A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units

Domingo, Luís R.; Ríos‐Gutiérrez, Mar; Barakat, Assem

doi:10.3390/molecules27196532

Cited by 6 publications

(2 citation statements)

References 75 publications

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“…A recent MEDT study on the unexpected ortho regioselectivity in the 32CA reactions of AYs derived from L-proline showed that the presence of two HBs at the MC-on , which are enhanced at the corresponding TS-on , can be responsible for the ortho regioselectivity of these 32CA reactions ( Domingo et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules

Barakat,

Alshahrani,

Al-Majid

et al. 2024

Front. Pharmacol.

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This study discusses the synthesis and use of a new library of spirooxindole-benzimidazole compounds as inhibitors of the signal transducer and activator of p53, a protein involved in regulating cell growth and cancer prevention. The text includes the scientific details of the [3 + 2] cycloaddition (32CA) reaction between azomethine ylide 7a and ethylene 3a within the framework of Molecular Electron Density Theory. The mechanism of the 32CA reaction proceeds through a two-stage one-step process, with emphasis on the highly asynchronous transition state structure. The anti-cancer properties of the synthesized compounds, particularly 6a and 6d, were evaluated. The inhibitory effects of these compounds on the growth of tumor cells (MDA-MB 231 and PC-3) were quantified using IC50 values. This study highlights activation of the p53 pathway by compounds 6a and 6d, leading to upregulation of p53 expression and downregulation of cyclin D and NF-κB in treated cells. Additionally, we explored the binding affinity of spirooxindole analogs, particularly compound 6d, to MDM2, a protein involved in regulation of p53. The binding mode and position of compound 6d were compared with those of a co-crystallized standard ligand, suggesting its potential as a lead compound for further preclinical research.

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Section: Resultsmentioning

confidence: 99%

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules

Barakat,

Alshahrani,

Al-Majid

et al. 2024

Front. Pharmacol.

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“…Recently, Barakat et al reported the synthesis of new spirooxindoles, IX, with the triazole moiety and a ferrocene scaffold using the 32CA reaction approach, and their mechanism was studied via molecular electron density theory (MEDT) [11,12]. Another representative example is the spirooxindole with a benzimidazole scaffold (see SP1 in Figure 1), which has been extensively studied and has shown to be a potent anti-cancer agent [13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity

Alshahrani,

Al-Majid,

Alamary

et al. 2023

Molecules

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A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the β-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step.

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One-Bond-Nucleophilicity and -Electrophilicity Parameters: An Efficient Ordering System for 1,3-Dipolar Cycloadditions

Mayer

Ofial

et al. 2023

J. Am. Chem. Soc.

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Diazoalkanes are ambiphilic 1,3-dipoles that undergo fast Huisgen cycloadditions with both electron-rich and electron-poor dipolarophiles but react slowly with alkenes of low polarity. Frontier molecular orbital (FMO) theory considering the 3-center-4-electron πsystem of the propargyl fragment of diazoalkanes is commonly applied to rationalize these reactivity trends. However, we recently found that a change in the mechanism from cycloadditions to azo couplings takes place due to the existence of a previously overlooked lower-lying unoccupied molecular orbital. We now propose an alternative approach to analyze 1,3dipolar cycloaddition reactions, which relies on the linear free energy relationship lg k 2 (20 °C) = s N (N + E) (eq 1) with two solvent-dependent parameters (N, s N ) to characterize nucleophiles and one parameter (E) for electrophiles. Rate constants for the cycloadditions of diazoalkanes with dipolarophiles were measured and compared with those calculated for the formation of zwitterions by eq 1. The difference between experimental and predicted Gibbs energies of activation is interpreted as the energy of concert, i.e., the stabilization of the transition states by the concerted formation of two new bonds. By linking the plot of lg k 2 vs N for nucleophilic dipolarophiles with that of lg k 2 vs E for electrophilic dipolarophiles, one obtains Vshaped plots which provide absolute rate constants for the stepwise reactions on the borderlines. These plots furthermore predict relative reactivities of dipolarophiles in concerted, highly asynchronous cycloadditions more precisely than the classical correlations of rate constants with FMO energies or ionization potentials. DFT calculations using the SMD solvent model confirm these interpretations.

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A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units

Cited by 6 publications

References 75 publications

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity

One-Bond-Nucleophilicity and -Electrophilicity Parameters: An Efficient Ordering System for 1,3-Dipolar Cycloadditions

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