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The reactivity of complexes [Fe2(μ‐S2)(CO)4L2] (L=CO (1), PPh3 (2)), with lithium alkynylide reagents generated in situ, was investigated. The behavior of the S2‐bridge in these compounds depends on the substitution at the diiron core. The reaction with the hexacarbonyl derivative 1 leads to the formation of the 1,2‐dithiolene bridged complex [Fe2(μ‐SCH=C(R)S)(CO)6] (3R) while the molecule [Fe2(μ‐SH)(μ‐SC≡CR)(CO)4(PPh3)2] (5R), with an open butterfly structure, is isolated when reacting the disubstituted derivative 2. The disubstituted dithiolene complex [Fe2(μ‐SCH=C(Ph)S)(CO)4(PPh3)2] (4Ph) can only be obtained by substitution of carbonyls with PPh3 in 3R. In the presence of piperidine, 5R isomerizes into the 1,1'‐dithiolene bridged derivative 6Ph. The novel compounds 4–6 were synthesized and characterized by IR and NMR spectroscopies. X‐ray crystallographic studies of the dithiolene complexes 3Ph–4Ph allowed their structural analysis. [ABSTRACT FROM AUTHOR]

Two series of novel hybrid heterocyclic compounds that combine the imidazole ring with bioactive piperidine, morpholine or piperazine heterosystems, through a hydrazone unit, were easily obtained by two competitive pathways. Starting from 5‐amino‐4‐cyanoformimidoyl imidazoles and 1‐aminopiperidine, 4‐aminomorpholine or 1‐amino‐4‐methylpiperazine under mild acidic media led to the selective synthesis of 5‐aminoimidazole 4‐carboxamidrazones, whereas the corresponding 4‐hydrazonoyl cyanide derivatives were obtained under stronger acidic conditions. These highly functionalized imidazoles provide convenient synthetic precursors to a vast array of heterocycles with potential pharmaceutical applications. The reaction mechanisms were elucidated on the basis of experimental assays and in silico calculations. The compounds were screened against colorectal cancer HCT116‐p53 wt cell line, and significant IC50 values of 3.69 μM and 4.83 μM were obtained. [ABSTRACT FROM AUTHOR]

In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart. [ABSTRACT FROM AUTHOR]

Stable boroxine-amine adducts comprising dative B←N bond(s) were prepared by mechanochemically-induced reactions of phenylboronic acid (PBA) and amines (pyridine, DMAP, 1Hpyrazole, piperidine, DABCO, hexamethylenetetramine, or 4,4'-bipyridine). In-situ Raman monitoring, ex-situ PXRD and DFT calculations were used for product identification. Stoichiometry of the product (3: 1, 3:2 or 6:1 adduct) was controlled by the amine structure and the molar ratio of the reactants. The 1:2 Hbonded assembly of PBA and 4,4'-bipyridine (bpy) was confirmed as an intermediate in the adduct formation for bpy. Competitive binding experiments indicated that the exchange of the amines in the 3:1 adducts follows the computed adduct stabilities that increase with the amine basicity. Following the DFT prediction, the first adduct with two different amines, DMAP and pip, bound to one boroxine moiety was isolated and structurally characterized. Results show that calculations can be used to predict possible and preferred product(s) and their spectral characteristics. [ABSTRACT FROM AUTHOR]

Linearly fused polycyclic piperidines represent common substructures in natural products and biologically active small molecules. We have devised a Pd‐catalyzed annulation strategy to these compounds that converts readily available 2‐tetralones and indanones into these scaffolds with the potential for control of both enantio‐ and diastereoselectivity. Importantly, these compounds can be chemoselectively functionalized, providing an efficient and robust methodology to these important nitrogen‐containing molecules. [ABSTRACT FROM AUTHOR]

Novel rhodium‐catalyzed [3+3] annulations of diazoenals and α‐amino ketones has been disclosed here. The reactivity of diazoenals has been switched from carbenoid to vinylogous NH‐insertion by altering acyclic to cyclic α‐amino ketones. In this direction, we report an efficient strategy to synthesize 1,2‐dihydropyridines (DHPs) and fused 1,4‐oxazines. Mechanistic investigation revealed that the formyl group is necessary for carbenoid [3+3] annulation and the cyclohexyl group is the dictating factor for vinylogous NH‐ insertion. The synthetic utility of 1,2‐dihydropyridines was demonstrated by synthesizing piperidine, pyrido[1,2‐a]indole, and 2‐pyridone scaffolds. Further, structural diversification of fused 1,4‐oxazines resulted in the short synthesis of hexahydroquinolin‐2(1H)‐ones, hexahydro quinolines and tetrahydroquinolinones via ring opening rearrangement and a new oxidative deformylation, respectively. [ABSTRACT FROM AUTHOR]

