Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy.

The p38MAPK-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38MAPK-MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38MAPK-MK2 axis via MK2 degradation. AG was found to bind to the activation loop of MK2, located at the interface of the p38MAPK-MK2 biomolecular complex. This interaction disrupted the complex formation and predisposed MK2 to proteasome-mediated degradation. We showed that AG induced MK2 degradation in a concentration- and time-dependent manner and exerted its anti-inflammatory effects by enhancing the mRNA-destabilizing activity of tristetraprolin, thereby inhibiting pro-inflammatory mediator production (e.g., TNF-α, MCP-1). Administration of AG via intratracheal (i.t.) route to mice induced MK2 downregulation in lung alveolar macrophages, but not lung tissues, and prevented macrophage activation. Our study also demonstrated that the anti-inflammatory effects achieved by AG via MK2 degradation were more durable and sustained than that achieved by the conventional MK2 kinase inhibitors (e.g., PF-3644022). Taken together, our findings illustrated a novel mode of action of AG by modulating the p38MAPK-MK2 signaling axis and would pave the way for the development of a novel class of anti-inflammatory agents targeting MK2 for degradation by harnessing the privileged scaffold of AG.

Polypharmacology of andrographolide: beyond one molecule one target.

Covering: 1951 to 2020Andrographolide is one of the most widely studied plant secondary metabolites, known to display diverse pharmacological actions. Current literature has documented a sizeable list of pharmacological targets for andrographolide, suggesting its multi-targeting nature. Many of these targets are central to the pathophysiology of highly prevalent diseases such as cardiovascular diseases, neurodegenerative disorders, autoimmunity, and even cancer. Despite its well-documented therapeutic efficacy in various disease models, for years, the discrepancies between in vivo bioavailability and bioactivity of andrographolide and the debate surrounding its multi-targeting properties (polypharmacology or promiscuity?) have hindered the development of this versatile molecule into a potential therapeutic agent. Is andrographolide a valuable lead for therapeutic development or a potential invalid metabolic panacea (IMP)? This perspective article aims to discuss this by considering various contributing factors to the polypharmacology of andrographolide.

Evaluation of 2-Bromoisobutyryl Catechol Derivatives for Atom Transfer Radical Polymerization-Functionalized Polydopamine Coatings.

The use of α-bromoisobutyryl-functionalized polydopamine (PDA), derived from an in situ mixture with dopamine (DA) and α-bromoisobutyryl bromide, enables surface-initiated atom transfer radical polymerization (SI-ATRP) of a broad range of methacrylate monomers for surface functionalization. Although the putative intermediate 2-bromo-N-(3,4-dihydroxyphenethyl)-2-methylpropanamide 1 has been proposed to account for the SI-ATRP activity of α-bromoisobutyryl-functionalized PDA, there has not been a systematic investigation on the efficacy of other catechol-derived 2-bromoisobutyryl derivatives for SI-ATRP. In this work, a number of catechol-derived ATRP initiators containing the 2-bromoisobutyryl moiety were designed and synthesized, in an effort to investigate the effect of changes in structure on initiator immobilization, and subsequent ATRP performance. The change in the length of the linker unit bearing the 2-bromoisobutyryl moiety, the introduction of a free amine group, or the replacement of the amide with an ester were found to have profound effects on the ability of the molecule to deposit ATRP-initiator-modified PDA coatings, as well as the subsequent SI-ATRP performance. Among the ATRP initiators synthesized, 5-(2-aminoethyl)-2,3-dihydroxyphenethyl 2-bromo-2-methylpropanoate hydrobromide 4·HBr was most efficiently incorporated into ATRP-initiator-modified PDA coatings and also the best at effecting SI-ATRP with 2-hydroxyethyl methacrylate; the high performance of this initiator is likely due to the presence of a free amine and an appropriately long methylene linker unit to the 2-bromoisobutyryl moiety. This methodology was found to be suitable for the functionalization of a range of organic and inorganic surfaces, for the fabrication of high-value surface-grafted polymer brush coatings for various applications.

Gold(I)-Catalyzed Intramolecular Hydroarylation of Phenol-Derived Propiolates and Certain Related Ethers as a Route to Selectively Functionalized Coumarins and 2H-Chromenes.

Methods are reported for the efficient assembly of a series of phenol-derived propiolates, including the parent system 56, and their Au(I)-catalyzed cyclization (intramolecular hydroarylation) to give the corresponding coumarins (e.g., 1). Simple syntheses of natural products such as ayapin (144) and scoparone (145) have been realized by such means, and the first of these subject to single-crystal X-ray analysis. A related process is described for the conversion of propargyl ethers such as 156 into the isomeric 2H-chromene precocene I (159), a naturally occurring inhibitor of juvenile hormone biosynthesis.

