An Experimental Validated Computational Method for pKa Determination of Substituted 1,2-Dihydroxybenzenes

Romero, Romina; Salgado, Pablo; Soto, César; Contreras, David; Melín, Victoria

doi:10.3389/fchem.2018.00208

Cited by 37 publications

(28 citation statements)

References 55 publications

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“…The presence of trihydroxybenzene substituent in EGC and EGCG seems to be less active. This could be related to the different pK a of the two substituents: 1,2‐dihydroxybenzene, pK a 9.45 17 ; 1,2,3‐trihydroxybenzene, pK a 9.01 18…”

Section: Resultsmentioning

confidence: 99%

Mass spectrometry in the study of molecular complexes between 5‐fluorouracil and catechins

et al. 2020

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Abstract5‐Fluorouracil (5FU) is a widely employed antineoplastic agent that acts as antimetabolite. However, 5FU activity is strongly reduced against a subset of cancer cells called cancer stem cells (CSCs), which are believed to be responsible for chemoresistance and tumour recurrence. It was found that epigallocatechin‐3‐gallate (EGCG), the most abundant catechin present in green tea extract, suppresses CSCs grown in various cancers. This chemosensitizing effect of EGCG was investigated in 5FU‐resistant (5FUR) CRC cells, showing that EGCG enhances 5FU‐induced cytotoxicity. However, the real mechanism of an improved 5FU chemosensitivity in the presence of EGCG was not evaluated. Considering the capability of catechins to form bimolecular noncovalent complexes, in the present study, the interaction of catechins and 5FU was studied by different mass spectrometric approaches. The ESI(+) and ESI(−) spectra of [5FU‐catechin] mixtures were studied, showing the formation of protonated and deprotonated bimolecular complexes, whose nature was confirmed by MS/MS experiments (product and precursor ion scans). To exclude the possible origin of these species as ESI artefacts, a further series of experiments were performed by high‐resolution liquid chromatography–mass spectrometry. By this approach, bimolecular complexes have been detected at retention times different from those of free 5FU and catechins, proving their presence in the original solution. Analogous studies were performed on 5FU‐green tea extract mixtures, showing that 5FU leads to complexes not only with EGCG but also with other catechins. These molecular species, differently to free 5FU drug alone, would in principle possess a new biological activity and could be an explanation of the described activity cited above.

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Section: Resultsmentioning

confidence: 99%

Mass spectrometry in the study of molecular complexes between 5‐fluorouracil and catechins

et al. 2020

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“…The comparative acidity of A-and B-rings can be critical, as flavonoid anions are better electron donors and radical scavengers than corresponding neutral molecules [99][100][101][102], whereas electron transfer at deprotonated hydroxyls prevails. Even though the pH in the reaction medium was 5.0, and less than 0.1% of catechin was ionized (taking into account the pKa 1 of catechin around 8.7 [103][104][105]), the kinetic rates of electron transfer are normally much greater than hydrogen atom transfer, and therefore a very low anion concentration can produce a large rate enhancement and dominate [93].…”

Section: Reaction Pathways With Adducts Formationmentioning

confidence: 99%

ABTS/PP Decolorization Assay of Antioxidant Capacity Reaction Pathways

Ilyasov

Beloborodov

Селиванова

et al. 2020

IJMS

319

161

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The 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS •+ ) radical cation-based assays are among the most abundant antioxidant capacity assays, together with the 2,2-diphenyl-1picrylhydrazyl (DPPH) radical-based assays according to the Scopus citation rates. The main objective of this review was to elucidate the reaction pathways that underlie the ABTS/potassium persulfate decolorization assay of antioxidant capacity. Comparative analysis of the literature data showed that there are two principal reaction pathways. Some antioxidants, at least of phenolic nature, can form coupling adducts with ABTS •+ , whereas others can undergo oxidation without coupling, thus the coupling is a specific reaction for certain antioxidants. These coupling adducts can undergo further oxidative degradation, leading to hydrazindyilidene-like and/or imine-like adducts with 3-ethyl-2-oxo-1,3-benzothiazoline-6-sulfonate and 3-ethyl-2-imino-1,3-benzothiazoline-6-sulfonate as marker compounds, respectively. The extent to which the coupling reaction contributes to the total antioxidant capacity, as well as the specificity and relevance of oxidation products, requires further in-depth elucidation. Undoubtedly, there are questions as to the overall application of this assay and this review adds to them, as specific reactions such as coupling might bias a comparison between antioxidants. Nevertheless, ABTS-based assays can still be recommended with certain reservations, particularly for tracking changes in the same antioxidant system during storage and processing.

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“…Another online pK a prediction platform developed by Luo et al gave the even lower pK a prediction of 6.39 in aqueous solution, using the ensemble machine learning method (RMSE = 1.76, r 2 = 0.918) [ 55 ], the algorithm integrated 35,000 experimental pK a values of the iBond database [ 56 ]. Compared to phenol (pK a = 9.95), fluostatin has a low pK a value due to the dramatic intramolecular hydrogen bonding between the two phenoxyl groups (the [OH…O] − distance in the monoanions: 1.50 Å) and strong substitution effect of two electron-withdrawing carbonyl groups [ 57 ]. According to the microspecies distribution analysis in the Marvin software suite, fluostatin readily deprotonates at approximately pH 5.0 or lower ( Figure 3 , the bottom inset).…”

Section: Resultsmentioning

confidence: 99%

Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis

Wang

Zhao

et al. 2020

Biomolecules

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Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C–C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6–311 + G(d,p)//6–31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10′-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10′) of the two reactant molecules maximizes the HOMO–LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST2− anion. In particular, the significant π–π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C–C coupling. The distortion/interaction–activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C–C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π–π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.

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An Experimental Validated Computational Method for pKa Determination of Substituted 1,2-Dihydroxybenzenes

Cited by 37 publications

References 55 publications

Mass spectrometry in the study of molecular complexes between 5‐fluorouracil and catechins

Mass spectrometry in the study of molecular complexes between 5‐fluorouracil and catechins

ABTS/PP Decolorization Assay of Antioxidant Capacity Reaction Pathways

Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis

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