Comparison of four digestion protocols on the physical characteristics of gastric digesta from cooked couscous using the Human Gastric Simulator.

In vitro digestion is widely employed in food, nutraceutical and pharmaceutical research, and numerous in vitro gastric digestion protocols have been proposed, with a wide range of experimental conditions. Differences in the simulated gastric fluids (pH, mineral content, enzyme type and enzyme activity) of different digestion protocols may alter the results for the digestion of the same meal. This study aimed to investigate how variations in the gastric secretion rate and composition in four in vitro digestion protocols (Infogest Riddet, Infogest Semi-dynamic, UC Davis and United States Pharmacopeia) impacted the physical properties of the emptied gastric digesta. Cooked couscous was used as a model meal and subjected to simulated gastric digestion using a dynamic gastric model, the Human Gastric Simulator (HGS). The digesta were collected from the outlet of the HGS after 15, 30, 60, 90, 120, 150, or 180 min. The gastric emptying of dry matter, pH, rheological properties, and particle size were evaluated. The digestion protocol significantly influenced the solid content and moisture content of the digesta (p < 0.001), particles per gram of dry matter (p < 0.0001), gastric emptying of dry matter (p < 0.003), shear stress at 0.45 s-1 and consistency coefficient (p < 0.0001). The presence of NaHCO3 in the Infogest Riddet and Infogest Semi-dynamic gastric secretions provided an additional buffering effect and increased the digesta pH during gastric digestion. Similarly, the inclusion of mucin in the UC Davis protocol resulted in a higher flow and viscoelastic properties of the emptied digesta. The highest dilution of gastric content in the United States Pharmacopeia (USP) protocol resulted in larger particles emptied from the HGS and the longest gastric emptying half-time of all digestion protocols. These findings provide new insights into the impact of digestion protocols on the digesta properties, which can be beneficial for the design and standardization of in vitro digestion models.

Robust Synthesis of Terpenoid Scaffolds under Mn(I)-Catalysis.

The 6/6/5-fused tricyclic scaffold is a central feature of structurally complex terpenoid natural products. A step-economical cascade transformation that leads to a complex molecular skeleton is regarded as a sustainable methodology. Therefore, we report the first Mn(I)-catalyzed C(sp2)-H chemoselective in situ dienylation and diastereoselective intramolecular Diels-Alder reaction using iso-pentadienyl carbonate to access 6/6/5-fused tricyclic scaffolds. To the best of our knowledge, there is no such report thus far to utilize iso-pentadienyl carbonate as a substrate in C-H activation catalysis. Extensive mechanistic studies, such as the isolation of catalytically active organo-manganese(I) complexes, 1,3-dienyl-intermediates, and isotopic labeling experiments have supported the proposed mechanism of this cascade reaction.

Iso-Pentadienyl Carbonate as a Five Carbon Synthon in Manganese(I)-Catalyzed Selective Linear 1,3-Dienylation.

Selective linear 1,3-dienylations are essential transformations, and numerous synthetic efforts have been documented. However, a general method enabling access to electron-rich, -poor, and biologically relevant dienyl molecules is in high demand. Hence, we report a straightforward method of manganese(I)-catalyzed C-H dienylation of arenes by using iso-pentadienyl carbonate as a five carbon synthon. This is a highly unprecedented report for selective linear 1,3-dienylation using manganese C-H activation catalysis. Our method facilitates the synthesis of varieties of dienes, including those suitable for normal or inverse electron demand Diels-Alder reactions, dienyl glycoconjugates, and unnatural amino acids. Extensive mechanistic studies, including isolation of C-H activated organo-manganese complex and isotopic analyses, have supported the proposed mechanism of this dienylation. The synthetic applicability of this method eased to deliver a 6/6/5-fused tricyclic nagilactone scaffold.

Cooked Rice-Based and Wheat-Based Food Structure Influenced Digestion Kinetics and Glycemic Response in Growing Pigs.