Direct Evidence for the Critical Role of 5,6-Dihydroxyindole in Polydopamine Deposition and Aggregation.

The definitive role of the intermediate 5,6-dihydroxyindole (DHI) in the formation of polydopamine (PDA) coatings from aqueous dopamine (DA) has not been clearly elucidated and remains highly controversial. Our foray into this debate as reported in this study agrees with some reported assertions that DHI-based coatings are not synonymous with PDA coatings. Our conclusion arises from a systematic comparison of the components and properties of DHI-based coatings and PDA coatings. In addition, through careful copolymerization studies of DA and DHI, our studies reported herein unequivocally suggest that both DA and DHI are partial building blocks for PDA formation. Our results also provide additional evidence of the critical role of DHI in controlling the thickness of PDA coatings, through competitive events between PDA aggregation in solutions and deposition onto substrates. These findings highlight the complex interplay between both DHI and uncyclized DA moieties in the formation of adhesive catechol/amine materials.

A compendium of small molecule direct-acting and host-targeting inhibitors as therapies against alphaviruses.

Alphaviruses were amongst the first arboviruses to be isolated, characterized and assigned a taxonomic status. They are globally widespread, infecting a large variety of terrestrial animals, birds, insects and even fish. Moreover, they are capable of surviving and circulating in both sylvatic and urban environments, causing considerable human morbidity and mortality. The re-emergence of Chikungunya virus (CHIKV) in almost every part of the world has caused alarm to many health agencies throughout the world. The mosquito vector for this virus, Aedes, is globally distributed in tropical and temperate regions and capable of thriving in both rural and urban landscapes, giving the opportunity for CHIKV to continue expanding into new geographical regions. Despite the importance of alphaviruses as human pathogens, there is currently no targeted antiviral treatment available for alphavirus infection. This mini-review discusses some of the major features in the replication cycle of alphaviruses, highlighting the key viral targets and host components that participate in alphavirus replication and the molecular functions that were used in drug design. Together with describing the importance of these targets, we review the various direct-acting and host-targeting inhibitors, specifically small molecules that have been discovered and developed as potential therapeutics as well as their reported in vitro and in vivo efficacies.

Labdane diterpenoids as potential anti-inflammatory agents.

The search for new anti-inflammatory agents is challenging due to the complexity of the inflammatory process and its role in host defense. Over the past few decades, a significant body of evidence has emerged, supporting the prominent role of labdane diterpenoids in therapeutic interventions of various inflammatory diseases. The anti-inflammatory activity of labdane diterpenoids has been attributed mainly to the inhibition of nuclear factor-κB (NF-κB) activity, the modulation of arachidonic acid (AA) metabolism and the reduction of nitric oxide (NO) production. This article provides extensive coverage of naturally occurring labdane diterpenes, discovered between 1981 and 2016, which have been verified as NF-κB, NO, or AA modulators. Herein, we also discuss the role of Michael acceptor, a common structural feature present in most of the active labdane diterpenes, and its association with NF-κB signaling inhibition. In the cases where a sufficient amount of data exists, structure-activity relationship (SAR) studies and clinical studies performed on the anti-inflammatory labdane diterpenoids are also discussed.

Mimics of pramanicin derived from pyroglutamic acid and their antibacterial activity.

Mono and dihydroxypyrrolidinones are readily available by direct oxygenation of a pyroglutamate-derived bicyclic lactam with high diastereoselectivity, and these may be manipulated further in protected or unprotected form by Grignard addition to a pendant Weinreb amide to give acylhydroxypyrrolidinones, which are analogues of the natural product, pramanicin. Preliminary bioassay against S. aureus and E. coli indicated that some compounds exhibit selective Gram-negative antibacterial activity, and may offer promise for the development of novel systems suitable for antibacterial drug development.

An efficient synthesis of an exo-enone analogue of LL-Z1640-2 and evaluation of its protein kinase inhibitory activities.

An efficient synthesis of an exo-enone analogue (5) of resorcylic acid lactone (RAL), natural product LL-Z1640-2 (1), has been achieved using a Ni-catalysed regioselective reductive coupling macrocyclisation of an alkyne-aldehyde as a key step. The synthetic route is significantly shorter than those for the natural product and avoids the isomerisation problem of the cis-double bond in the molecule. The preliminary biological evaluation showed that the exo-enone analogue is a potent inhibitor of several important kinases relevant to cancer drug development.

Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling.

Differentiation of human pluripotent stem cells as embryoid bodies (EBs) has been achieved previously with p38alfa MAPK inhibitors such as SB203580 with moderate efficiency of 10-15%. We synthesized and screened 42 compounds that are 2,4,5-trisubstituted azole analogues of SB203580 for efficient cardiomyocyte differentiation. Our screen identified novel compounds that have similar cardiac differentiation activity as SB203580. However, the cardiac differentiation did not correlate with p38alfa MAPK inhibition, indicating an alternative mechanism in cardiac differentiation. Upon profiling several 2,4,5-trisubstituted azole compounds against a panel of 97 kinases we identified several off targets, among them casein kinases 1 (CK1). The cardiomyogenic activities of SB203580 and its analogues showed a correlation with post mesoderm Wnt/beta-catenin pathway inhibition of CK1 epsilon and delta. These findings united the mechanism of 2,4,5-trisubstituted azole with the current theory of Wnt/beta-catenin regulated pathway of cardiac differentiation. Consequently an efficient cardiomyocyte protocol was developed with Wnt activator CHIR99021 and 2,4,5-trisubstituted azoles to give high yields of 50-70% cardiomyocytes and a 2-fold increase in growth.

Synthesis of mimics of pramanicin from pyroglutamic acid and their antibacterial activity.

Epoxypyrrolidinones are available by epoxidation of carboxamide-activated bicyclic lactam substrates derived from pyroglutamate using aqueous hydrogen peroxide and tertiary amine catalysis. In the case of an activating Weinreb carboxamide, further chemoselective elaboration leads to the efficient formation of libraries of epoxyketones. Deprotection may be achieved under acidic conditions to give epoxypyroglutaminols, although the ease of this process can be ameliorated by the presence of internal hydrogen bonding. Bioassay against S. aureus and E. coli indicated that some compounds exhibit antibacterial activity. These libraries may be considered to be structural mimics of the natural products pramanicin and epolactaene. More generally, this outcome suggests that interrogation of bioactive natural products is likely to permit the identification of "privileged" structural scaffolds, providing frameworks suitable for optimization in a short series of chemical steps that may accelerate the discovery of new antibiotic chemotypes. Further optimization of such systems may permit the rapid identification of novel systems suitable for antibacterial drug development.

An amidation/cyclization approach to the synthesis of N-hydroxyquinolinones and their biological evaluation as potential anti-plasmodial, anti-bacterial, and iron(II)-chelating agents.

A 26-member library of novel N-hydroxyquinolinone derivatives was synthesized by a one-pot Buchwald-type palladium catalyzed amidation and condensation sequence. The design of these rare scaffolds was inspired from N-hydroxypyridones and 2-quinolinones classes of compounds which have been shown to have rich biological activities. The synthesized compounds were evaluated for their anti-plasmodial and anti-bacterial properties. In addition, these compounds were screened for their iron(II)-chelation properties. Notably, four of these compounds exhibited anti-plasmodial activities comparable to that of the natural product cordypyridone B.

Synthesis of neplanocin A and its 3'-epimer via an intramolecular Baylis-Hillman reaction.

The key cyclopentenyl intermediate 11b was synthesized in 4 steps from d-ribose in 41% overall yield via an efficient intramolecular Baylis-Hillman reaction. This novel key intermediate can be modified easily and transformed to neplanocin A (1a) and its 3'-epimer (1b).

Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity.

An efficient approach for the introduction of 3-acyl side chain groups onto a core tetramate system, which are suitable for further manipulation by nucleophilic displacement or Horner-Wadsworth-Emmons coupling, provides access to a diverse library of substituted tetramates related to two distinct classes of natural products, equisetin and pramanicin. Assessment against S. aureus and E. coli indicated that some compounds exhibit significant antibacterial activity, providing unusual leads for further optimisation in the drug discovery process.

Design, synthesis and biological evaluation of FLT3 covalent inhibitors with a resorcylic acid core.

