Exploring the broad-spectrum activity of carbohydrate-based Iberin analogues: From anticancer effect to antioxidant properties L.A. Prieto, N. Khiar-Fernández, J.M. Calderón-Montaño, M. López-Lázaro, J. Lucía-Tamudo, J.J. Nogueira, R. León, N. Moreno, V. Valdivia, R. Recio, I. Fernández European Journal of Medicinal Chemistry, 2025 Iberin is a lower homologue of sulforaphane (SFN) which has shown effectiveness in addressing various pathologies, including its anti-inflammatory properties, antitumor activity against various cancers, and antimicrobial effects. Building on this activity, a series of carbohydrate-based analogues of the natural isothiocyanate (ITC) iberin were synthesized, and their anticancer and antioxidant activities were evaluated. Cytotoxicity studies on three cancer cell lines using Resazurin assay demonstrated significant cytotoxic activity, particularly against bladder cancer . The sulfonyl derivatives exhibited the most potent effects, with IC 50 values comparable to those of reference natural isothiocyanates (from 10 to 20 μM). Computational simulations support the hypothesis that carbohydrate-based ITCs can interact with STAT3's SH2 domain in a manner similar to SFN, laying the groundwork for their potential development as STAT3-targeted anticancer agents . The antioxidant potential of these compounds was assessed by their ability to activate the Nrf2 factor, yielding CD values (concentration required to double luciferase activity compared to basal conditions) between 1.55 and 10.36 μM, without cytotoxicity at these concentrations. Notably, the phenylsulfone derivative 22β displayed slightly higher or comparable antioxidant activity to that of natural isothiocyanates. Based on these findings, this phenylsulfone analogue was selected as the optimal compound due to its dual anticancer and antioxidant activities. An additional advantage of this carbohydrate-based ITC is that it is a solid compound, making it easier to handle than natural isothiocyanates, which are typically liquids.
Stereoselective Synthesis of Chiral C2-Symmetric 1,3- and 1,5-Bis-Sulfoxides Guided by the Horeau Principle: Understanding the Influence of the Carbon Chain Nature in Its Ability for Metal Coordination Nazaret Moreno-Rodríguez, L. Alberto Prieto, Victoria Valdivia, Rocío Recio, Inmaculada Fernández Journal of Organic Chemistry, 2024 The stereoselective synthesis of two distinct types of C2-symmetric chiral bis-sulfoxides, 1,3- and 1,5-bis(sulfinyl) derivatives, has been achieved based on the DAG methodology. The 1,5-bis(sulfinyl) derivatives constitute a new family of tridentate chiral ligands thanks to the presence of an additional sulfenyl or sulfinyl group in the carbon chain acting as a bridge. A systematic development and optimization of two synthetic routes, one for each ligand family, have been undertaken, highlighting the strategic utilization of Horeau’s law to enhance enantioselectivity. Additionally, palladium (Pd) and ruthenium (Ru) complexes derived from the synthesized bis-sulfoxides were prepared, and their structures were elucidated through spectroscopic analysis. Isolation of Pd(II) complexes involving 1,3-bis-sulfoxides was exclusively achieved using trifluoroacetates as coligands. In the case of Ru(II) complexes, the trans geometry could be determined for 1,3-bis-sulfoxides. The introduction of a third sulfur atom as a coordinating element in the 1,5-bis(sulfinyl) derivatives facilitates the formation of two distinct tricoordinated Ru(II) complexes. The structure of these complexes is intricately influenced by the oxidation state adopted by the central sulfur on the chain, whether as a thioether or as a sulfoxide.
Synthesis and in vitro cytotoxicity of benzoxazole-based PPARα/γ antagonists in colorectal cancer cell lines Nazaret Moreno‐Rodríguez, Antonio Laghezza, Carmen Cerchia, Darina V. Sokolova, Tatiana S. Spirina, Barbara De Filippis, Virgilio Romanelli, Rocío Recio, Inmaculada Fernández, Fulvio Loiodice, Vadim S. Pokrovsky, Alessandra Ammazzalorso, Antonio Lavecchia Archiv Der Pharmazie, 2024 A series of benzoxazole‐based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator‐activated receptor (PPAR)α and PPARγ activity. All tested compounds showed a dual antagonist profile on both PPAR subtypes; based on transactivation results, seven compounds were selected to test their in vitro antiproliferative activity in a panel of eight cancer cell lines with different expression rates of PPARα and PPARγ. 3f was identified as the most cytotoxic compound, with higher potency in the colorectal cancer cell lines HT‐29 and HCT116. Compound 3f induced a concentration‐dependent activation of caspases and cell‐cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.
