Control de la reactividad en plataformas moleculares multifuncionales y su aplicación a la construcción molecular orientada a la diversidad. Éteres propargílicos vinílicos como un caso de estudio

En este tutorial se muestra con el ejemplo de los éteres propargílicos vinílicos, bloques sintéticos multifuncionales, como es posible instrumentalizar la reactividad emergente de la combinación de sus grupos funcionales para el diseño y desarrollo de procesos dominó (cascada) ramificados para la generación de complejidad molecular orientada a la diversidad.

Tejedor, David; García-Tellado, Fernando.

Anales de química 119(1): 18-24 (2023)

Importance of Precursor Adaptability in the Assembly of Molecular Organic Cages

Rondelli, Manuel; Hernández Daranas, Antonio; Martín, Tomás.

The Journal of Organic Chemistry, 8: 2113-2121 (2023)

Guanidine derivatives containing the chalcone skeleton are potent antiproliferative compounds against human leukemia cells

In this study, we investigated the effects of eleven synthetic guanidines containing the 1,3-diphenylpropenone core on the viabilities of six human cancer cells. The most cytotoxic compound against human cancer cells of this series contains a N-tosyl group and a N-methylpiperazine moiety 6f. It was cytotoxic against leukemia cells (U-937, HL-60, MOLT-3, and NALM-6) with significant effects against Bcl-2-overexpressing U-937/Bcl-2 cells as well as the human melanoma SK-MEL-1 cell line. It exhibited low cytotoxicity against quiescent or proliferating human peripheral blood mononuclear cells. The IC value for the leukemia U-937 cells was 1.6 ± 0.6 µM, a similar value to that in the antineoplastic agent etoposide. The guanidine containing a N-phenyl substituent 6i was also as cytotoxic as the guanidine containing the N-tosyl substituent and the N-methylpiperazine group 6f against human U-937 leukemia cells and both synthetic guanidines were potent apoptotic inducers. Cell death was mediated by the activation of the initiator caspase-9 and the executioner caspase-3, and associated with the release of cytochrome c. These synthetic guanidines are potent cytotoxic compounds against several human leukemia cells and even the human melanoma cell line SK-MEL-1 and might be useful in the development of new strategies in the fight against cancer.

Estévez, Francisco; Saavedra, Ester; Brouard, Ignacio; Peyrac, Jesús; Hernández-Garcés, Judith; García, Celina; Quintana, José; Estévez, Francisco.

International Journal of Molecular Sciences 23(24): 15518 (2022)

Chemical Stability of Petrichorins

The structure of petrichorin C1 (4) converted from petrichorin C (3) was determined using NMR spectroscopy and X-ray crystallography. The chemical stability of petrichorins A and C (1 and 3) was investigated by NMR spectroscopy, X-ray crystallography, and calculations.

Chunshun Li; Sarotti, Ariel M.; Hernández Daranas, Antonio; Xiaohua Wu; Shao-Liang Zheng; Blodgett, Joshua A. V.; Shugeng Cao.

The Journal of Organic Chemistry, 12(9), 2179: 1-14 (2022)

Dynamic Hydroxyl–Yne Reaction with Phenols

Dynamic Covalent Chemistry (DCvC) has gained increasing importance in supramolecular chemistry and materials science. Herein we prove the dynamic nature of the exchange between phenols and vinyl ethers. Exchange is fast at room temperature and under mild conditions. The equilibrium constants and the electronic effect of the phenol substituents were calculated. This novel incorporation to the DCvC toolbox could be quite useful, and as a proof it was used for the synthesis of a responsive molecular cage.

Santos, Tanausú; Pérez-Pérez, Yaiza; Rivero, David S.; Diana-Rivero, Raquel; García-Tellado, Fernando; Tejedor, David; Carrillo Fumero, Romen.

Organic Letters, 24(45), 8401–8405 (2022)

May the Force (Field) Be with You: On the Importance of Conformational Searches in the Prediction of NMR Chemical Shifts

NMR data prediction is increasingly important in structure elucidation. The impact of force field selection was assessed, along with geometry and energy cutoffs. Based on the conclusions, we propose a new approach named mix-J-DP4, which provides a remarkable increase in the confidence level of complex stereochemical assignments—100% in our molecular test set—with a very modest increment in computational cost.

Cuadrado, Cristina; Hernández Daranas, Antonio; Sarotti, Ariel M.

