Do Chemformers Dream of Organic Matter? Evaluating a Transformer Model for Multistep Retrosynthesis.

Synthesis planning of new pharmaceutical compounds is a well-known bottleneck in modern drug design. Template-free methods, such as transformers, have recently been proposed as an alternative to template-based methods for single-step retrosynthetic predictions. Here, we trained and evaluated a transformer model, called the Chemformer, for retrosynthesis predictions within drug discovery. The proprietary data set used for training comprised ∼18 M reactions from literature, patents, and electronic lab notebooks. Chemformer was evaluated for the purpose of both single-step and multistep retrosynthesis. We found that the single-step performance of Chemformer was especially good on reaction classes common in drug discovery, with most reaction classes showing a top-10 round-trip accuracy above 0.97. Moreover, Chemformer reached a higher round-trip accuracy compared to that of a template-based model. By analyzing multistep retrosynthesis experiments, we observed that Chemformer found synthetic routes, leading to commercial starting materials for 95% of the target compounds, an increase of more than 20% compared to the template-based model on a proprietary compound data set. In addition to this, we discovered that Chemformer suggested novel disconnections corresponding to reaction templates, which are not included in the template-based model. These findings were further supported by a publicly available ChEMBL compound data set. The conclusions drawn from this work allow for the design of a synthesis planning tool where template-based and template-free models work in harmony to optimize retrosynthetic recommendations.

Carbon 14 synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites.

Carbon 14 labeled Iclepertin (BI 425809, 1) and its major metabolites were needed for ADME and several other studies necessary for the advancement of this drug candidate in clinical trials. Iclepertin is composed of two main chemical blocks, (R)-5-(methylsulfonyl)-2-([1,1,1-trifluoropropan-2-yl]oxy)benzoic acid (2), and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. In the first synthesis of carbon 14 labeled 1, 2-fluorobenzoic acid, carboxyl-14 C was converted to [14 C]-2 in three steps and then coupled to 3 to provide [14 C]-1a in 45% overall yield. In the second synthesis, [14 C]-3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [14 C]-1b in 20% overall yield. Both synthetic routes provided [14 C]-1a and [14 C]-1b with specific activities higher than 53 mCi/mmol and radiochemical, chemical, and enantiomeric purities above 98%. Two major metabolites of 1, BI 761036 and BI 758790, were also prepared labeled with carbon 14 using intermediates already available from the synthesis of [14 C]-1.

Expanding the Rare-Earth Metal BINOLate Catalytic Multitool beyond Enantioselective Organic Synthesis.

Shibasaki's rare earth alkali metal BINOLate (REMB) framework has provided chemists with a general catalyst platform to access a range of enantioenriched small molecules from the single, commercially available pro-ligand (R)- or (S)-BINOL. A defining feature of these heterobimetallic frameworks is the high level of catalyst tunability, achieved through the simple modulation of the central rare-earth cation and peripheral alkali metal cations. While this family of multifunctional catalysts displays impressive generality and catalytic capability, detailed mechanistic understanding of these complex, multimetallic systems was lacking prior to our investigations. This backdrop served as initial inspiration for our investigations of this privileged class of complexes over the past decade, which have led to new and exciting advances in catalysis and beyond.In this Account, we describe our investigations using Shibasaki's framework focusing on the central metal-ion, the BINOLate ligands, and the secondary sphere cations. Our studies began with an investigation into the Lewis acidity of the complexes, where we demonstrated that Lewis bases readily coordinate to REMB frameworks when lithium occupies the secondary coordination sphere. This observation was contrasted by the complexes containing sodium or potassium in the secondary coordination sphere, as the rare earth cation is evidently less accessible for substrate binding. Our efforts in understanding the ligand exchange of the complexes enabled the discovery that associative processes dominate the mechanism of ligand exchange and LA/LA (Lewis acid/Lewis acid) and LA/BB (Lewis acid/Brønsted base) catalysis by the REMB frameworks. Replacing metal cations in the secondary coordination sphere with the N,N,N',N'-tetramethylguanidinium cation delivered an effective precatalyst that is air and water stable over the course of 6 months.To expand the reactivity of the REMB, we investigated the ability of UIV cations to occupy the primary coordination sphere and ZnEt+ and Cu(DBU)+ cations to occupy the secondary coordination sphere. Synthesizing the REMB complexes using the thiol congener monothioBINOL provided an unusual anionic REMB framework, driven by the oxophilicity of the lithium cations. Using the REMB as a platform for investigating the CeIII/CeIV redox couple, we demonstrated that, while oxidative cerium functionalization is observed in the case of lithium containing REMBs, salt elimination is observed in the sodium, potassium, and cesium containing REMBs. Furthermore, we found that while the rate of heterogeneous electron transfer for CeIII was ks(CsI) > ks(KI) > ks(NaI) > ks(LiI), the rates of reaction with the oxidant trityl chloride trended in the opposite order with kobs(LiI) ≫ kobs(NaI) > kobs(KI) > kobs(CsI). We attribute this to the ability to form inner-sphere complexes with the oxidant, rather than differences in redox potential or reorganization energies.Applying our knowledge in ligand exchange and redox behavior of Ce containing REMB complexes, we detailed the mechanism for oxidation of the heterochiral cerium REMB frameworks, reiterating the importance of the formation of inner-sphere complexes in the oxidation chemistry of cerium. There are many different avenues for both organic and inorganic investigation of Shibasaki's REMB framework, and our works have demonstrated the richness of the structural chemistry and properties of this framework that inform mechanism and properties of these privileged catalysts.

