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New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4 H -1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined.

The ability to differentiate and selectively activate remote C-H bonds represents a perennial challenge in the field of C-H activation. Since its first report in 2012, a now-established "directing template" (DT) approach remains demonstrably effective for the functionalization of remote C-H bonds. As selectivity is hypothesized to be principally determined by the optimal positioning of the reactive catalyst to a target C-H bond, a DT's spatial factors are particularly important toward achieving high selectivity, though a systematic study on its requisite factors remain unelucidated. Through an in-depth analysis of 119 structurally unique published remote DTs, this report summarizes the key factors that are central toward achieving high selectivity at defined aryl positions, which are experimentally corroborated through the development of new aliphatic meta and para-selective DTs for electronically unbiased arenes. These empirical rules, which summarize key distance and geometric factors, are expected to be useful tools for the future development of site-selective arene C-H activation as well as other reactions that rely on covalent/noncovalent DT-mediated remote regioselection.

Ergosterol exert the important function in maintaining the fluidity and osmotic pressure of fungal cells, and its key biosynthesis enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) displayed the obvious synergistic effects. Therefore, we expected to discover the novel antifungal compounds with dual-target (SE/CYP51) inhibitory activity. In the progress, we screened the different kinds of potent fragments based on the dual-target (CYP51, SE) features, and the method of fragment-based drug discovery (FBDD) was used to guide the construction of three different series of benzodioxane compounds. Subsequently, their chemical structures were synthesized and evaluated. These compounds displayed the obvious biological activity against the pathogenic fungal strains. Notably, target compounds 10a-2 and 22a-2 possessed the excellent broad-spectrum anti-fungal activity (MIC 50 , 0.125-2.0 μg/mL) and the activity against drug-resistant strains (MIC 50 , 0.5-2.0 μg/mL). Preliminary mechanism studies have confirmed that these compounds effectively inhibited the dual-target (SE/CYP51) activity, they could cause fungal rupture and death by blocking the bio-synthetic pathway of ergosterol. Further experiments discovered that compounds 10a-2 and 22a-2 also maintained a certain of anti-fungal effect in vivo. In summary, this study not only provided the new dual-target drug design strategy and method, but also discover the potential antifungal compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

A unique N , O -bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp 2 )-H (intra/intermolecular) arylation of unactivated arenes has been developed to expedite access to (Het)biaryl scaffolds under UV-irradiation at room temperature. The protocol tolerated diverse functional groups and substitution patterns, affording the target products in moderate to excellent yields. Mechanistic investigations were also carried out to better understand the reaction pathway. Furthermore, the synthetic applicability of this unified approach has been showcased via the construction of biologically relevant 4-quinolone, tricyclic lactam and sultam derivatives.

Syntenin stimulates exosome production and its expression is upregulated in many cancers and implicated in the spread of metastatic tumor. These effects are supported by syntenin PDZ domains interacting with syndecans. We therefore aimed to develop, through a fragment-based drug design approach, novel inhibitors targeting syntenin-syndecan interactions. We describe here the optimization of a fragment, 'hit' C58, identified by in vitro screening of a PDZ-focused fragment library, which binds specifically to the syntenin-PDZ2 domain at the same binding site as the syndecan-2 peptide. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 45 and 57 (IC 50  = 33 μM and 47 μM; respectively), two representatives of syntenin-syndecan interactions inhibitors, that selectively affect the syntenin-exosome release. These findings demonstrate that it is possible to identify small molecules inhibiting syntenin-syndecan interaction and exosome release that may be useful for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

Benzoquinolizidinone systems were synthesized in both enantiomeric forms from L-glutamic acid. The key chiral arylethylglutarimide intermediate was synthesized from dibenzylamino-glutamate and homoveratrylamine. Aldol reaction of the glutarimide afforded a mixture of syn and anti -aldol adducts. Subsequent regioselective hydride reduction of the glutarimide carbonyl followed by N -acyliminium ion cyclization afforded a product with opposite absolute configurations at C3 and C11b. Cope elimination of the dibenzylamino group then converted the two diastereomers into enantiomers.

Modular construction of polyfunctional arenes from abundant feedstocks stands as an unremitting pursue in synthetic chemistry, accelerating the discovery of drugs and materials. Herein, using the multiple C-H activation strategy with versatile imidate esters, the expedient delivery of molecular libraries of densely functionalized sulfur-containing arenes was achieved, which enabled the concise construction of biologically active molecules, such as Bipenamol.