New derivatives of crown compounds were successfully prepared via multicomponent reactions of a thia‐podand, an β‐keto ester and ammonium acetate based on modifications of the Petrenko‐Kritschenko reaction. The structure of the synthesized compounds was identified by physical‐chemical methods of analysis including IR, NMR, HRMS, and single‐crystal X‐ray diffraction. In addition, an in vitro assay against the α‐glucosidase of synthetic compounds was first evaluated and showed positive results. The most active compound exhibited an IC50 value of 5.69±0.27 μM, which is 37 fold more potent than the standard drug of acarbose (IC50 208.42±4.68 μM). Furthermore, prediction of ADMET parameters revealed that almost all synthesized trithiacrown ether derivatives expressed drug‐like characteristics. Our results provide useful evidence that crown ether compounds are not only good chelators with metal ions but also scaffolds for developing lead candidates in the treatment of diabetic disease. [ABSTRACT FROM AUTHOR]

An approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pKa(H) and LogP). [ABSTRACT FROM AUTHOR]

The possibility of stratifying patients according to differences in ROS proto‐oncogene 1 (ROS1) fusion partners has been discussed. This study aimed to clarify the clinicopathological differences between two SDC4::ROS1 positive NSCLC cases who had different responses to crizotinib. Cytology and pathology samples from two NSCLC cases with SDC4::ROS1 who were diagnosed and treated with crizotinib at Nihon University Itabashi Hospital were obtained. Case 1 has been well‐controlled with crizotinib for over 5 years, but case 2 was worse and overall survival was 19 months. Sequencing analysis of ROS1 fusion genes was performed by reverse‐transcription‐PCR and Sanger's sequencing methods. In addition, thyroid transcription factor (TTF)‐1, ROS‐1, Ki67, and phosphorylated extracellular signal‐regulated kinase (pERK)1/2 expression were investigated using immunohistochemistry. Sequencing analysis showed SDC4 exon2::ROS1 exon 32 (exon33 deleted) in case 1, and coexistence of SDC4 exon2::ROS1 exon 34 and SDC4 exon2::ROS1 exon35 in case 2. The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same. [ABSTRACT FROM AUTHOR]

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2‐azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well‐defined exit vectors. To achieve the synthesis of 2‐azanorbornanes, new strain‐release reagent, azahousane, is introduced along with its photosensitized strain‐release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2‐azanorbornanes with good selectivities. [ABSTRACT FROM AUTHOR]

1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2S−NCO, to give spirocyclic β‐lactams. Reduction of the β‐lactam ring with alane produced 1‐azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent‐free analogue with high activity. [ABSTRACT FROM AUTHOR]

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2‐azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well‐defined exit vectors. To achieve the synthesis of 2‐azanorbornanes, new strain‐release reagent, azahousane, is introduced along with its photosensitized strain‐release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2‐azanorbornanes with good selectivities. [ABSTRACT FROM AUTHOR]

1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2S−NCO, to give spirocyclic β‐lactams. Reduction of the β‐lactam ring with alane produced 1‐azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent‐free analogue with high activity. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

A copper‐catalyzed dearomative alkynylation of pyridines is reported with excellent regio‐ and enantioselectivities. The synthetically valuable enantioenriched 2‐alkynyl‐1,2‐dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three‐component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N‐ ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2‐addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non‐activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono‐alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported. [ABSTRACT FROM AUTHOR]

A copper‐catalyzed dearomative alkynylation of pyridines is reported with excellent regio‐ and enantioselectivities. The synthetically valuable enantioenriched 2‐alkynyl‐1,2‐dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three‐component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N‐ ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2‐addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non‐activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono‐alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported. [ABSTRACT FROM AUTHOR]

Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations. These instructions are variable and rarely based on dedicated studies in people with obesity. This review briefly discusses the current clinical use of body measurements to guide chronic dosing instructions and highlights the need for obesity‐specific dosing instructions when the half‐life of a drug is prolonged (typically through increased volume of distribution) in people with obesity. Examples of drugs with apparent opportunities for either ramp‐up, loading, or washout instructions for patients based on body mass index are identified, specifically for vortioxetine, posaconazole, and brexpiprazole. We call for inclusion of people with obesity in clinical studies as a special subpopulation during drug development and propose the use of body mass index to guide dosing decisions among these patients. [ABSTRACT FROM AUTHOR]