Navigating the Pauson-Khand Reaction in Total Syntheses of Complex Natural Products.

"Total synthesis endeavors provide wonderful opportunities to discover and invent new synthetic reactions as a means to advance organic synthesis in general. Such discoveries and inventions can occur when the practitioner faces intransigent problems that cannot be solved by known methods and/or when method improvements are desired in terms of elegance, efficiency, cost-effectiveness, practicality, or environmental friendliness" (K. C. Nicolaou et al. from their review in CCS Chem. 2019, 1, 3-37). To date tens of thousands of bioactive compounds have been isolated from plants, microbes, marine invertebrates, and other sources. These chemical structures have been studied by chemists who scanned the breadth of natural diversity toward drug discovery efforts. Drug-likeness of natural products often possesses common features including molecular complexity, protein-binding ability, structural rigidity, and three-dimensionality. Considering certain biologically important natural products are scarce from natural supply, total synthesis may provide an alternative solution to generating these compounds and their derivatives for the purpose of probing their biological functions. Natural products bearing quaternary carbon stereocenters represent a group of biologically important natural entities that are lead compounds in the development of pharmacological agents and biological probes. However, the stereocontrolled introduction of quaternary carbons, with vicinal patterns that substantially expand the complexity of molecular architectures and chemical space in particular, presents distinct challenges because of the high steric repulsion between substituents. Though remarkable advance has been seen for quaternary carbon stereocenter generation, the process remains a daunting challenge given that the formation of highly congested stereocenters increases the difficulty in achieving orbital overlap.In the past two decades, our group has initiated a program to develop synthetic strategies and methods with the aim of advancing the frontiers of the total syntheses of biologically important complex natural products bearing all-carbon quaternary stereogenic centers. Typical endeavors have involved the use of a Pauson-Khand (PK) reaction as a key step in constructing core structures with all-carbon quaternary stereogenic center(s), with the aid of well-orchestrated thiourea-Co- and thiourea-Pd-catalyzed PK reactions. These methodological advances have enabled us to achieve total syntheses of a series of topologically complex natural products with diverse structural features. These methods will enable the assembly of molecules with improved biological functions and provide tool compounds for elucidation of mechanism of action or identification of potential cellular targets.

Electrocatalytic Hydrogenation of Biomass-Derived Organics: A Review.