A series of simplified ring-opened resorcylic acid lactone (RAL) derivatives were conveniently synthesized to target FLT3 and its mutants either irreversibly or reversibly. Our design of covalent FLT3 inhibitors is based on cis-enone RALs (e.g., L-783,277) that have a ß-resorcylic acid as the core structure. The designed compounds contain three types of Michael acceptors (acrylamide, vinylsulfonamide and maleimide) as potential covalent traps of a cysteine residue at the binding site of kinases. A variety of functional substitutions were also introduced to maximize the binding interactions. Biological evaluations revealed that compound 17, despite the presence of a highly reactive maleimide Michael acceptor, is a potent covalent FLT3 inhibitor which shows some specificity in cellular assays. On the other hand, compounds 2 and 6 containing acrylamide or vinylsulfonamide groups are reversible towards FLT3 binding, and are potent and selective inhibitors of mutant FLT3-ITD versus wt-FLT3. They also inhibit cell proliferation in FLT3-ITD expressing cell line MV-4-11 as compared to wt-FLT3 expressing cell line THP-1 and non-FLT3 cell lines (K562, HL60 and Hek-293T).

Searching for "environmentally-benign" antifouling biocides.

As the result of the ecological impacts from the use of tributyltins (TBT) in shipping, environmental legislation for the registration of chemicals for use in the environment has grown to a monumental challenge requiring product dossiers to include information on the environmental fate and behavior of any chemicals. Specifically, persistence, bioaccumulation and toxicity, collectively known as PBT, are properties of concern in the assessment of chemicals. However, existing measurements of PBT properties are a cumbersome and expensive process, and thus not applied in the early stages of the product discovery and development. Inexpensive methods for preliminary PBT screening would minimize risks arising with the subsequent registration of products. In this article, we evaluated the PBT properties of compounds reported to possess anti-fouling properties using QSAR (quantitative structure-activity relationship) prediction programs such as BIOWIN™ (a biodegradation probability program), KOWWIN™ (log octanol-water partition coefficient calculation program) and ECOSAR™ (Ecological Structure Activity Relationship Programme). The analyses identified some small (Mr < 400) synthetic and natural products as potential candidates for environmentally benign biocides. We aim to demonstrate that while these methods of estimation have limitations, when applied with discretion, they are powerful tools useful in the early stages of research for compound selection for further development as anti-foulants.

Total syntheses of the coumarin-containing natural products pimpinellin and fraxetin using Au(I)-catalyzed intramolecular hydroarylation (IMHA) chemistry.

The title natural products (1 and 2, respectively) have been synthesized by Au(I)-catalyzed intramolecular hydroarylation (IMHA) of the relevant aryl propiolate esters (e.g., 13), which were themselves formed by reaction of the corresponding phenols with either 3-(trimethylsilyl)propiolic acid or propiolic acid and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide. (±)-Purpurasol (3) was readily derived from fraxetin (2) by established procedures.

Tri-substituted imidazole analogues of SB203580 as inducers for cardiomyogenesis of human embryonic stem cells.

The p38α mitogen-activated protein kinase (MAPK) inhibitor SB203580 had been reported to enhance the cardiomyogenesis of human embryonic stem cells (hESCs). To investigate if tri-substituted imidazole analogues of SB203580 are equally effective inducers for cardiomyogenesis of hESCs, and if there is a correlation between p38α MAPK inhibition and cardiomyogenesis, we designed and synthesized a series of novel tri-substituted imidazoles with a range of p38α MAPK inhibitory activities. Our studies demonstrated that suitably designed analogues of SB203580 can also be inducers of cardiomyogenesis in hESCs and that cell growth is affected by changes in the imidazole structures.

Self-supported chiral titanium cluster (SCTC) as a robust catalyst for the asymmetric cyanation of imines under batch and continuous flow at room temperature.

A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine-cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self-supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium-alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98 % enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed-bed reactor to carry out the cyanation under continuous flow. Up to 97 % ee and quantitative conversion with a throughput of 45 mg h(-1) were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three-component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98 %. Synthetically useful ee values were also obtained for challenging α-branched aliphatic aldehyde by using the three-component continuous Strecker reaction.

Copper-catalyzed oxidative amidation of aldehydes with amine salts: synthesis of primary, secondary, and tertiary amides.

A practical method for the amidation of aldehydes with economic ammonium chloride or amine hydrochloride salts has been developed for the synthesis of a wide variety of amides by using inexpensive copper sulfate or copper(I) oxide as a catalyst and aqueous tert-butyl hydroperoxide as an oxidant. This amidation reaction is operationally straightforward and provides primary, secondary, and tertiary amides in good to excellent yields for most cases utilizing inexpensive and readily available reagents under mild conditions. In situ formation of amine salts from free amines extends the substrate scope of the reaction. Chiral amides are also synthesized from their corresponding chiral amines without detectable racemization. The practicality of this amide formation reaction has been demonstrated in an efficient synthesis of the antiarrhythmic drug N-acetylprocainamide.