HOCA (aza-Henry reaction) in The 24th International Electronic Conference on Synthetic Organic Chemistry (Nov 2020)

Asymmetric aza-Henry reaction of hydrazones

I. G. Sonsona, J. V. Alegre-Requena,* E. Marqués-López, M. C. Gimeno, R. P. Herrera*

10.3390/ecsoc-24-08411 (registering DOI)

Abstract: In this work, the enantioselective organocatalyzed addition of nitroalkanes to N-benzoyl hydrazones has been developed for the first time. In order to find a chiral organocatalyst suitable to promote the reaction under high stereo-control and reaction rates, the catalytic activity of several cinchone-derived Brønsted bases was evaluated. As a result of the study, simple quinine alkaloid was able to catalyze, in the optimal reaction conditions, the synthesis of alkyl substituted betha-nitroalkylhydrazides with good yields (up to 91%) and enantiomeric excesses (up to 77%), while quinidine alkaloid was used to obtain the opposite enantiomer with similar catalytic results. Moreover, the further recrystallization of the corresponding enantio-enriched mixtures led to the obtainment of each enantiomer with ee up to 94%. The scope of the catalytic method was explored (14 examples), and the effect of substitutients present in the substrates was evaluated in terms of activity and selectivity. Additionally, the catalyzed reaction pathway was study ab initio in order to understand the successful chiral induction by the catalyst. Hence, in the transition state of the rate limiting step (RLS), quinine is acting as bifunctional catalyst activating both substrates simultaneously. This step involves the protonation of the hydrazone and the attack of the nitronate anion to the sp2 prochiral center in a concerted process. Experimental kinetic studies support this reaction mechanism.

Keywords: Organocatalysis; Asymmetric catalysis; aza-Henry reaction

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DHPs in 6th International Electronic Conference on Medicinal Chemistry (Nov 2020)

Novel ureido-dihydropyridine scaffolds as theranostic agents

F. Auria-Luna,* S. Ardevines, E. Marqués-López, E. Romanos, V. Fernández-Moreira, M. C. Gimeno, I. Marzo, R. P. Herrera

10.3390/ECMC2020-07419 (registering DOI)

Abstract: The potential as anticancer agents of 1,4-dihydropyridines (1,4-DHPs) and their pioneering urea derivatives have been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice. 1,4-DHPs show moderate cytotoxicity. However, when the urea moiety is introduced, an extraordinary increase in their antiproliferative activity is observed, proving an interesting synergy between these two scaffolds. Remarkably, when enantiomerically enriched samples are examined, they result to be in almost all cases less to equally active. This effect could be caused by a complex amalgam of physical and chemical contributions. The studied compounds present luminescent properties and a biodistribution study in cancer cells has been performed. Fluorescence microscopy showed that some of the 1,4-DHP derivatives accumulated in the lysosomes, whilst their urea counterparts targeted the cell membrane, which can be key to explain the different cytotoxic activity and imply a different mechanism of action. Finally, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the test subjects was observed, which could support their use in preclinical tumour models. Recently, we have been exploring the biological properties of 1-benzamido-1,4-dihydropyridine derivatives and the preliminary results on cytotoxicity will be commented.

Keywords: cancer, 1,4-dihydropyridine, fluorescence, mice, theranosis, urea

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Further knowledge on DHP just published!

We did it again! Congratulations guys!

Novel ureido-dihydropyridine scaffolds as theranostic agents, Auria-Luna, F.; Marqués-López, E.; Romanos, E.; Fernández-Moreira, V.; Gimeno, M. C.; Marzo, I.; Herrera, R. P. Bioorg. Chem. 2020https://doi.org/10.1016/j.bioorg.2020.104364.

Abstract. In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo.

In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions.

The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

Keywords. Cancer; 1,4-dihydropyridine; fluorescence; mice; theranostic agent; urea

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Overview on asymmetric fluorination reactions by means of ORGANOCATALYSIS

Asymmetric Fluorination Reactions Promoted by Chiral Hydrogen‐Bonding‐Based Organocatalysts, Auria-Luna, F.; Mohammadi, S.; Divar, M.; Gimeno, M. C.; Herrera, R. P. Adv. Synth. Catal. 2020, https://doi.org/10.1002/adsc.202000848

Abstract. Fluorinated compounds can exhibit interesting biological properties. The importance of these species has made that the chemistry of fluorine has experienced a great development. On this review, the recent advances on asymmetric fluorination reactions promoted by chiral hydrogen‐bonding‐based organocatalysts are discussed. Hence, examples using phosphoric acid, carboxylic acid, (thio)urea and squaramide derivatives are illustrated. The growth of this field is amazing. We have only considered pivotal works in which direct fluorination takes place using a fluorinating agent, leaving aside the reactions where a fluorine atom is incorporated from the beginning as part of other reactants. Herein, the scarce existing examples on this field of research have been compiled.
1 Introduction
2 Chiral anionic phase-transfer catalysts
2.1 Phosphoric acids as precatalysts
2.2. Carboxylic acids as precatalysts
3 (Thio)urea derivatives as organocatalysts for asymmetric fluorination reactions
3.1 Chiral thiourea catalysts
3.2 Chiral urea catalysts
4  Chiral  squaramides  as  organocatalysts  for  asymmetric fluorination reactions
5 Summary and outlook

Keywords. fluorination; hydrogen-bond; organocatalysis; phosphoric acid; squaramide; thiourea.

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Happy birthday SARA!

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Our junior and senior students already laureate!

Sandra, Guillermo, Sara and Esther, CONGRATULATIONS!

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Available “Early View” of the last publication with David and Juanvi

Self‐Assembly of Hollow Organic Nanotubes Driven by Arene Regioisomerism, Alegre-Requena, J. V.; Herrera, R. P.; Díaz Díaz, D. ChemPlusChem 2020, https://doi.org/10.1002/cplu.202000473

Abstract. Arene regioisomerism in low‐molecular‐weight gelators can be exploited as a tool to modulate the micro‐structures of the corresponding xerogel networks by using the three different possible substitution patterns orthometa and para. This aromatic regioisomer‐driven strategy has been used with a cholesterol‐based gelator to prepare hollow self‐assembled organic nanotubes (S‐ONTs) with inside and outside diameters of ca. 35 and 140 nm, respectively. Electron microscopy imaging and theoretical calculations were employed to rationalize the formation mechanism of these S‐ONTs. From the three possible regioisomers, only the ortho‐disubstituted cholesteryl‐based gelator showed the optimal angle and distance between substituents to afford the formation of the cyclic assemblies required for nanotube growth by assembling 30–40 units of the gelator. This study opens fascinating opportunities to expand the synthesis of controllable and unique microstructures by modulating geometrical parameters through aromatic regioisomers.

Keywords. Gel, nanotubes, regioisomers, self-assembly, supramolecular chemistry

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Maru’s promotion!

Last Wednesday, 29th July, was a great and important day for HOCA group. My right hand and good friend Maru, became Associate Professor after an excellent and emotive public exam.

Well done Maru and congratulations from all of us!!!!!

Now, enjoy the summer with your family!



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Last results on heterocycles biological properties studies have been recently spread online

I Multifunctional Metallodrugs in Diagnosis and Therapy Meeting
MultiMetDrugs (27 de Julio)

In the frame of the 1st Group Meeting of the Spanish network MultiMetDrugs coordinated by Prof. Gimeno’s group, Fer faced the prelude to his doctoral thesis defense presenting his last results in front of many little screens.
Well done!! Congratulations!

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