A convenient synthetic protocol for the construction of spiro[indoline‐3,3′‐quinoline]‐2,5′‐dione motifs was successfully developed by base promoted one‐pot three‐component reaction. In the presence of piperidine, three‐component reaction of ammonium acetate, aromatic aldehydes and the in situ generated 3‐isatyl 1,4‐dicarbonyl compounds, which were derived from base mediated addition of dimedone to 3‐methyleneoxindoles, resulted in two diastereoisomers of spiro[indoline‐3,3′‐quinoline]‐2,5′‐dione derivatives in good yields and with good diastereoselectivity. The stereochemistry of the reaction was clearly elucidated by isolation of two diastereomers and determination of several single crystal structures. [ABSTRACT FROM AUTHOR]

Nitrogen‐containing benzimidazole, piperazine, and piperidine are significant pharmacophores in medicinal chemistry and drug development. Many medications, lead compounds, and various reagents have these N‐containing scaffolds. This review concentrated on the development of novel therapeutic agents as well as the broad range of pharmacological actions demonstrated by benzimidazole, piperazine, and piperidine hybrids. The review emphasizes these hybrids′ potential, range, and medical significance. The review also discusses the structural criteria for benzimidazole, piperazine, and piperidine hybrids created by diverse chemists to be physiologically effective against a variety of disorders. [ABSTRACT FROM AUTHOR]

The analysis of organic acids in complex mixtures by LC‐MS can often prove challenging, especially due to the poor sensitivity of negative ionization mode required for detection of these compounds in their native (i.e., underivatized or untagged) form. These compounds have also been difficult to measure using supercritical fluid chromatography (SFC)‐MS, a technique of growing importance for metabolomic analysis, with similar limitations based on negative ionization. In this report, the use of a high proton affinity N‐(4‐aminophenyl)piperidine derivatization tag is explored for the improvement of organic acid detection by SFC‐MS. Four organic acids (lactic, succinic, malic, and citric acids) with varying numbers of carboxylate groups were derivatized with N‐(4‐aminophenyl)piperidine to achieve detection limits down to 0.5 ppb, with overall improvements in detection limit ranging from 25‐to‐2100‐fold. The effect of the derivatization group on sensitivity, which increased by at least 200‐fold for compounds that were detectable in their native form, and mass spectrometric detection are also described. Preliminary investigations into the separation of these derivatized compounds identified multiple stationary phases that could be used for complete separation of all four compounds by SFC. This derivatization technique provides an improved approach for the analysis of organic acids by SFC‐MS, especially for those that are undetectable in their native form. [ABSTRACT FROM AUTHOR]

The in vitro antibacterial activity of brand‐new fused pyrido[2,1‐a]isoquinoline compounds was investigated. The desired pyrido[2,1‐a]isoquinoline derivatives 5, 9, and 10 were obtained by heating 2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐1‐yl)acetonitrile 1 with ethylacetate derivatives 2, 6, and 7 in refluxing acetonitrile, while piperidine was present as a catalytic quantity. Under the same conditions, compound 1 was refluxed with compounds 11a–f to give the corresponding compounds 12a–f. [ABSTRACT FROM AUTHOR]

3‐Aminopiperidines are a valuable motif present in small molecule pharmaceuticals and bioactive natural products. Synthesis of these moieties via olefin diamination would be an attractive approach, however significant challenges remain with regards to both regioselectivity and exogenous nucleophile scope. Herein, we report a metal‐free olefin diamination via a "heterocyclic group transfer" (HGT) reaction of I(III) N‐HVI reagents, giving rise to 3‐aminopiperidines with high selectivity. The HGT strategy leverages heteroarenes as oxidatively masked amine nucleophiles, giving rise to (hetero)arylonium salt products which are isolated via simple trituration and provide a versatile handle for downstream diversification. This represents only the second 6‐endo selective I(III)‐mediated diamination reaction and mechanistic studies indicate ring opening of an intermediate aziridinium ion is responsible for the 6‐endo selectivity. [ABSTRACT FROM AUTHOR]