Tegumental carbonic anhydrase from the worm Schistosoma mansoni (SmCA) is considered a new anti-parasitic target because suppressing its expression interferes with schistosome metabolism and virulence. Here, we present the inhibition profiles of selenoureido compounds on recombinant SmCA and resolution of the first X-ray crystal structures of SmCA in adduct with a selection of such inhibitors. The key molecular features of such compounds in adduct with SmCA were obtained and compared to the human isoform hCA II, in order to understand the main structural factors responsible for enzymatic affinity and selectivity. Compounds that more specifically inhibited the schistosome versus human enzymes were identified. The results expand current knowledge in the field and pave the way for the development of more potent antiparasitic agents in the near future.

A series of novel substituted bisurea 1,4-Diisocyanatobenzene compounds were designed, synthesized and introduced as potent anticancer compounds and screened for their in vitro anti-proliferative activities in human cancer cell lines. The structures of all titled compounds were characterized using Fourier-transform infrared mass spectra, nuclear magnetic resonance spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. A selected group of ten derivatives were apprised for their anti-proliferative activity. The compounds 3d and 3e displayed potent anticancer activity with low IC 50 value of 5.40, and 5.89 μM against HeLa cancer cell lines. The observed apoptosis data has demonstrated that compounds 3d and 3e induce the activaties of caspase-9 and caspase-3, the compounds 3d and 3e regulated fungal zone inhibition. Due to promising growth inhibitions, the all synthesized compounds were allowed to campaign includes quantum-polarized-ligand, quantum mechanical and molecular mechanical, docking experiments. The compounds 3d and 3e have exhibited a higher affinity for ERK/MAP kinase and CDK2 proteins. The molecular docking interactions have demonstrated two stage inhibition of cancer cells by binding with ERK/MAP kinase and CDK2 leads to inactivation of cell proliferation,cell cycle progression,cell divisionanddifferentiation, and hypo-phosphorylation of ribosome leading cells to restricts at point boundary of the G1/S phase. The long-range molecular dynamics, 150 ns, simulations were also revealed more consistency by 3d. Our study conclude good binding propensity for active-tunnel of ERK/MAP kinase and CDK2 proteins, by 3d (1,1'-(1,4-phenylene) bis(3-(2-chlorobenzyl)urea)), to suggest that the designed and synthesized 3d is to use as selective novel nuclei in anti-cancer chemotherapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G i/o -coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.

To continue our ongoing studies on discovery of new potent antifungal leads, 43 novel pyrazole-aromatic containing carboxamides were rationally designed and synthesized. Bioassays indicated that most target compounds displayed good in vitro antifungal activities against Botrytis cinerea, Rhizoctonia cerealis and Sclerotinia sclerotiorum and in vivo antifungal activity against R. solani. Compound 11ea exhibited the most significant in vitro activity against R. cerealis (EC 50  = 0.93 μg/mL) with about 2-fold more potent than a previously reported lead compound A1 (EC 50  = 2.01 μg/mL), and about 11-fold more potent than the positive control/commercial succinate dehydrogenase inhibitor thifluzamide (EC 50  = 23.09 μg/mL). Structure-activity relationship analysis and molecular docking simulations indicated that the presence of difluoromethyl pyrazole-(m-benzene) carboxamide scaffold obviously increased the antifungal activity. The further enzymatic bioassay showed that both thifluzamide and compound 11ea displayed excellent SDH inhibitory effects, and fluorescence quenching analysis suggested that they may share the same target SDH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The hexadehydro-Diels-Alder (HDDA) reaction is the thermal cyclization of an alkyne and a 1,3-diyne to generate a benzyne intermediate. This is then rapidly trapped, in situ, by a variety of species to yield highly functionalized benzenoid products. In contrast to nearly all other methods of aryne generation, no other reagents are required to produce an HDDA benzyne. The versatile and customizable nature of the process has attracted much attention due not only to its synthetic potential but also because of the fundamental mechanistic insights the studies often afford. The authors have attempted to provide here a comprehensive compilation of publications appearing by mid-2020 that describe experimental results of HDDA reactions.