BACKGROUND: How starch-based food structure can affect the rate and extent of digestion in the small intestine and resulting glycemic response is not properly understood. One possible explanation is that food structure influences gastric digestion, which subsequently determines digestion kinetics in the small intestine and glucose absorption. However, this possibility has not been investigated in detail. OBJECTIVES: Using growing pigs as a digestion model for adult humans, this study aimed to investigate how physical structure of starch-rich foods affects small intestinal digestion and glycemic response. METHODS: Male growing pigs (21.7 ± 1.8 kg, Large White × Landrace) were fed one of the 6 cooked diets (250-g starch equivalent) with varying initial structures (rice grain, semolina porridge, wheat or rice couscous, or wheat or rice noodle). The glycemic response, small intestinal content particle size and hydrolyzed starch content, ileal starch digestibility, and portal vein plasma glucose were measured. Glycemic response was measured as plasma glucose concentration collected from an in-dwelling jugular vein catheter for up to 390 min postprandial. Portal vein blood samples and small intestinal content were measured after sedation and euthanasia of the pigs at 30, 60, 120, or 240 min postprandial. Data were analyzed with a mixed-model ANOVA. RESULTS: The plasma glucose Δmaxoverall and iAUCoverall for couscous and porridge diets (smaller-sized diets) were higher than that of intact grain and noodle diets (larger-sized diets): 29.0 ± 3.2 compared with 21.7 ± 2.6 mg/dL and 5659 ± 727 compared with 2704 ± 521 mg/dL⋅min, for the smaller-sized and larger-sized diets, respectively (P < 0.05). Ileal starch digestibility was not significantly different between the diets (P ≥ 0.05). The iAUCoverall was inversely related to the starch gastric emptying half-time of the diets (r = -0.90, P = 0.015). CONCLUSIONS: Starch-based food structure affected the glycemic response and starch digestion kinetics in the small intestine of growing pigs.

Influence of food macrostructure on the kinetics of acidification in the pig stomach after the consumption of rice- and wheat-based foods: Implications for starch hydrolysis and starch emptying rate.

How the stomach can serve as a biochemical environment for starch digestion and the implications on starch emptying are not well-understood. Biochemical changes during gastric digestion of cooked wheat- and rice-based diets of varying particle size and microstructure were investigated using a growing pig model. In larger-particle size diets (rice grain, rice noodle, pasta), pH >3 was maintained in the proximal stomach digesta even until 240 min digestion, resulting in extended remaining amylase activity and accumulation of maltose from starch hydrolysis in the stomach. In smaller-particle size diets (couscous, rice couscous, semolina porridge), gastric acidification occurred faster to produce homogeneous intragastric pH and deactivated amylase. The hypothesis of the study was that food macrostructure would impact gastric acidification kinetics, and the resulting biochemical environment for starch hydrolysis in the stomach may further affect the mechanisms of food breakdown in the stomach and gastric emptying of starch.

Lipid-Based Nanocarrier System for the Effective Delivery of Nutraceuticals.

Nutraceuticals possess several health benefits and functions; however, most nutraceuticals are prone to degradation in the gastrointestinal environment and have poor bioavailability. Application of a novel carrier system is of increasing importance to overcome obstacles and provide efficient applicability. Lipid-based nanocarriers provide a large surface-to-mass ratio, enhanced intestinal absorption by solubilization in the intestinal milieu, intestinal lymphatic transport, and altering enterocyte-based transport. A critical overview of the current limitation, preparation, and application of lipid-based nanocarriers (liposomes and niosomes) and lipid nanoparticles (SLNs and NLCs) is discussed. Physical and gastrointestinal stability and bioavailability of nanoencapsulated nutraceuticals are considered as well.

Mucoadhesive Delivery System: A Smart Way to Improve Bioavailability of Nutraceuticals.

The conventional oral administration of many nutraceuticals exhibits poor oral bioavailability due to the harsh gastric conditions and first-pass metabolism. Oral mucosa has been recognized as a potential site for the delivery of therapeutic compounds. The mucoadhesive formulation can adhere to the mucosal membrane through various interaction mechanisms and enhance the retention and permeability of bioactive compounds. Absorption of bioactive compounds from the mucosa can improve bioavailability, as this route bypasses the hepatic first-pass metabolism and transit through the gastrointestinal tract. The mucosal administration is convenient, simple to access, and reported for increasing the bioactive concentration in plasma. Many mucoadhesive polymers, emulsifiers, thickeners used for the pharmaceutical formulation are accepted in the food sector. Introducing mucoadhesive formulations specific to the nutraceutical sector will be a game-changer as we are still looking for different ways to improve the bioavailability of many bioactive compounds. This article describes the overview of buccal mucosa, the concept of mucoadhesion and related theories, and different techniques of mucoadhesive formulations. Finally, the classification of mucoadhesive polymers and the mucoadhesive systems designed for the effective delivery of bioactive compounds are presented.

