barrierless Potential Energy Path: Trifluoromethyl Carbenes Enhance Primary C–H Bond Functionalization

Jonathan Martínez-Laguna, Julia Altarejos, M. Ángeles Fuentes, Giuseppe Sciortino, Feliu Maseras,* Javier Carreras,* Ana Caballero,* Pedro J. Pérez*

JACS 2024, ASAP
DOI: 10.1021/jacs.4c13065

XX Simposio de Jóvenes Investigadores Químicos de la RSEQ

Ciudad Real (Spain), 18 – 91 November

The Chemical Biology Group from the University of Alcalá was well represented in the Young Research Symposium of the Spanish Royal Society of Chemistry hold in the city of Ciudad Real.

– Flash + Poster:
· Modulating the pseudokinase integrin-linked kinase through new small molecules
Marta Durán, Mercedes Griera Merino, Ana María Carozo, Sergio de Frutos García, José Luis Aceña, Laura Calleros, Diego Rodríguez Puyol, Javier García-Marín

– Poster:
· 1,1-Diamine scaffold synthesis under visible light irradiation
Guillermo Morales-Ortega, Javier Carreras

– Poster:
· Acid-mediated synthesis of fluorescent functionalized polycycles via catiionic cyclization of o-acryloyl-o’alkynylbiaryls
Alex Hipólito-Barriuso, Patricia García-García, Manuel Á. Fernández-Rodgríguez

Our research group members, Álvaro González and Clara Mañas were  at the recent doctoral hooding ceremony at the University of Alcalá. Accompanied by their thesis advisors,Dr. Juan J. Vaquero and Dr. Estíbaliz Merino, they celebrated the achievements of the new Ph.D. recipients.

Congrats!!

Combined Gold and Photoredox Catalysis: Synthesis of 3-Alkenyl-2H-Indazoles from 2-Alkynylazobenzenes

Clara Mañas, Estíbaliz Merino*

We disclose the intramolecular synthesis of 3-alkenyl-2<i>H</i>-indazoles from 2-alkynylazobenzenes promoted by a dual catalysis using AuCl3 and a ruthenium photocatalyst under irradiation with visible light. This reaction goes through a hydroamination of the alkynyl fragment. The yields are governed by the electronic factors. Control experiments and DFT calculations suggest that a radical and polar mechanisms are operating in parallel. This transformation goes through first formation and C-N bond and 1,2-hydride shift. Derivatization was also carried out to extend the versatility of this methodology.

Adv. Synth. Cat. 2024
DOI: 10.1002/adsc.202400990

Copper-Catalyzed Hydroamination of 2-Alkynylazobenzenes: Synthesis of 3-Alkenyl-2H-Indazole

Clara Mañas, Juan Herrero-Bourdieu, Estíbaliz Merino*

A copper-catalyzed intramolecular synthesis of 3-alkenyl-2H-indazoles from 2-alkynylazobenzenes is described. The reaction proceeds in a single step via C–N bond formation and a subsequent 1,2-hydride shift, affording products in high yields. DFT calculations suggest the 1,2-hydride shift as the rate-determining step. Further derivatization enables functionalization of the 3-alkenyl-2H-indazoles.

J. Org. Chem. 2024.
DOI: 10.1021/acs.joc.4c02144

Shaping cycles with light: a regiodivergent approach to tetracyclic aza-aromatic compounds

Clara Mañas, Ana Belén Ibarra, Estíbaliz Merino*

The development of regiodivergent methods that allow access to different structures from a single substrate through intramolecular processes is crucial for accelerating new molecule discovery, as well as making processes more sustainable and efficient in terms of waste production and economy. In this study, we report a novel regiodivergent cyclization procedure to access two distinct azapolyaromatic regioisomers from 2-alkynylazobenzenes. The key to achieving this regiodivergence lies in the presence or absence of a gold catalyst. The irradiation with visible light of 2-alkynylazobenzenes in the presence of a Ir photocatalyst affords 11H-indolo[1,2-b]indazoles, whereas under similar conditions with AuCl₃, indazolo[2,3-a]quinolines are produced. Control experiments and DFT calculations suggest that both transformations operate through different reaction mechanisms: the formation of 11H-indolo[1,2-b]indazoles involves a radical mechanism, whereas the formation of indazolo[2,3-a]quinolines appears to proceed predominantly through a polar mechanism. This transformation enables the one-step conversion of simple 2-alkynylazobenzenes into diverse azapolyaromatic structures via an intramolecular visible light-promoted process, holding significant potential for new nitrogenated heterocycles.

Org. Chem. Front. 2024.
DOI: 10.1039/d4qo01606h

As every year, the University of Alcalá has celebrated its solemn opening ceremony for the academic year with the traditional procession, from the Cathedral to the Main Hall, of the academic community formed by university professors dressed in academic ropes.

This year, Prof. Patrica García García, Dr. Estíbaliz Merino and Dr. Javier Carreras have attended to the ceremony due to their recent appointment as Full professor and Associate Professors respectively. They have been accompanied by the Emeritus Prof. Juan Jose Vaquero

Congrats!

Selective Synthesis of Boron-Functionalized Indenes and Benzofulvenes by BCl3-Promoted Cyclizations of ortho-Alkynylstyrenes

Marcos Humanes, Ester Sans-Panadés, Cintia Virumbrales, Ana Milián, Roberto Sanz, Patricia García-García*, Manuel A. Fernández-Rodríguez*

Org. Lett. 2024, ASAP
DOI: acs.orglett.4c02092

A selective, metal-free synthesis of boron-functionalized indenes and benzofulvenes via BCl₃-mediated cyclization of o-alkynylstyrenes is described. The method allows precise control over product formation by adjusting reaction conditions. These borylated products were utilized in diverse C–B bond derivatizations and in the total synthesis of Sulindac, a nonsteroidal anti-inflammatory drug, demonstrating the versatility and practicality of the developed methodology for synthetic applications.

X SEQT Young Research Symposium

Madrid (Spain), July 12

Our PhD student Marta Duran has attended to the annual meeting for young researchers organized by the Spanish Society of Medicinal Chemistry

https://sites.google.com/view/seqtxyrs/home?authuser=0

– Flash & Poster:
· Targeting chronic kidney dissease trough new small molecules modulating the pseudokinase Integrin-Linked Kinase
Marta Durán Martínez, Mercedes Griera Merino, Sergio de Frutos García, José Luis Aceña, Laura Calleros, Diego Rodríguez Puyol, Javier García Marín