Marine Drugs, 20(11), 699: 1-12 (2022)

Structure-activity relationships reveal a 2-furoyloxychalcone as a potent cytotoxic and apoptosis inducer for human U-937 and HL-60 leukaemia cells

Synthetic flavonoids with new substitution patterns have attracted attention as potential anticancer drugs. Here, twelve chalcones were synthesized and their antiproliferative activities against five human tumour cells were evaluated. This series of chalcone derivatives was characterized by the presence of an additional aromatic or heterocyclic ring linked by an ether, in the case of a benzyl radical, or an ester or amide functional group in the case of a furoyl radical. In addition, the influence on cytotoxicity by the presence of one or three methoxy groups or a 2,4-dimethoxy-3-methyl system on the B ring of the chalcone scaffold was also explored. The results revealed that the most cytotoxic chalcones contain a furoyl substituent linked by an ester or an amide through the 2′-hydroxy or the 2′-amino group of the A ring of the chalcone skeleton, with IC50 values between 0.2 ± 0.1 μM and 1.3 ± 0.1 μM against human leukaemia cells. The synthetic chalcone 2′-furoyloxy-4-methoxychalcone (FMC) was, at least, ten-fold more potent than the antineoplastic agent etoposide against U-937 cells and displayed less cytotoxicity against human peripheral blood mononuclear cells. Treatment of U-937 and HL-60 cells with FMC induced cell cycle arrest at the G2-M phase, an increase in the percentage of sub-G1 and annexin-V positive cells, the release of mitochondrial cytochrome c, activation of caspase and poly(ADP-ribose) polymerase cleavage. In addition, it inhibited tubulin polymerization in vitro in a concentration dependent manner. Cell death triggered by this chalcone was decreased by the pan-caspase inhibitor z-VAD-fmk and was dependent of the generation of reactive oxygen species. We conclude that this furoyloxychalcone may be useful in the development of a potential anti-leukaemia strategy.

Rosario, Henoc del; Saavedra, Ester; Brouard, Ignacio; González-Santana, Daniel; García Cortés, Celia; Spínola-Lasso, Elena; Tabraue, Carlos; Quintana, José; Estévez, Francisco.

Bioorganic Chemistry 127: 105926 (2022)

Iron(III)-Catalyzed Synthesis of 2‑Alkyl Homoallyl Sulfonyl Amides: Antiproliferative Study and Reactivity Scope of Aza-Prins Cyclization

A direct, catalytic, and complementary method to obtain 2-substituted homoallyl sulfonyl amides is described, starting from sulfonyl amides, aldehydes, and allyltrimethylsilane using iron(III) chloride as a sustainable catalyst. The scope of the process and the reactivity in aza-Prins cyclization is evaluated and supported by density functional theory (DFT) studies. Finally, an evaluation of the antiproliferative activity for this family of sulfonyl amides is also included.

Carballo, Rubén M.; Padrón, José M.; Fernández, Israel; Cruz, Daniel A.; Grmusa, Luana; Martín, Víctor S.; Padrón, Juan I.

Journal of Organic Chemistry

Synthesis of Tetrahydroazepines through Silyl Aza-Prins Cyclization Mediated by Iron(III) Salts

A new methodology for the synthesis of sevenmembered unsaturated azacycles (tetrahydroazepines) was developed. It is based on the powerful aza-Prins cyclization in combination with the Peterson-type elimination reaction. In a single reaction step, a C−N, C− C bond and an endocyclic double bond are formed. Under mild reaction conditions and using iron(III) salts as sustainable catalysts, tetrahydroazepines with different degrees of substitution are obtained directly and efficiently. DFT calculations supported the proposed mechanism.

Sinka, Victoria; Fernández, Israel; Padrón, Juan I.

Journal of Organic Chemistry

Synthesis of Oxazole–Tetrahydropyran Hybrids and Study on Their Antiproliferative Activity Against Human Tumour Cells

A series of triazole linked tetrahydropyran–oxazole hybrids was synthesized based on a previously reported lead compound with selective antiproliferative activity against human tumour cell lines. The series was prepared to evaluate the impact of LogP and different modifications in the activity, and the new compounds were assayed against A549, HBL-100, HeLa, SW1573, T-47D, and WiDr cell lines. Also, the potentiality to be P-gp substrate was tested. The compounds exhibited good antiproliferative results when compared with the standards cisplatin and 5-fluorouracil. In silico studies to evaluate pharmacokinetic properties using pkCSM software were also carried out.

Quintana, Vanesa; González-Bakker, Aday; Padrón, Juan I.; Martín, Víctor S.; Padrón, José M.; Davyt, Danilo; Valdomir, Guillermo.

European Journal of Organic Chemistry