Correction: Tracking physical breakdown of rice- and wheat-based foods with varying structures during gastric digestion and its influence on gastric emptying in a growing pig model.

Correction for 'Tracking physical breakdown of rice- and wheat-based foods with varying structures during gastric digestion and its influence on gastric emptying in a growing pig model' by Joanna Nadia et al., Food Funct., 2021, DOI: 10.1039/D0FO02917C.

Tracking physical breakdown of rice- and wheat-based foods with varying structures during gastric digestion and its influence on gastric emptying in a growing pig model.

There is currently a limited understanding of the effect of food structure on physical breakdown and gastric emptying of solid starch-based foods during gastric digestion. Moisture uptake, pH, particle size, rheological, and textural properties of six solid starch-based diets from different sources (Durum wheat and high amylose white rice) and of different macrostructures (porridge, native grain, agglomerate/couscous, and noodle) were monitored during 240 min of gastric digestion in a growing pig model. Changes in the physical properties of the gastric digesta were attributed to the influence of gastric secretions and gastric emptying, which were both dependent on the buffering capacity and initial macrostructure of the diets. Differences between the proximal and distal stomach regions were found in the intragastric pH and texture of the gastric digesta. For example, rice couscous, which had the smallest particle size and highest buffering capacity among the rice-based diets, had the shortest gastric emptying half-time and no significant differences between proximal and distal stomach digesta physical properties. Additionally, a relationship between gastric breakdown rate, expressed as gastric softening half-time from texture analysis, and gastric emptying half-time of dry matter was also observed. These findings provide new insights into the breakdown processes of starch-based solid foods in the stomach, which can be beneficial for the development of food structures with controlled rates of breakdown and gastric emptying during digestion.

Streamlined Symmetrical Total Synthesis of Disorazole B1 and Design, Synthesis, and Biological Investigation of Disorazole Analogues.

Taking advantage of the C2-symmetry of the antitumor naturally occurring disorazole B1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product allowed for an expeditious entry to this family of compounds. Application of the developed synthetic strategies and methods provided a series of designed analogues of disorazole B1, whose biological evaluation led to the identification of a number of potent antitumor agents and the first structure-activity relationships (SARs) within this class of compounds. Specifically, the substitutions of the epoxide units and lactone moieties with cyclopropyl and lactam structural motifs, respectively, were found to be tolerable for biological activities and beneficial with regard to chemical stability.

Serendipitous Synthesis of Pyridoquinazolinones via an Oxidative C-C Bond Cleavage.

A direct one-pot copper-catalyzed oxidative C-C bond cleavage route to the synthesis of pyridoquinazolinones is described. This one-pot strategy involves a copper-catalyzed C-N coupling followed by concomitant C(sp3)-H oxidation and amidation via oxidative C-C bond cleavage under an O2 atmosphere to deliver the target molecules in high yields.

Glycopeptides by Linch-Pin C-H Activations for Peptide-Carbohydrate Conjugation by Manganese(I)-Catalysis.

Late-stage C-H glycosylations of structurally complex amino acids and peptides were accomplished by means of racemization-free manganese(I)-catalyzed C-H activation. Thus, glycosylative modifications proved to be viable by a linch-pin approach, featuring chemo- and site-selective C-H transformations. The peptide-saccharide conjugation provided modular access to structurally complex glycopeptides, likewise enabling the assembly of fluorescent-labelled glycopeptides.

Copper Catalyzed Oxidative C-C Bond Cleavage of 1,2-Diketones: A Divergent Approach to 1,8-Naphthalimides, Biphenyl-2,2'-dicarboxamides, and N-Heterocyclic Amides.