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and antiproliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, β1 subunit), trypsin-like (T-L, β2 subunit) and chymotrypsin-like (ChT-L, β5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC 50 values of 9.90 ± 0.61, 44.83 ± 4.23 and 22.27 ± 0.15 μM against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC 50  = 12.47 ± 0.21, 53.12 ± 2.56 and 26.37 ± 0.5 μM), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC 50  = 1.72 ± 0.14-20.8 ± 0.5 μM and compounds 13 and 28 were found to be the most active compounds with IC 50 values of 1.79 ± 0.21 and 1.72 ± 0.14 μM, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Current therapies for acute leukemias (ALs) are associated with severe adverse reactions and high relapse rates, which makes the search for new antileukemic agents a necessity. Therefore, the aim of this study was to evaluate the effects of a new sulfonamide, S1, in AL cells K562 and Jurkat., Methods: The cytotoxic activity of S1 was assessed using MTT method. The involvement of apoptosis in the mechanism of cell death was assessed by flow cytometry and fluorescence microscopy., Results: Our results demonstrated that S1 induced morphological changes suggestive of apoptosis in both K562 and Jurkat cells. Additionally, S1 was not cytotoxic to normal erythrocytes and mononuclear cells and had a highly selective cytotoxicity for AL lineages. The mechanisms of cell death induced by S1 in K562 cells involves cell cycle arrest at G2/M phase and the activation of both extrinsic and intrinsic apoptosis, with an increased FasR and AIF expression and the loss of mitochondrial potential. As for Jurkat, we observed cell cycle blockade at G0/G1 phase, phosphatidylserine exposure and the involvement of intrinsic apoptosis only, with mitochondrial potential loss and a reduced expression of Survivin.  Although sulfonamide S1 did not altered Bcl-2 and Bax expression in AL cell lines, it was able to activate caspase-3 in K562 cells., Conclusion: Our results suggest that sulfonamide S1 may be a promising candidate for the development of new drugs for the treatment of ALs.

Combined photochemical arylation, "nuisance effect" (S N Ar) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out of control" in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S N Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified., (© 2020 Wiley-VCH GmbH.)

A series of allosteric kidney-type glutaminase (GLS) inhibitors possessing a mercaptoethyl (SCH 2 CH 2 ) linker were synthesized in an effort to further expand the structural diversity of chemotypes derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a prototype allosteric inhibitor of GLS. BPTES analog 3a with a mercaptoethyl linker between the two thiadiazole rings was found to potently inhibit GLS with an IC 50 value of 50 nM. Interestingly, the corresponding derivative with an n-propyl (CH 2 CH 2 CH 2 ) linker showed substantially lower inhibitory potency (IC 50  = 2.3 μM) while the derivative with a dimethylsulfide (CH 2 SCH 2 ) linker showed no inhibitory activity at concentrations up to 100 μM, underscoring the critical role played by the mercaptoethyl linker in the high affinity binding to the allosteric site of GLS. Additional mercaptoethyl-linked compounds were synthesized and tested as GLS inhibitors to further explore SAR within this scaffold including derivatives possessing a pyridazine as a replacement for one of the two thiadiazole moiety., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Behavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release., Objective: The aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization., Methods: In the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV., Results: Taken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum., Conclusion: The behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Ur Rehman et al.)

We report a biocompatible and rapid reaction between cysteine thiols and 2,4-difluoro-6-hydroxy-1,3,5-benzenetricarbonitrile (DFB), which enables the efficient cyclization of peptides in neutral aqueous solutions. The reaction was further applied to cyclize peptides displayed on the phage surface without reducing phage infectivity, thus affording high-quality cyclic peptide libraries useful for screening of cyclic peptide ligands. Using the DFB-cyclic peptide library, we identified ligands that can distinguish the pro-survival protein Bcl-xl from its close relative Bcl-2. Therefore, this study on one hand reports a useful reaction for the construction of cyclic peptide libraries, and on the other hand presents valuable hits for further design of selective Bcl-xl ligands.

Calixarene-analogous metacyclophanes (CAMs) are a special class of cyclophanes that are cyclic polyaromatic hydrocarbons containing three or more aromatic rings linked by one or more methylene bridging groups. They can be considered to be analogues of calixarenes, since, in both types of molecules, the component aromatic rings are linked by methylene groups, which are meta to each other. Since the prototype or classical calix[4]arene consists of four benzene rings each linked by methylene bridges, which are also meta to each other, it can be considered to be an example of a functionalized [1.1.1.1]metacyclophane. A metacyclophane (MCP) that consists of three individual hydroxyl-group functionalized aromatic rings linked by methylene groups, e.g., a trihydroxy[1.1.1]MCP may therefore, by analogy, be termed in the broadest sense as a "calix[3]arene" or a "calix[3]arene-analogous metacyclophane". Most of the CAMs reported have been synthesized by fragment coupling approaches. The design, synthesis and development of functionalized CAMs, MCPs, calixarenes and calixarene analogues has been an area of great activity in the past few decades, due their potential applications as molecular receptors, sensors and ligands for metal binding, and for theoretical studies, etc. In this review article, we focus mainly on the synthesis, structure and conformational properties of [1.1.1]CAMs, i.e., "calix[3]arenes" and their analogues, which contain three functionalized aromatic rings and which provide new scaffolds for further explorations in supramolecular and sensor chemistry.

Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis(( E )-3-bromobenzylidene)piperidin-4-one 3 displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis(( E )-2-bromobenzylidene) cyclic compounds 4a - n to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of 4a - n exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl ( 4d ), benzyl ( 4e ), or acyl ( 4k - m ) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl ( 4f ) and 3-phenylpropyl ( 4g ) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent ( 4h - j ). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.

As traditional cancer treatment methods, photodynamic therapy (PDT) and photothermal therapy (PTT) can eliminate primary tumors, but they cannot inhibit extensive tumor metastasis and local recurrence. Herein, in order to prevent intermolecular accumulation and improve photostability, indocyanine green (ICG) is spontaneously adsorbed onto a covalent organic framework (COF) with high affinity through π-π conjugation, and then chicken ovalbumin (OVA) is coated on the surface of COF@ICG via an electrostatic interaction force. The resultant COF@ICG@OVA can ablate primary tumors under 650 nm and 808 nm laser irradiation due to its high photothermal conversion efficiency (η = 35.75%) and ability to produce reactive oxygen species (ROS). Tumor-associated antigens are also produced after combinational PTT/PDT therapy. By further combining with anti-PD-L1 checkpoint blockade therapy, it can effectively eliminate primary tumors and inhibit the metastasis of cancer cells by generating strong immune responses. Taken together, COF@ICG@OVA nanoparticles offer an efficient synergistic therapeutic modality for the treatment of tumor metastasis.

The high rate of the 'click-to-release' reaction between an allylic substituted trans -cyclooctene linker and a tetrazine activator has enabled exceptional control over chemical and biological processes. Here we report the development of a new bioorthogonal cleavage reaction based on trans -cyclooctene and tetrazine, which allows the use of highly reactive trans -cyclooctenes, leading to 3 orders of magnitude higher click rates compared to the parent reaction, and 4 to 6 orders higher than other cleavage reactions. In this new pyridazine elimination mechanism, wherein the roles are reversed, a trans -cyclooctene activator reacts with a tetrazine linker that is substituted with a methylene-linked carbamate, leading to a 1,4-elimination of the carbamate and liberation of a secondary amine. Through a series of mechanistic studies, we identified the 2,5-dihydropyridazine tautomer as the releasing species and found factors that govern its formation and subsequent fragmentation. The bioorthogonal utility was demonstrated by the selective cleavage of a tetrazine-linked antibody-drug conjugate by trans -cyclooctenes, affording efficient drug liberation in plasma and cell culture. Finally, the parent and the new reaction were compared at low concentration, showing that the use of a highly reactive trans -cyclooctene as the activator leads to a complete cycloaddition reaction with the antibody-drug conjugate in seconds vs hours for the parent system. Although the subsequent release from the IEDDA adduct is slower, we believe that this new reaction may allow markedly reduced click-to-release reagent doses in vitro and in vivo and could expand the application scope to conditions wherein the trans -cyclooctene has limited stability.

Lactisole, which has a 2-phenoxy propionic acid skeleton, is well-known as an inhibitor of sweet taste receptors. We recently revealed some of the structure-activity relationships of the aromatic ring and chiral center of lactisole. Photoaffinity labeling is one of the common chemical biology methods to elucidate the interaction between bioactive compounds and biomolecules. In this paper, the novel asymmetric synthesis of lactisole derivatives with common photophores (benzophenone, azide and trifluoromethyldiazirine) for photoaffinity labeling is described. The synthetic compounds are subjected to cell-based sweet taste receptors, and the substitution with trifluoromethyldiazirinyl photophore shows the highest affinity to the receptor of the synthesized compounds., Competing Interests: The authors declare no conflict of interest.