With the well‐documented chemical and biological applications, piperidine and pyridine are among the most important N‐heterocycles, and a new synthetic strategy, especially one with an alternative bond‐forming design, is of general interest. Using the gold‐catalyzed intermolecular condensation of amine and diyne‐ene, we report herein the first example of enantioselective 1,2‐dihydropyridine synthesis through a formal [3+2+1] fashion (up to 95 % yield, up to 99 % e.e.). [ABSTRACT FROM AUTHOR]

With the well‐documented chemical and biological applications, piperidine and pyridine are among the most important N‐heterocycles, and a new synthetic strategy, especially one with an alternative bond‐forming design, is of general interest. Using the gold‐catalyzed intermolecular condensation of amine and diyne‐ene, we report herein the first example of enantioselective 1,2‐dihydropyridine synthesis through a formal [3+2+1] fashion (up to 95 % yield, up to 99 % e.e.). [ABSTRACT FROM AUTHOR]

Substituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and 'chiral pool' strategies. Herein, we report multi‐enzymatic and chemo‐enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee >99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N‐heterocycles using either platinum(0)‐catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one‐pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr ≥98:2) and isolated yields of up to 73%. Lead‐likeness analysis of five representative products using an open‐source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery. [ABSTRACT FROM AUTHOR]

In this paper, we report a gold(I)‐catalyzed cascade cyclization of N‐ or O‐nucleophile tethered‐vinylidenecyclopropanes (VDCPs), resulting in the synthesis of pyrrole, furan, pyrrolidine, and piperidine skeletons in 30%‐98% yields. Depending on the carbon chain length connecting the nucleophile and VDCPs, two reaction pathways are available, leading to different products. Both α‐amino VDCPs and α‐hydroxyl VDCPs, where nucleophiles and VDCPs are connected by a methylene group, undergo intramolecular nucleophilic addition and aromatization, followed by ring‐opening of the cyclopropane unit to produce substituted pyrroles and furans. By extending the chain length to three or four carbons, it becomes possible to form pyrrolidines and piperidines with a cyclobutene moiety via ring expansion of the cyclopropane unit, accompanied by gold carbene induced vinylogous nucleophilic addition. [ABSTRACT FROM AUTHOR]

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six‐membered nitrogen‐containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool‐based (internal asymmetric induction), (2) chiral auxiliary‐based (relayed asymmetric induction) and (3) asymmetric catalysis‐based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products. [ABSTRACT FROM AUTHOR]

Novel hybrid series of benzenesulfonamide coupled with piperidine, morpholine, and N,N‐dimethylethanamine moieties at sulfonyl group were designed through pharmacophore hybridization, synthesized, and evaluated for cancer treatment. Benzenesulfonamide‐based derivatives had been synthesized, structurally elucidated, and biologically evaluated as potent VEGFR2 kinase and topoisomerase II inhibitors with cytotoxicity against MCF‐7 and HepG2 cells. Interestingly, the most cytotoxic compound against MCF‐7 and HepG2 cells exhibited promising IC50 values of 0.08 and 0.186 μM, respectively, compared to Doxorubicin as the reference drug with IC50 values of 7.67 and 8.28 μM. It exhibited promising dual enzyme inhibition VEGFR2 and Topoisomerase II with IC50 values of 13.24 nM and 8.3 μM compared to Sorafenib and Doxorubicin as standard drugs. It significantly stimulated total apoptotic breast cancer cell death by 55.25‐fold (34.26 % compared to 0.62 for the control), arresting the cell cycle at S‐phase, which affected the apoptosis‐mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the anti‐apoptotic gene Bcl‐2. A molecular docking study was conducted to confirm the binding affinity of the designed compounds towards VEGFR2 and Topoisomerase II proteins with good binding energy and interactive modes as their co‐crystallized ligands. [ABSTRACT FROM AUTHOR]

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C‐fluorocurine, C‐profluorocurine, C‐mavacurine, normavacurine, 16‐epi‐pleiocarpamine and taberdivarine H. We designed a strategy involving late‐stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2‐indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4‐addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C‐profluorocurine and C‐fluorocurine were finalized by the dihydroxylation of C‐mavacurine and a pinacol rearrangement, respectively. [ABSTRACT FROM AUTHOR]

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C‐fluorocurine, C‐profluorocurine, C‐mavacurine, normavacurine, 16‐epi‐pleiocarpamine and taberdivarine H. We designed a strategy involving late‐stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2‐indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4‐addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C‐profluorocurine and C‐fluorocurine were finalized by the dihydroxylation of C‐mavacurine and a pinacol rearrangement, respectively. [ABSTRACT FROM AUTHOR]