Sustainable energy generation calls for a shift away from centralized, high-temperature, energy-intensive processes to decentralized, low-temperature conversions that can be powered by electricity produced from renewable sources. Electrocatalytic conversion of biomass-derived feedstocks would allow carbon recycling of distributed, energy-poor resources in the absence of sinks and sources of high-grade heat. Selective, efficient electrocatalysts that operate at low temperatures are needed for electrocatalytic hydrogenation (ECH) to upgrade the feedstocks. For effective generation of energy-dense chemicals and fuels, two design criteria must be met: (i) a high H:C ratio via ECH to allow for high-quality fuels and blends and (ii) a lower O:C ratio in the target molecules via electrochemical decarboxylation/deoxygenation to improve the stability of fuels and chemicals. The goal of this review is to determine whether the following questions have been sufficiently answered in the open literature, and if not, what additional information is required:(1)What organic functionalities are accessible for electrocatalytic hydrogenation under a set of reaction conditions? How do substitutions and functionalities impact the activity and selectivity of ECH?(2)What material properties cause an electrocatalyst to be active for ECH? Can general trends in ECH be formulated based on the type of electrocatalyst?(3)What are the impacts of reaction conditions (electrolyte concentration, pH, operating potential) and reactor types?

Installing the "magic methyl"- C-H methylation in synthesis.

The selective and efficient C-H methylation of sp2 and sp3 carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures.

Organic fluorescent probes for monitoring autophagy in living cells.

As a ubiquitous degradation process in cells, autophagy plays important roles in various biological activities. However, the abnormality of autophagy is closely related to many diseases, such as aging, neurological disorder, and cancer. Thus, monitoring the process of autophagy in living cells has high significance in biological studies and diagnosis of related diseases. In order to real-time and in situ monitor the process of autophagy, various organic fluorescent probes have been explored in recent years owing to the advantages such as handy staining processes, flexible molecular design strategies, and near-nondestructive detection. However, this interesting and frontier topic has not been reviewed so far. In this tutorial review, we will focus on the latest breakthrough results of organic fluorescent probes in monitoring autophagy of living cells, especially the probe design strategies based on the several microenvironment changes of the autophagy process, and the responding mechanisms and bio-imaging applications in the autophagy process. In addition, we will discuss the shortcomings and limitations of the probes developed, such as susceptible to interference, unable to monitor the whole process, and lack of clinical applications. Finally, we will highlight some challenges and further opportunities in this field. This tutorial review may promote the development of more robust fluorescent probes to further reveal the mechanisms of autophagy, which is the basis of degradation and recycling of cell components.

l-Lysine-Based Gelators for the Formation of Oleogels in Four Vegetable Oils.

Supramolecular oleogel is a soft material with a three-dimensional structure, formed by the self-assembly of low-molecular-weight gelators in oils; it shows broad application prospects in the food industry, environmental protection, medicine, and other fields. Among all the gelators reported, amino-acid-based compounds have been widely used to form organogels and hydrogels because of their biocompatibility, biodegradation, and non-toxicity. In this study, four Nα, Nε-diacyl-l-lysine gelators (i.e., Nα, Nε-dioctanoyl-l-lysine; Nα, Nε-didecanoyl-l-lysine; Nα, Nε-dilauroyl-l-lysine; and Nα, Nε-dimyristoyl-l-lysine) were synthesized and applied to prepare oleogels in four kinds of vegetable oils. Gelation ability is affected not only by the structure of the gelators but also by the composition of the oils. The minimum gel concentration (MGC) increased with the increase in the acyl carbon-chain length of the gelators. The strongest gelation ability was displayed in olive oil for the same gelator. Rheological properties showed that the mechanical strength and thermal stability of the oleogels varied with the carbon-chain length of the gelators and the type of vegetable oil. The microstructure of oleogels is closely related to the carbon-chain length of gelators, regardless of oil type. The highest oil-binding capacity (OBC) was obtained in soybean oil for all four gelators, and Nα, Nε-dimyristoyl-l-lysine showed the best performance for entrapping oils.

Reducing Challenges in Organic Synthesis with Stereoselective Hydrogenation and Tandem Catalysis.

Tandem catalysis enables the rapid construction of complex architectures from simple building blocks. This Perspective shares our interest in combining stereoselective hydrogenation with transformations such as isomerization, oxidation, and epimerization to solve diverse challenges. We highlight the use of tandem hydrogenation for preparing complex natural products from simple prochiral building blocks and present tandem catalysis involving transfer hydrogenation and dynamic kinetic resolution. Finally, we underline recent breakthroughs and opportunities for asymmetric hydrogenation.