Biological evaluation of carbohydrate-based aprepitant analogs for neuroblastoma treatment Victoria Valdivia, Rocío Recio, Patricia Lerena, Esther Pozo, Rosario Serrano, Raúl Calero, Cristina Pintado, Manuel Pernia Leal, Nazaret Moreno-Rodríguez, Juan Ángel Organero, Noureddine Khiar, Inmaculada Fernández European Journal of Medicinal Chemistry, 2024 Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC50 values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.
Synthesis and characterization of enantiopure chiral NH2/SO palladium complexes Nazaret Moreno-Rodriguez, L. Gabriel Borrego, Rocío Recio, Victoria Valdivia, M. Carmen Nicasio, Eleuterio Álvarez, Noureddine Khiar, Inmaculada Fernández Organic and Biomolecular Chemistry, 2023 The synthetic method developed for the preparation of NH2/SO palladium complexes proved to be also an effective approach forN-desulfinylation. Furthermore, the Pd complexes demonstrated a highertransinfluence of PhSO compared totBuSO.
Enantioselective synthesis of 4-amino-3,4-dihydrocoumarins and their non-cyclic hydroxyester precursors: Biological evaluation for the treatment of glioblastoma multiforme Lorenzo G. Borrego, Rocío Recio, Nazaret Moreno, Ahmed Chelouan, Eleuterio Álvarez, Antonio Sánchez-Coronilla, Carlos Caro, John R. Pearson, Maria Luisa García-Martín, Noureddine Khiar, Inmaculada Fernández European Journal of Medicinal Chemistry, 2022 The stereoselective addition of ethyl acetate enolate to the C═N bond of N-tert-butylsulfinylimines has been investigated in depth. A significant effect of the LHMDS amount and the N-sulfinylimine nature on the stereoselectivity of the process was observed. Conditions were found where sulfinylimines of differently substituted salicylaldehydes derivatives, ethyl acetate, and LHMDS afforded the corresponding addition products as a single diastereomer in good yields. The developed protocol was successfully applied to the first stereoselective synthesis of differently substituted 4-amino-3,4-dihydrocoumarin derivatives. Computational models confirmed the prominent role of the ortho aryl substituent in the stereoselectivity of the process. A significant and selective cytotoxic activity against Glioblastoma Multiforme (GBM) cancer line has been determined for the noncyclic hydroxy ester derivative.
Benzothiazole Derivatives Endowed with Antiproliferative Activity in Paraganglioma and Pancreatic Cancer Cells: Structure–Activity Relationship Studies and Target Prediction Analysis Rosa Amoroso, Laura De Lellis, Rosalba Florio, Nazaret Moreno, Mariangela Agamennone, Barbara De Filippis, Letizia Giampietro, Cristina Maccallini, Inmaculada Fernández, Rocío Recio, Alessandro Cama, Marialuigia Fantacuzzi, Alessandra Ammazzalorso Pharmaceuticals, 2022 The antiproliferative effects played by benzothiazoles in different cancers have aroused the interest for these molecules as promising antitumor agents. In this work, a library of phenylacetamide derivatives containing the benzothiazole nucleus was synthesized and compounds were tested for their antiproliferative activity in paraganglioma and pancreatic cancer cell lines. The novel synthesized compounds induced a marked viability reduction at low micromolar concentrations both in paraganglioma and pancreatic cancer cells. Derivative 4l showed a greater antiproliferative effect and higher selectivity index against cancer cells, as compared to other compounds. Notably, combinations of derivative 4l with gemcitabine at low concentrations induced enhanced and synergistic effects on pancreatic cancer cell viability, thus supporting the relevance of compound 4l in the perspective of clinical translation. A target prediction analysis was also carried out on 4l by using multiple computational tools, identifying cannabinoid receptors and sentrin-specific proteases as putative targets contributing to the observed antiproliferative activity.