An application of nucleophilic cyclization and oxidation of nonemissive Schiff bases via cyanide boosting copper catalysis to synthesize fluorescent benzazole derivatives in high conversion yield is disclosed. This approach is highlighted by broad substrate scope, fast reaction time, and mild conditions and can efficiently proceed in living cells or Arabidopsis root tissues. Furthermore, this methodology can be applied for selective detection of Cu 2+ and CN - .

In spite of their various pharmacological properties the anti-inflammatory potential of benzo[c]phenanthridines remained underexplored. Thus, for the first time PDE4 inhibitory potential of 11,12-dihydro benzo[c]phenanthridine/benzo[c]phenanthridine was assessed in vitro. Elegant synthesis of these compounds was performed via a multi-step sequence consisting of a Pd-catalyzed unusual construction of 4-allyl isocoumarin ring and FeCl 3 -mediated intramolecular regio- as well as site-selective arene-allyl cyclization as key steps. The overall strategy involved Sonogashira coupling followed by isocoumarin and isoquinolone synthesis, then chlorination and subsequent cyclization to afford a range of 11,12-dihydro derivatives. One of these dihydro compounds was converted to the corresponding benzo[c]phenanthridine that showed concentration dependent inhibition of PDE4B affording an initial hit molecule. The SAR study suggested that 11,12-dihydro analogs were less potent than the compound having unsaturation at the same part of the ring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4'-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (K i  = 0.11-1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [ 18 F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [ 18 F]7a exhibited the highest uptake in the midbrain, whereas [ 18 F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [ 18 F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [ 18 F]7a is a promising lead for the further development of novel [ 18 F]-labeled PET imaging agents for SERT binding sites in the brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

3-Bromo-1,2,4,5-tetrazine has been synthesized in an oxidant- and metal-free method. The synthesis is scalable and relies on inexpensive starting materials. 3-Bromo-1,2,4,5-tetrazine can undergo nucleophilic aromatic substitutions with differently substituted heteroatoms under mild conditions. In particular, its excellent reactivity has been used to attain chemoselective protein labeling. The resulting labeled lysines can react with strained dienophiles to trigger fast click-to-release (CtR) biorthogonal reactions. The characterization of the CtR reaction in physiological conditions and a therapeutically relevant example with the monoclonal antibody Trastuzumab to showcase its application is presented. Finally, 3-bromo-1,2,4,5-tetrazine has been used to achieve site-selective protein labeling through the genetic incorporation of the first unnatural amino acid bearing an unsubstituted 1,2,4,5-tetrazin-3-yl functionality, which can also undergo CtR reactions.

Silyl triflate precursors to benzyne and related intermediates have emerged as valuable synthetic building blocks. However, data addressing the safety of employing these silyl triflate precursors are lacking. We report the calorimetric analysis of a typical Kobayashi procedure for forming and trapping benzyne using a silyl triflate precursor. Our findings suggest that, unlike benzenediazonium carboxylate precursors to benzyne, silyl triflates may be employed under mild conditions without severe concern for runaway reaction.

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.

The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (K Is ) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: K Is , 250.0 and 5080 nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (K Is , 8.9-51.5 nM); they were almost equally potent to AAZ (K I , 12.0 nM) and had superior potency to SLC-0111 (K I , 960.0 nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with K I values of 3.9-36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (K Is , 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with K I values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (K Is , 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Controlling the cleavage of carbon-carbon bonds during a chemical reaction is a substantial challenge; however, synthetic methods that accomplish this objective produce valuable and often unexplored reactivity. We have designed a mild process to generate α,α-difluorobenzyl carbanions in the presence of potassium carbonate by exploiting the cleavage of C-C bonds during the release of trifluoroacetate. The initiating reagent is potassium carbonate, which represents an improvement over existing protocols that require a strong base. Fragmentation studies across substituted arenes and heteroarenes were conducted along with computational analyses to elucidate reactivity trends. Furthermore, the mildly generated α,α-difluorobenzyl carbanions from electron-deficient aromatics and heteroaromatic rings can react with aldehydes to create derivatives of difluoromethylbenzenes, which are valuable synthetic targets.