Developing a variation of 3D-QSAR/MD method in drug design.

In continuation of the previous reports on a combination of 3D-quantitative structure-activity relationships (QSAR) with computational molecular dynamics (MD) studies, a new variation of 3D-QSAR/MD method has been employed for drug-design as an alternative or supplementary for the typical experimental methods. The presented method is more cost-effective and less time-consuming than the previous methods and avoids several restrictions of experimental methods, such as validity estimation, and predictability. For this purpose, seven inhibitors for bromodomain (BRD)-containing protein, as an important protein in the development of different types of cancer and responsible for oncogenic rearrangements, have been selected to study of their interactions by docking and MD simulations using molecular mechanics/generalized born surface area (MM/GBSA) method. To build the proposed model, a common variant of 3D-QSAR methods, comparative molecular field analysis has been employed using a dataset of 100 MD-extracted ligand conformations and their corresponding MM/GBSA BRD4-binding energies. The results showed excellent predictability of the generated model for both the training set and test groups. Finally, two new inhibitors were selected among total 4000 designed derivatives (generated through evolutionary techniques) using the proposed 3D-QSAR-MD model. The potentials of these inhibitors were assessed by MD simulations, which showed the higher inhibitory of these compounds than the previous inhibitors. Therefore, this method showed high potentials for acceleration of the procedure of drug design and a basis for joining researchers in computational biology and pharmaceutical sciences.

A Survival Guide for the "Electro-curious".

The appeal and promise of synthetic organic electrochemistry have been appreciated over the past century. In terms of redox chemistry, which is frequently encountered when forging new bonds, it is difficult to conceive of a more economical way to add or remove electrons than electrochemistry. Indeed, many of the largest industrial synthetic chemical processes are achieved in a practical way using electrons as a reagent. Why then, after so many years of the documented benefits of electrochemistry, is it not more widely embraced by mainstream practitioners? Erroneous perceptions that electrochemistry is a "black box" combined with a lack of intuitive and inexpensive standardized equipment likely contributed to this stagnation in interest within the synthetic organic community. This barrier to entry is magnified by the fact that many redox processes can already be accomplished using simple chemical reagents even if they are less atom-economic. Time has proven that sustainability and economics are not strong enough driving forces for the adoption of electrochemical techniques within the broader community. Indeed, like many synthetic organic chemists that have dabbled in this age-old technique, our first foray into this area was not by choice but rather through sheer necessity. The unique reactivity benefits of this old redox-modulating technique must therefore be highlighted and leveraged in order to draw organic chemists into the field. Enabling new bonds to be forged with higher levels of chemo- and regioselectivity will likely accomplish this goal. In doing so, it is envisioned that widespread adoption of electrochemistry will go beyond supplanting unsustainable reagents in mundane redox reactions to the development of exciting reactivity paradigms that enable heretofore unimagined retrosynthetic pathways. Whereas the rigorous physical organic chemical principles of electroorganic synthesis have been reviewed elsewhere, it is often the case that such summaries leave out the pragmatic aspects of designing, optimizing, and scaling up preparative electrochemical reactions. Taken together, the task of setting up an electrochemical reaction, much less inventing a new one, can be vexing for even seasoned organic chemists. This Account therefore features a unique format that focuses on addressing this exact issue within the context of our own studies. The graphically rich presentation style pinpoints basic concepts, typical challenges, and key insights for those "electro-curious" chemists who seek to rapidly explore the power of electrochemistry in their research.

From Molecules to Molecular Surfaces. Exploiting the Interplay Between Organic Synthesis and Electrochemistry.