Background: To assess the efficacy and safety of anaplastic lymphoma kinase inhibitors (ALKIs) for the treatment of advanced‐stage ALK rearrangement‐positive non–small cell lung cancer (NSCLC). Methods: We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) that included patients with ALK‐positive NSCLC receiving ALKIs. The outcomes of the study included overall survival (OS), progression‐free survival (PFS), objective response rate (ORR), and treatment‐related adverse events (TRAEs) of grade ≥3. Results: A total of 12 RCTs consisting of 3169 patients with eight treatment options were included in this study. Our results showed that ALKIs have superior efficacy in OS, PFS, and ORR than chemotherapy or crizotinib (first‐generation ALKI). Our study showed that only alectinib has a significant improvement in OS compared to chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.40–0.94). Alectinib appeared to have better OS than crizotinib (HR, 0.66; 95% CI, 0.45–0.95). Ensartinib has a significant PFS advantage over alectinib (HR, 0.62; 95% CI, 0.40–0.96). The surface under the ranking curve indicated that ensartinib (99.0%) was the highest rank regarding PFS. Moreover, both ensartinib and ceritinib showed significantly higher TRAEs of grade ≥3 compared with chemotherapy (risk ratios [RR], 2.74; 95% CI, 1.45–5.18; RR, 1.80; 95% CI, 1.26–2.57, respectively). Conclusions: These results indicated that alectinib could be associated with the best therapeutic efficacy and well‐tolerance AEs in the treatment of ALK‐positive NSCLC. [ABSTRACT FROM AUTHOR]

An inexpensive, simple, and greener catalytic system with lower toxicity using CuFe2O4 nanoparticles in the presence of piperidine and dry toluene as a solvent has been reported for the synthesis of 1,4‐diphenylbutadiyne‐1,3, via C−H activated aerobic Csp−Csp homocoupling. This protocol provides 66 % of yield at the gram‐scale level making it appropriate for production at a larger scale. The catalyst shows reusability for up to five cycles without losing any significant catalytic activity. [ABSTRACT FROM AUTHOR]

Sulfamethazine [N1‐(4,6‐dimethylpyrimidin‐2‐yl)sulfanilamide] is an antimicrobial drug that possesses functional groups capable of acting as hydrogen‐bond donors and acceptors, which make it a suitable supramolecular building block for the formation of cocrystals and salts. We report here the crystal structure and solid‐state characterization of the 1:1 salt piperidinium sulfamethazinate (PPD+·SUL−, C5H12N+·C12H13N4O2S−) (I). The salt was obtained by the solvent‐assisted grinding method and was characterized by IR spectroscopy, powder X‐ray diffraction, solid‐state 13C NMR spectroscopy and thermal analysis [differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)]. Salt I crystallized in the monoclinic space group P21/n and showed a 1:1 stoichiometry revealing proton transfer from SUL to PPD to form salt I. The PPD+ and SUL− ions are connected by N—H+...O and N—H+...N interactions. The self‐assembly of SUL− anions displays the amine–sulfa C(8) motif. The supramolecular architecture of salt I revealed the formation of interconnected supramolecular sheets. [ABSTRACT FROM AUTHOR]

We have developed a sequential hydride shift process involving a [1,8]‐hydride shift. When cinnamylidene malonates having a biphenyl core were treated with 30 mol% Yb(OTf)3 and 10 mol% iPr2NEt, the desired sequential [1,8]‐[1,5]‐hydride shift process proceeded smoothly to afford synthetically challenging nine‐membered carbocycle‐fused piperidine derivatives in good chemical yields (up to 77%). Notably, the desired nine‐membered carbocycles could not be obtained by a single [1,8]‐hydride shift/cyclization process, suggesting that the employment of the sequential system is crucial to achieving the reaction. [ABSTRACT FROM AUTHOR]