A series of copolymers containing a glycolated 1,4-dithienyl-2,3,5,6-tetrafluorophenylene unit copolymerized with thiophene, bithiophene, thienothiophene and 1,2,4,5-tetrafluorobenzene comonomer units were designed and synthesised by direct heteroarylation polymerisation. The optical, electrochemical, electrochromic and solid-state structural properties of the copolymers were investigated. The copolymers exhibit stable redox properties in organic solvents and promising redox properties in thin film configuration with an aqueous electrolyte. Finally, the potential of the copolymers as active materials in organic electrochemical transistors (OECTs) was assessed, and promising performance was shown as an accumulation-mode OECT material with a peak transconductance of 0.17 mS and a good on/off ratio of 10 5 for the thiophene copolymer., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Palladium/norbornene cooperative catalysis has emerged as a distinct approach to construct polyfunctionalized arenes from readily available starting materials. This Review provides a comprehensive overview of this field, including the early stoichiometric investigations, catalytic reaction developments, as well as the applications in the syntheses of bioactive compounds and polymers. The section of catalytic reactions is divided into two parts according to the reaction initiation mode: Pd(0)-initiated reactions and Pd(II)-initiated reactions.

One of the core barriers to developing C-H activation reactions is the ability to distinguish between multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp 2 )-H bonds have been selectively activated in the presence of proximate ones. Yet achieving such unconventional site selectivity with C(sp 3 )-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid-derived directing group and a 2-pyridone ligand that enables the preferential activation of the distal γ-C(sp 3 )-H bond over the proximate β-C(sp 3 )-H bonds for a wide range of alcohol-derived substrates. A competition experiment between the five- and six-membered cyclopalladation step, as well as kinetic experiments, demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp 3 )-H activation.

Targeting of protein tyrosine phosphatase-1B (PTP1B) has emerged as a promising strategy for therapeutic intervention of diabetes and obesity. Investigation of new inhibitors with good bioavailability and high selectivity is the major challenge of drug discovery program targeting PTP1B. Therefore, herein, new neutral benzene-sulfonamide containing compounds were designed, synthesized and biologically evaluated as potent PTP1B inhibitors. New series of thiazolidine, oxazolidine, thiazinan, oxazinan, oxazole, thiazole, tetrazole, cyanopyridine, chromenone, and iminochromene of benzene-sulfonamide derivatives (MSE-1 to MSE-15) were synthesized in a good yield under mild condition using sulfadiazine as a starting material. Among the synthesized compounds, MSE-13 and MSE-14 showed the most in vitro potent PTP-1B inhibitory activity (IC 50 of 0.88 µM and 3.33 µM, respectively). Animal treatment by the target compounds significantly improved the insulin resistance, diminished plasma glucose level, decreased initial body weight, and normalized the serum lipid profile compared to pioglitazone, a standard PTP1B inhibitor. The molecular modeling study showed a high affinity and selectivity of our synthesized compounds to the active site and B-site of PTP1B holding hydrogen bonding, hydrophobic, and electrostatic interactions. Furthermore, Electrostatic Surface Potential (ESP) and HOMO/LUMO analysis indicated the importance of sulfamoyl moiety for PTP1B binding. In silico ADME predictions of such compounds also showed the promising pharmacokinetic and physicochemical properties. The proposed compounds could be considered a lead inhibitory scaffold to PTP1B., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report a new system for the silylation of aryl C-H bonds. The combination of [Ir(cod)(OMe)] 2 and 2,9-Me 2 -phenanthroline (2,9-Me 2 -phen) catalyzes the silylation of arenes at lower temperatures and with faster rates than those reported previously, when the hydrogen byproduct is removed, and with high functional group tolerance and regioselectivity. Inhibition of reactions by the H 2 byproduct is shown to limit the silylation of aryl C-H bonds in the presence of the most active catalysts, thereby masking their high activity. Analysis of initial rates uncovered the high reactivity of the catalyst containing the sterically hindered 2,9-Me 2 -phen ligand but accompanying rapid inhibition by hydrogen. With this catalyst, under a flow of nitrogen to remove hydrogen, electron-rich arenes, including those containing sensitive functional groups, undergo silylation in high yield for the first time, and arenes that underwent silylation with prior catalysts react over much shorter times with lower catalyst loadings. The synthetic value of this methodology is demonstrated by the preparation of key intermediates in the synthesis of medicinally important compounds in concise sequences comprising silylation and functionalization. Mechanistic studies demonstrate that the cleavage of the aryl C-H bond is reversible and that the higher rates observed with the 2,9-Me 2 -phen ligand are due to a more thermodynamically favorable oxidative addition of aryl C-H bonds.