For many years, we have been looking at electrochemistry as a tool for exploring, developing, and implementing new synthetic methods for the construction of organic molecules. Those efforts examined electrochemical methods and mechanisms and then exploited them for synthetic gain. Chief among the tools utilized was the fact that in a constant current electrolysis the working potential at the electrodes automatically adjusted to the oxidation (anode) or reduction (cathode) potential of the substrates in solution. This allowed for a systematic examination of the radical cation intermediates that are involved in a host of oxidative cyclization reactions. The result has been a series of structure-activity studies that have led to far greater insight into the behavior of radical cation intermediates and in turn an expansion in our capabilities of using those intermediates to trigger interesting synthetic reactions. With that said, the relationship between synthetic organic chemistry and electrochemistry is not a "one-way" interaction. For example, we have been using modern synthetic methodology to construct complex addressable molecular surfaces on electroanalytical devices that in turn can be used to probe biological interactions between small molecules and biological receptors in "real-time". Synthetic chemistry can then be used to recover the molecules that give rise to positive signals so that they can be characterized. The result is an analytical method that both gives accurate data on the interactions and provides a unique level of quality control with respect to the molecules giving rise to that data. Synthetic organic chemistry is essential to this task because it is our ability to synthesize the surfaces that defines the nature of the biological problems that can be studied. But the relationship between the fields does not end there. Recently, we have begun to show that work to expand the scope of microelectrode arrays as bioanalytical devices is teaching us important lessons for preparative synthetic chemistry. These lessons come in two forms. First, the arrays have taught us about the on-site generation of chemical reagents, a lesson that is being used to expand the use of paired electrochemical strategies for synthesis. Second, the arrays have taught us that reagents can be generated and then confined to the surface of the electrode used for that generation. This has led to a new approach to taking advantage of molecular recognition events that occur on the surface of an electrode for controlling the selectivity of a preparative reaction. In short, the confinement strategy developed for the arrays is used to ensure that the chemistry in a preparative electrolysis happens at the electrode surface and not in the bulk solution. This Account details the interplay between synthetic chemistry and electrochemistry in our group through the years and highlights the opportunities that interplay has provided and will continue to provide in the future.

Mutual kinetic resolution: probing enantiorecognition phenomena and screening for kinetic resolution with racemic reagents.

Enantiorecognition between a racemic reagent and a racemic substrate can be a valuable process in organic synthesis. This review highlights representative examples of this phenomenon and the use of mutual kinetic resolution as a method for screening of kinetic and/or parallel kinetic resolutions.

Advances in deep eutectic solvents and water: applications in metal- and biocatalyzed processes, in the synthesis of APIs, and other biologically active compounds.

Owing to a growing awareness towards environmental impact, the search for "greener", safer, and cost-effective solvents able to replace petroleum-derived solvents has never been greater today. In this context, the use of environmentally responsible solvents like water and the so-called deep eutectic solvents (DESs), constructed from bio-based compounds, has recently experienced important growth in several fields of sciences. This short review highlights the key features of the chemistry of water and (hydrated) DESs when applied to metal- and biocatalyzed transformations as well as to the synthesis of active pharmaceutical ingredients (APIs) and other biologically relevant compounds by providing, through discussion of all relevant literature over the past five years, a comparison of the outcomes of the reactions when carried out in one or the other solvent.

Copper-Promoted Functionalization of Organic Molecules: from Biologically Relevant Cu/O2 Model Systems to Organometallic Transformations.

Copper is one of the most abundant and less toxic transition metals. Nature takes advantage of the bioavailability and rich redox chemistry of Cu to carry out oxygenase and oxidase organic transformations using O2 (or H2O2) as oxidant. Inspired by the reactivity of these Cu-dependent metalloenzymes, chemists have developed synthetic protocols to functionalize organic molecules under enviormentally benign conditions. Copper also promotes other transformations usually catalyzed by 4d and 5d transition metals (Pd, Pt, Rh, etc.) such as nitrene insertions or C-C and C-heteroatom coupling reactions. In this review, we summarized the most relevant research in which copper promotes or catalyzes the functionalization of organic molecules, including biological catalysis, bioinspired model systems, and organometallic reactivity. The reaction mechanisms by which these processes take place are discussed in detail.

In vivo organic synthesis by metal catalysts.

The metal-catalyzed reactions have given various chemical modifications that could not be achieved through basic organic chemistry reactions. In the past decade, many metal-mediated catalytic systems have carried out different transformations in cellulo, such as decaging of fluorophores, drug release, and protein conjugation. However, translating abiotic metal catalysts for organic synthesis in vivo, including bacteria, zebrafish, or mice, could encounter numerous challenges regarding their biocompatibility, stability, and reactivity in the complicated biological environment. In this review, we categorize and summarize the relevant advances in this research field by emphasizing the system's framework, the design of each transformation, and the mode of action. These studies disclose the massive potential of the emerging field and the significant applications in synthetic biology.