Background: To explore the efficacy and prognostic factors of different treatment modalities on anaplastic lymphoma kinase (ALK)+ non‐small cell lung cancer (NSCLC) patients with brain metastases (BMs). Methods: A total of 86 patients were enrolled into the study. They were divided into two cohorts based on their history of treatment with ALK tyrosine kinase inhibitors (ALK‐TKIs) prior to the incidence of BMs. ALK‐TKI‐naïve patients with BMs were included in cohort 1 (n = 59); patients who developed BMs after ALK‐TKIs treatment were enrolled in cohort 2 (n = 27). Prognostic factors related with overall survival (OS) when treated with ALK‐TKIs were assessed in multivariable analysis. Results: With a median follow‐up of 41.8 months, the median OS was 34.8 months. In cohort 1, the OS, intracranial progression‐free survival (iPFS), and progression‐free survival (PFS) were 38.7 months (95% CI: 23.3 to 54.1), 18.5 months (95% CI: 9.6 to 27.4), and 19.1 months (95% CI: 13.7 to 24.5), respectively. Significantly improved OS and iPFS were noted in those patients in which second‐generation ALK‐TKIs versus crizotinib were initiated (OS: not reached vs. 29.0 months, p = 0.040; iPFS: 22.8 vs. 11.9 months, p = 0.035). In cohort 2, patients who experienced BMs as a result of the treatment failure of ALK‐TKIs had a median OS of 27.1 months. Considerable duration of stable disease in patients with measurable BMs was observed (iPFS: 11.5 months, 95% CI: 4.4 to 18.6; PFS: 12.2 months, 95% CI: 3.2 to 21.1). Conclusion: Second‐generation ALK‐TKIs further improved the duration of intracranial response and survival in ALK+ NSCLC patients with BMs in a real‐world setting. The potent intracranial efficacy of second‐generation ALK‐TKIs might generate the lowered urgency of local treatment. [ABSTRACT FROM AUTHOR]

We disclose herein a catalytic borrowing hydrogen method that enables an unprecedented, economical one‐pot access to enantiopure tetrahydropyridines with minimal reagent use or waste formation. This method couples a few classes of readily available substrates with commercially available 1,3‐amino alcohols, and delivers the valuable tetrahydropyridines of different substitution patterns free of N‐protection. Such transformations are highly challenging to achieve, as multiple redox steps need to be realized in a cascade and numerous side reactions including a facile aromatization have to be overcome. Highly diastereoselective functionalizations of tetrahydropyridines also result in a general access to enantiopure di‐ and tri‐substituted piperidines, which ranks the topmost frequent N‐heterocycle in commercial drugs. [ABSTRACT FROM AUTHOR]

We disclose herein a catalytic borrowing hydrogen method that enables an unprecedented, economical one‐pot access to enantiopure tetrahydropyridines with minimal reagent use or waste formation. This method couples a few classes of readily available substrates with commercially available 1,3‐amino alcohols, and delivers the valuable tetrahydropyridines of different substitution patterns free of N‐protection. Such transformations are highly challenging to achieve, as multiple redox steps need to be realized in a cascade and numerous side reactions including a facile aromatization have to be overcome. Highly diastereoselective functionalizations of tetrahydropyridines also result in a general access to enantiopure di‐ and tri‐substituted piperidines, which ranks the topmost frequent N‐heterocycle in commercial drugs. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) commonly occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for treating AUD. Here, we examined the role of 2‐arachidonoylglycerol (2‐AG)‐mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice. We tested the hypothesis that pharmacological augmentation of 2‐AG signaling could reduce hyperalgesia during withdrawal. Methods: Male and female C57BL/6J mice were tested during withdrawal from a continuous access two‐bottle choice (2BC) paradigm to investigate how eCB signaling modulates mechanical and thermal sensitivity during withdrawal. Mice were pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184 to elevate levels of 2‐AG. Rimonabant or AM630 were given to block CB1 and CB2 receptor activity, respectively. DO34 was given to reduce 2‐AG by inhibiting the 2‐AG synthetic enzyme diacylglycerol lipase (DAGL). Results: After 72 h of withdrawal, male and female mice exhibited increased mechanical, but not thermal, hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with JZL184. The effects of JZL184 were prevented by coadministration of either the CB1 or the CB2 antagonist. DO34, Rimonabant, and AM630 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even 1 week into withdrawal. Conclusions: Our findings demonstrate the critical role of 2‐AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2‐AG levels reducing sensitivity, and inhibition of 2‐AG signaling exacerbating sensitivity. These data suggest that 2‐AG augmentation represents a novel approach to the treatment of alcohol withdrawal‐associated hyperalgesia and AUD in patients with comorbid pain disorders. [ABSTRACT FROM AUTHOR]