We report here a simple and efficient copper catalyzed oxidative C-C bond cleavage of stable aromatic cyclic-fused and acyclic 1,2-diketones to deliver amides and imides in high yields. This newly developed protocol provides an excellent tool to transform structurally different 1,2-diketones into different products under the same reaction conditions. The key synthetic features of this methodology are the formation of 1,8-naphthalimides and biphenyl-2,2'-dicarboxamide motifs in high yields. The fluorescent studies of 1,8-naphthalimide derivatives were also carried out in order to show the potential application of these scaffolds.

Syntheses of Cyclopropyl Analogues of Disorazoles A1 and B1 and Their Thiazole Counterparts.

Modular syntheses of disorazoles A1 and B1 analogues in which the epoxide moieties of the natural products were replaced with cyclopropyl units have been achieved. Targeted as part of a structure-activity relationships study, these syntheses were successfully extended to the thiazole counterparts of these analogues. The retrosynthetically defined fragments were assembled through Yamaguchi esterification, Cu/Pd-catalyzed cross-coupling, Yamaguchi macrolactonization, and Cu-catalyzed cross-coupling as the key reactions. Further synthetic and biological investigations of such analogues are expected to lead to the discovery and development of potential payloads for antibody-drug conjugates as targeted cancer therapies.

Transition-Metal-Free Multicomponent Approach to Stereoenriched Cyclopentyl-isoxazoles through C-C Bond Cleavage.

An efficient multicomponent reaction for the synthesis of stereoenriched cyclopentyl-isoxazoles from camphor-derived α-oximes, alkynes, and MeOH is reported. Our method involved a series of cascade transformations, including the in situ generation of an IIII catalyst, which catalyzed the addition of MeOH to a sterically hindered ketone. Oxidation of the oxime, and rearrangement of the α-hydroxyiminium ion generated a nitrile oxide in situ, which, upon [3+2] cycloaddition reaction with an alkyne, delivered the regioselective product. This reaction was very selective for the syn-oxime. This multicomponent approach was also extended to the synthesis of a new glycoconjugate, camphoric ester-isoxazole C-galactoside.

Stereoselective Ring-Opening of gem-Difluorocyclopropanes: An Entry to Stereo-defined (E,E)- and (E,Z)-Conjugated Fluorodienes.

The ring-opening of gem-difluorocyclopropyl acetaldehydes producing selectively (E,E)- and (E,Z)-conjugated fluorodienals is described. Two stereo-divergent methods are presented to access both stereoisomers from a common precursor, in high yield and selectivity. The mechanistic aspect of these transformations is discussed.

Copper-Catalyzed Cascade Amination Route to N-Aryl Benzimidazoquinazolinones.

An efficient one-pot Cu-catalyzed C-H functionalization/two-fold C-N bond formation protocol for the syntheses of N-aryl benzimidazoquinazolinones is being reported. This strategy involves a Cu-catalyzed C-N bond coupling reaction between N-anilinoquinazolinones and aryl/heteroaryl halides followed by acetate ligand-assisted intramolecular C-H amination.a This reaction is high-yielding and straightforward for the synthesis of anti-cancer drug analogues of benzimidazoquinazolinones.

Recent Trends in Copper-Catalyzed C-H Amination Routes to Biologically Important Nitrogen Scaffolds.

Nitrogen-containing heterocycles have found remarkable applications in natural product research, material sciences, and pharmaceuticals. Although the synthesis of this interesting class of compounds attracted the interest of generations of organic chemists, simple and straightforward assembly methods based on transition-metal catalysis have regularly been elusive. The recent advancements in the development of C-H functionalization have helped in accomplishing the synthesis of a variety of complex heterocycles from simple precursors. This Focus Review summarizes the recent advances in one particular field: the copper-catalyzed C-N bond formation reactions via C-H bond functionalization to furnish a comprehensive range of nitrogen heterocycles. Applicability and synthetic feasibility of a particular reaction represent major requirements for the inclusion in this review.

A one-pot copper catalyzed biomimetic route to N-heterocyclic amides from methyl ketones via oxidative C-C bond cleavage.

A direct one-pot Cu-catalyzed biomimetic oxidation of methyl ketones to pharmaceutically important N-heterocyclic amides is reported. The scope of the method is broad, scalable, and mild, and the reaction is tolerant with various acid, base sensitive functionalities with multiple heteroatoms and aryl halides. The extensive mechanistic studies suggest that this reaction follows the Luciferin-Luciferase-like pathway.