Assembly strategies of organic-based imaging agents for fluorescence and photoacoustic bioimaging applications.

The results of numerous studies have led to the development of supramolecular (assembled) organic substances for use in biomedical imaging as part of comprehensive approaches to the diagnosis of diseases. This review summarizes recent advances that have been made in the design and fabrication of assembled organic dyes for fluorescence and photoacoustic bioimaging.

One-Dimensional Organic-Inorganic Material (C6H9N2)2BiCl5: From Synthesis to Structural, Spectroscopic, and Electronic Characterizations.

The new organic-inorganic compound (C6H9N2)2BiCl5 (I) has been grown by the solvent evaporation method. The one-dimensional (1D) structure of the allylimidazolium chlorobismuthate (I) has been determined by single crystal X-ray diffraction. It crystallizes in the centrosymmetric space group C2/c and consists of 1-allylimidazolium cations and (1D) chains of the anion BiCl52-, built up of corner-sharing [BiCl63-] octahedra which are interconnected by means of hydrogen bonding contacts N/C-H⋯Cl. The intermolecular interactions were quantified using Hirshfeld surface analysis and the enrichment ratio established that the most important role in the stability of the crystal structure was provided by hydrogen bonding and H···H interactions. The highest value of E was calculated for the contact N⋯C (6.87) followed by C⋯C (2.85) and Bi⋯Cl (2.43). These contacts were favored and made the main contribution to the crystal packing. The vibrational modes were identified and assigned by infrared and Raman spectroscopy. The optical band gap (Eg = 3.26 eV) was calculated from the diffuse reflectance spectrum and showed that we can consider the material as a semiconductor. The density functional theory (DFT) has been used to determine the calculated gap, which was about 3.73 eV, and to explain the electronic structure of the title compound, its optical properties, and the stability of the organic part by the calculation of HOMO and LUMO energy and the Fukui indices.

New Bioconjugated Technetium and Rhenium Folates Synthesized by Transmetallation Reaction with Zinc Derivatives.

The zinc dithiocarbamates functionalized with folic acid 2Zn and 3Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1Zn). Zinc complexes 2Zn and 3Zn show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes 2Zn or 3Zn and the cation fac-[99mTc(H2O)3(CO)3]+, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[99mTc(CO)3(SS)(P)] bioconjugated to folic acid (2Tc and 3Tc). In spite of the low solubility of 2Zn and 3Zn in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2Re and 3Re) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2Tc and 3Tc indicate low specific binding to folate receptors. In summary, Tc-99m folates 2Tc and 3Tc were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step.

Fabrication and Evaluation of Celecoxib Oral Oleogel to Reduce the Inflammation of Ulcerative Colitis.

Oleogel consists of hydrophobic solvent and an oleogelator. In this study, attempts were made to study the influence of Celecoxib solubility, concentration and dispersability on its release, absorption, and biological performance. Oleogels were prepared to study the formulation variables on its stability and release. Castor oil was selected as the oil and the oleogelator concentration was 4.5% w/w. F3 revealed the highest release and stability compared to other formulae. The percent permeated across the rat intestine showed a 7.5-fold increase over free Celecoxib, and its lifetime was found to be greater than 18 months. The efficacy of free Celecoxib and oleogel formulae to treat rats with ulcerative colitis was done via the induction of ulcerative colitis (UC) through administration of 5% dextran sodium sulphate (DSS). Celecoxib besides its formulae significantly reduced the release of Leucine rich 2 glycoprotein (LRG), Myeloperoxidase (MPO), Tumor necrosis factor-α (TNF-α), proinflammatory cytokine expression, High mobility group box 1 (HMGB1), Nuclear factor kappa B (NF-ΚB), Trefoil Factor 3 (TFF3), Metalloproteinase-3 (MMP3), and miRNA31. Moreover, F3 significantly increased the colonic cAMP in DSS treated rats and reduced the intestinal inflammation beside healing of mucosa and restitution of the epithelium of the gastrointestinal tract.