The first useful enantioselective Pd‐catalyzed asymmetric allylic alkylation of α‐fluoro‐β‐ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α‐fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3‐fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ionophore antibiotics improve the efficiency of energy metabolism, which has driven their use as a feed additive in ruminants for decades. Currently, they have not been approved in many countries, generating a challenge for the immediate search for plant extracts with a similar mode of action on rumen metabolism. This study evaluated the effects of enriched Prosopis juliflora (mesquite) piperidine alkaloid extract (MPA) levels as an alternative phytoadditive to sodium monensin (MON) in sheep. RESULTS: The MPA diet did not differ from MON with regard to nutrient intake. A quadratic effect (P < 0.05) was observed for organic matter and neutral detergent fibre digestibility, with respective maximum point at 25.40 and minimum point at 0.95 mg kg−1 MPA. The MPA levels linearly decreased (P < 0.05) faecal nitrogen loss. MPA did not differ from MON with regard to nutrient digestibility, and MPA levels increased (P < 0.05) the proportion of digestible energy and metabolizability from dietary gross energy. The MPA levels linearly decreased (P < 0.05) enteric CH4 production, the yield showing lower (P < 0.05) energy loss as CH4 than MON. CONCLUSION: The results show that MPA levels of 17.3 and 27.8 mg kg−1 are enteric CH4 inhibitors and enhance energy and protein utilization, indicating a promising alternative to MON for ruminants. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

A catalytic asymmetric vinylogous Mannich/annulation/acylation reaction of 2‐ethylidene 1,3‐indandiones with isatin N‐Boc ketimines has been developed, which furnished a series of chiral spiro‐oxindole piperidine derivatives with polyaromatic scaffolds in 30–67% yield and 93–98% ee. The DFT computational calculation is used to probe and explain the origin of the enantioselectivity and observed formation of O‐acetylated products. [ABSTRACT FROM AUTHOR]

Hitherto unknown bis(β‐oximinoalkyl)malonates were demonstrated to be convenient platforms for the synthesis of saturated N‐heterocycles. Upon heterogeneous catalytic hydrogenation, these dioximes undergo reductive cyclization to give substituted piperidine‐4,4'‐dicarboxylates, which are valuable building blocks in medicinal chemistry. By using dioximes bearing an additional ester group in the side chain, tandem piperidine/pyrrolidinone ring closure leading to indolizidinone framework was showcased in this work. A modular synthesis of initial bis(β‐oximinoalkyl)malonates (both symmetrically and unsymmetrically substituted) was accomplished via a sequential Michael addition of two nitrosoalkene molecules to malonic ester. The mechanism of the reductive cyclization of dioximes to piperidines was investigated by isotope scrambling experiments and isolation of intermediates. [ABSTRACT FROM AUTHOR]

The utility of 2‐diphenylphosphoryloxy‐1,3‐dienes for the construction of substituted six‐membered nitrogen heterocycles is presented. These dienes undergo boron trifluoride‐promoted aza‐Diels–Alder reactions when reacted with imines or related species formed in situ using aldehydes and amine derivatives. The stability of the dienes allows this three‐component reaction to be carried out with no special precautions to eliminate water or air. Thirty‐one examples of this process are presented. The usefulness of the enol phosphate functional group is highlighted in further reactions after the cycloaddition step to generate functionalized piperidenes or pyridines. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral protein tyrosine kinase inhibitor approved for the treatment of rheumatoid arthritis, active psoriatic arthritis and ulcerative colitis. Its efficient production remains a challenge due to the two consecutive stereogenic centers associated to the piperidine ring. In this study, an enzymatic dynamic kinetic resolution‐asymmetric reductive amination was developed to prepare enantiomerically complementary cis‐1‐benzyl‐N,4‐ dimethylpiperidin‐3‐amine and its analogues. Two enantiocomplementary imine reductases (IREDs) were identified for the synthesis of (3R,4R)‐ and (3S,4S)‐1‐benzyl‐N,4‐dimethylpiperidin‐3‐amine in high isolated yields (83% and 91%) with excellent stereoselectivity (97% and >99% ee values) and diastereoselectivity (>99:1 dr), providing a green methodology for the production of the key intermediate of tofacitinib. [ABSTRACT FROM AUTHOR]