The differential dihydrofunctionalization of terminal alkynes is accomplished through the reductive three-component coupling of terminal alkynes, aryl halides, and pinacolborane. The transformation results in hydrofunctionalization of both π-bonds of an alkyne in a single reaction promoted by cooperative action of a copper/palladium catalyst system. The differential dihydrofunctionalization reaction has excellent substrate scope and can be accomplished in the presence of esters, nitriles, alkyl halides, epoxides, acetals, alkenes, aryl halides, and silyl ethers. Mechanistic experiments indicate that the reaction proceeds through copper-catalyzed hydroboration followed by a second hydrocupration. The resulting heterobimetallic complex is the key intermediate that participates in the subsequent palladium-catalyzed cross-coupling, which furnishes benzylic alkyl boronate products.

An efficient protocol to construct β-d-gluco-/galactosaminosyl linkages was established using nonparticipating and strong electron-withdrawing C-2-2,4-dinitrobenzenesulfonamide (DNsNH)-directed S N 2-like glycosylation of glycosyl ortho-hexynylbenzoates. The reaction is applicable to a wide range of O-, N-, and C-nucleophiles and features convenient conversion of DNsNH into AcNH in high yield under mild conditions. Oligomerization-ready trisaccharide, composed of β-d-(1→3)-glucosamino residues, has been achieved, setting a solid foundation for the synthesis of oligosaccharides associated with Neisseria meningitidis capsular polysaccharide.

Herein, we report on the photoredox-initiated gold-mediated C(sp 2 )-CF 3 and C(sp 2 )-N coupling reactions. By adopting gold as a platform for probing metallaphotoredox catalysis, we demonstrate that cationic gold(III) complexes are the key intermediates of the C-C and C-N coupling reactions. The high-valent gold(III) intermediates are accessed by virtue of photoredox catalysis through a radical chain process. In addition, the bond-forming step of the coupling reactions is the reductive elimination from cationic gold(III) intermediates, which is supported by isolation and crystallographic characterization of key Au(III) intermediates.

Background: With respect to the increase in the average life expectancy, Alzheimer Disease (AD), the most common form of age-related dementia, has become a major threat to the population over the age of 65 during the past several decades. The majority of AD treatments are focused on cholinergic and amyloid hypotheses., Objective: In this study, three series of diphenyl-2-(2-(4-substitutedpiperazin-1-yl)ethyl)pyridazin- 3(2H)-one derivatives were designed, synthesized and investigated for their ability to inhibit both cholinesterase enzymes and amyloid-β aggregation., Method: The inhibitory activities of the synthesized compounds on AChE (from electric eel) and BChE (from equine serum) were determined by the modified Ellman's method. The reported thioflavin T-based fluorometric assay was performed to investigate the effect of the selected compounds on the aggregation of Aβ1-42. The cytotoxic effect of the compounds (4g, 11g and 18g) was monitored in 3T3 cell lines to gain insight into therapeutic potential of the compounds by using MTT assay. The crystal structures of the AChE (1EVE) and BChE (1P0I) enzymes were retrieved from the RCSB Protein Data Bank and Molecular Operating Environment (MOE) software was used for molecular docking of the ligands., Results: Among the tested compounds, 5,6-diphenyl derivative 18g was identified as the most potent and selective AChE inhibitor (IC50 = 1.75 µM, Selectivity Index for AChE > 22.857). 4,6- Diphenyl derivative 11g showed the highest and the most selectivity for BChE (IC50= 4.97 µM, SI for AChE < 0.124). Interestingly, 4,5-diphenyl derivative 4g presented dual cholinesterase inhibition (AChE IC50= 5.11 µM; BChE IC50= 14.16 µM, SI for AChE = 2.771)., Conclusion: Based on biological activity results and low toxicity of the compounds, it can be said that diphenyl substituted pyridazinone core is a valuable scaffold. Especially, dual inhibitory potencies of 4,5-diphenylpyridazin-3(2H)-one core for the cholinesterase enzymes and Aβ- aggregation makes this core a promising disease-modifying agent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Benzynes formed by heating a suitable triyne (or tetrayne) substrate are shown to react with in situ generated alkynyl copper species. The latter are compatible with the polyyne substrates and two types of chemistries have been achieved: (i) 1-bromo-1-alkynes efficiently undergo net bromoalkynylation of the (unsymmetrical) benzynes and (ii) in situ generated alkynylcopper species give rise to hydroalkynylation products. The regiochemical preferences of these two modes of reaction are complementary to one another with respect to the position of alkynyl substituent in the final products., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a new highly crystalline 2D π-conjugated hexagonal mesoporous covalent organic framework material, TrzCOF, through the solvothermal polycondensation of 1,3,5-tri(4-formylbiphenyl) benzene [Ph7(CHO)3, TFBPB] with 2,4,6-tris(4-aminophenyl)-1,3,5-triazine (TAPT) and it displayed excellent anticancer activity for human colorectal carcinoma HCT-116 cells.

Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin-chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8-thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Diaryl ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as "difficult-to-reduce" ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora ( KpADH) has been identified as a robust biocatalyst due to its high conversion of diaryl ketone substrate (4-chlorophenyl)(pyridine-2-yl)ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a "polarity scanning" strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2-CPMK ProR and Mu-S5-CPMK ProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a "polar gate" for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro- S orientation of CPMK is defined when it passes through the "polar gate" in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky diaryl ketones and provides structural insight into the mechanism of stereoselective inversion.

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.

3,5-Bis(arylidene)-4-piperidone (BAP) derivatives display good antitumour and anti-inflammatory activities because of their double α,β-unsaturated ketone structural characteristics. If N-benzenesulfonyl substituents are introduced into BAPs, the configuration of the BAPs would change significantly and their anti-inflammatory activities should improve. Four N-benzenesulfonyl BAPs, namely (3E,5E)-1-(4-methylbenzenesulfonyl)-3,5-bis[4-(trifluoromethyl)benzylidene]piperidin-4-one dichloromethane monosolvate, C 28 H 21 F 6 NO 3 S·CH 2 Cl 2 , (4), (3E,5E)-1-(4-fluorobenzenesulfonyl)-3,5-bis[4-(trifluoromethyl)benzylidene]piperidin-4-one, C 27 H 18 F 7 NO 3 S, (5), (3E,5E)-1-(4-nitrobenzenesulfonyl)-3,5-bis[4-(trifluoromethyl)benzylidene]piperidin-4-one, C 27 H 18 F 6 N 2 O 5 S, (6), and (3E,5E)-1-(4-cyanobenzenesulfonyl)-3,5-bis[4-(trifluoromethyl)benzylidene]piperidin-4-one dichloromethane monosolvate, C 28 H 18 F 6 N 2 O 3 S·CH 2 Cl 2 , (7), were prepared by Claisen-Schmidt condensation and N-sulfonylation. They were characterized by NMR, FT-IR and HRMS (high resolution mass spectrometry). Single-crystal structure analysis reveals that the two 4-(trifluoromethyl)phenyl rings on both sides of the piperidone ring in (4)-(7) adopt an E stereochemistry of the olefinic double bonds. Molecules of both (4) and (6) are connected by hydrogen bonds into one-dimensional chains. In (5) and (7), pairs of adjacent molecules embrace through intermolecular hydrogen bonds to form a bimolecular combination, which are further extended into a two-dimensional sheet. The anti-inflammatory activity data reveal that (4)-(7) significantly inhibit LPS-induced interleukin (IL-6) and tumour necrosis factor (TNF-α) secretion. Most importantly, (6) and (7), with strong electron-withdrawing substituents, display more potential inhibitory effects than (4) and (5).

In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues., (Copyright © 2018. Published by Elsevier Inc.)

Cobalt/nickel-dual catalyzed hydroarylation of terminal olefins with iodoarenes builds complexity from readily available starting materials, with a high preference for the Markovnikov (branched) product. Here, we advance a mechanistic model of this reaction through the use of reaction progress kinetic analysis (RPKA), radical clock experiments, and stoichiometric studies. Through exclusion of competing hypotheses, we conclude that the reaction proceeds through an unprecedented alkylcobalt to nickel direct transmetalation. Demonstration of catalytic alkene prefunctionalization, via spectroscopic observation of an organocobalt species, distinguishes this Csp 2 -Csp 3 cross-coupling method from a conventional transmetalation process, which employs a stoichiometric organometallic nucleophile, and from a bimetallic oxidative addition of an organohalide across nickel, described by radical scission and subsequent alkyl radical capture at a second nickel center. A refined understanding of the reaction leads to an optimized hydroarylation procedure that excludes exogenous oxidant, demonstrating that the transmetalation is net redox neutral. Catalytic alkene prefunctionalization by cobalt and engagement with nickel catalytic cycles through direct transmetalation provides a new platform to merge these two rich areas of chemistry in preparatively useful ways.