Background: The efficacy difference between the second‐ and third‐generation of anaplastic lymphoma kinase‐tyrosine kinase inhibitors (ALK‐TKIs) after crizotinib failure in advanced ALK‐positive non–small cell lung cancer (NSCLC) has not been clarified. This study evaluates the efficacy of different sequential patterns after crizotinib progression. Methods: Data of patients who met the study criteria were retrospectively analyzed. The Kaplan–Meier method was used to draw survival curves, log‐rank method was used to compare the differences between groups, and Cox multivariate analysis was used to evaluate the significance of influencing factors. Results: A total of 128 patients developed disease progression after crizotinib. The overall survival (OS) of 57 patients in the sequential second‐generation ALK‐TKIs group was significantly longer than that of 65 patients with other systemic treatment (58.5 months vs. 33.0 months, p < 0.001); The OS of the direct sequential lorlatinib group was significantly longer than the second‐generation ALK‐TKIs group (114.0 months vs. 58.5 months, p = 0.020). Similarly, of the 48 patients who developed disease progression after first‐ and second‐generation ALK‐TKIs treatment, 16 patients with sequential lorlatinib had significantly longer OS than the others (62.0 months vs. 43.0 months, p = 0.014). The progression‐free survival (PFS) of second‐line and third‐ or later‐line lorlatinib were statistically different (20.0 months vs. 5.5 months, p = 0.011). Conclusions: The application of next‐generation ALK‐TKIs after crizotinib progression significantly prolonged survival, whereas direct sequencing lorlatinib seemed advantageous. Similarly, lorlatinib also prolonged survival in patients with first‐ and second‐generation ALK‐TKIs failure. [ABSTRACT FROM AUTHOR]

Background: Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)‐rearranged non–small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)‐based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies. Methods: A total of 75 eligible patients were enrolled from Sun Yat‐sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis‐free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log‐rank test was performed to describe the difference of BMFS risk. Results: Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C‐index], 0.762; 95% confidence interval [CI], 0.663–0.861) and validation cohort (C‐index, 0.724; 95% CI, 0.601–0.847). Conclusion: We have developed a CT‐based radiomics model to predict subsequent BM in patients with non‐brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM. [ABSTRACT FROM AUTHOR]

A selective Pd‐catalyzed C(3)−H cis‐functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono‐ and cis‐selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other reported heterocycle C(sp3)−H functionalization reactions, which is facilitated by a DoE optimization. A one‐pot C−H functionalization‐epimerization procedure provides the trans‐3,4‐disubstituted isomers directly. Divergent aminoquinoline removal is accomplished with the installation of carboxylic acid, alcohol, amide and nitrile functional groups. Overall, fragment compounds suitable for screening are generated in 3–4 steps from readily‐available heterocyclic carboxylic acids. [ABSTRACT FROM AUTHOR]

Objective: Chronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH–driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. Methods: Potential associations of chronic knee pain with single‐nucleotide polymorphisms (SNPs) in the gene‐encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N‐[1‐(1‐oxopropy)‐4‐piperidinyl]‐N′‐(trifluoromethoxy)phenyl]‐urea (TPPU) on weight‐bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs. Results: In human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9‐DHET and 14,15‐DHET. EET levels were unchanged by TPPU administration. Conclusion: Our novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain. [ABSTRACT FROM AUTHOR]

Background: Dopamine neuron firing in the ventral tegmental area (VTA) and dopamine release in the nucleus accumbens have been implicated in reward learning. Ethanol is known to increase both dopamine neuron firing in the VTA and dopamine levels in the nucleus accumbens. Despite this, some discrepancies exist between the dose of ethanol required to enhance firing in vivo and ex vivo. In the present study we investigated the effects of peripheral dopamine 2 subtype receptor antagonism on ethanol's effects on dopamine neurotransmission. Methods: Plasma catecholamine levels were assessed following ethanol administration across four different doses of EtOH. Microdialysis and voltammetry were used to assess the effects of domperidone pretreatment on ethanol‐mediated increases in dopamine release in the nucleus accumbens. A place conditioning paradigm was used to assess conditioned preference for ethanol and whether domperidone pretreatment altered this preference. Open‐field and loss‐of‐righting reflex paradigms were used to assess the effects of domperidone on ethanol‐induced sedation. A rotarod apparatus was used to assess the effects of domperidone on ethanol‐induced motor impairment. Results: Domperidone attenuated ethanol's enhancement of mesolimbic dopamine release under non‐physiological conditions at intermediate (1.0 and 2.0 g/kg) doses of ethanol. Domperidone also decreased EtOH‐induced sedation at 2.0 g/kg. Domperidone did not alter ethanol conditioned place preference nor did it affect ethanol‐induced motor impairment. Conclusions: These results show that peripheral dopamine 2 receptors mediate some of the effects of ethanol on nonphysiological dopamine neurotransmission, although these effects are not related to the rewarding properties of ethanol. [ABSTRACT FROM AUTHOR]