Aligned carbon nanotube-based electronics on glass wafer.

Carbon nanotubes (CNTs), due to excellent electronic properties, are emerging as a promising semiconductor for diverse electronic applications with superiority over silicon. However, until now, the supposed superiority of CNTs by "head-to-head" comparison within a well-defined voltage range remains unrealized. Here, we report aligned CNT (ACNT)-based electronics on a glass wafer and successfully develop a 250-nm gate length ACNT-based field-effect transistor (FET) with an almost identical transfer curve to a "90-nm" node silicon device, indicating a three- to four-generation superiority. Moreover, a record gate delay of 9.86 ps is achieved by our ring oscillator, which exceeds silicon even at a lower supply voltage. Furthermore, the fabrication of basic logic gates indicates the potential for further digital integrated circuits. All of these results highlight ACNT-based FETs on the glass wafer as an effective solution/platform for further development of CNT-based electronics.

Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin (1, LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1, permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated SNAr macrocyclizations that establish the tricyclic skeleton of 1. Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin (1), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.

Divergent Total Synthesis and Characterization of Maxamycins.

A new streamlined and scaled divergent total synthesis of pocket-modified vancomycin analogs is detailed that provides a common late-stage intermediate [Ψ[C(═S)NH]Tpg4]vancomycin (LLS = 18 steps, 12% overall yield, >5 g prepared) to access both existing and future pocket modifications. Highlights of the approach include an atroposelective synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon (11), a one-pot enzymatic glycosylation for direct conversion to [Ψ[C(═S)NH]Tpg4]vancomycin (12), and new powerful methods for the late-stage conversion of the embedded thioamide to amidine/aminomethylene pocket modifications. Incorporation of two peripheral modifications provides a scalable total synthesis of the maxamycins, all prepared from aglycon 11 without use of protecting groups. Thus, both existing and presently unexplored pocket-modified analogues paired with a range of peripheral modifications are accessible from this common thioamide intermediate. In addition to providing an improved synthesis of the initial member of the maxamycins, this is illustrated herein with the first synthesis and examination of maxamycins that contain the most effective of the pocket modifications (amidine) described to date combined with two additional peripheral modifications. These new amidine-based maxamycins proved to be potent, durable, and efficacious antimicrobial agents that display equipotent activity against vancomycin-sensitive and vancomycin-resistant Gram-positive organisms and act by three independent synergistic mechanisms of action. In the first such study conducted to date, one new maxamycin (21, MX-4) exhibited efficacious in vivo activity against a feared and especially challenging multidrug-resistant (MRSA) and vancomycin-resistant (VRSA) S. aureus bacterial strain (VanA VRS-2) for which vancomycin is inactive.

1,2,3,5-Tetrazines: A General Synthesis, Cycloaddition Scope, and Fundamental Reactivity Patterns.

Despite the explosion of interest in heterocyclic azadienes, 1,2,3,5-tetrazines remain unexplored. Herein, the first general synthesis of this new class of heterocycles is disclosed. Its use in the preparation of a series of derivatives, and the first study of substituent effects on their cycloaddition reactivity, mode, and regioselectivity provide the foundation for future use. Their reactions with amidine, electron-rich, and strained dienophiles reveal unique fundamental reactivity patterns (4,6-dialkyl-1,2,3,5-tetrazines > 4,6-diaryl-1,2,3,5-tetrazines for amidines but slower with strained dienophiles), an exclusive C4/N1 mode of cycloaddition, and dominant alkyl versus aryl control on regioselectivity. An orthogonal reactivity of 1,2,3,5-tetrazines and the well-known isomeric 1,2,4,5-tetrazines is characterized, and detailed kinetic and mechanistic investigations of the remarkably fast reaction of 1,2,3,5-tetrazines with amidines, especially 4,6-dialkyl-1,2,3,5-tetrazines, established the mechanistic origins underlying the reactivity patterns and key features needed for future applications.

Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines.

1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism of the 1,2,3-triazine/1,2,3,5-tetrazine-amidine reaction as well as its intrinsic reactivity remains underexplored. By using 15N-labeling, kinetic investigations, and kinetic isotope effect studies, complemented by extensive computational investigations, we show that this reaction proceeds through an addition/N2 elimination/cyclization pathway, rather than the generally expected concerted or stepwise Diels-Alder/retro Diels-Alder sequence. The rate-limiting step in this transformation is the initial nucleophilic attack of an amidine on azine C4, with a subsequent energetically favored N2 elimination step compared with a disfavored stepwise formation of a Diels-Alder cycloadduct. The proposed reaction mechanism is in agreement with experimental and computational results, which explains the observed reactivity of 1,2,3-triazines and 1,2,3,5-tetrazines with amidines.

Reaction Scope of Methyl 1,2,3-Triazine-5-carboxylate with Amidines and the Impact of C4/C6 Substitution.

A comprehensive study of the reaction scope of methyl 1,2,3-triazine-5-carboxylate (3a) with alkyl and aryl amidines is disclosed, reacting at room temperature at remarkable rates (<5 min, 0.1 M in CH3CN) nearly 10000-fold faster than that of unsubstituted 1,2,3-triazine and providing the product pyrimidines in high yields. C4 Methyl substitution of the 1,2,3-triazine (3b) had little effect on the rate of the reaction, whereas C4/C6 dimethyl substitution (3c) slowed the room-temperature reaction (<24 h, 0.25 M) but displayed an unaltered scope, providing the product pyrimidines in similarly high yields. Measured second-order rate constants of the reaction of 3a-c, the corresponding nitriles 3e and 3f, and 1,2,3-triazine itself (3d) with benzamidine and substituted derivatives quantitated the remarkable reactivity of 3a and 3e, verified the inverse electron demand nature of the reaction (Hammett ρ = -1.50 for substituted amidines, ρ = +7.9 for 5-substituted 1,2,3-triazine), and provided a quantitative measure of the impact of 4-methyl and 4,6-dimethyl substitution on the reactivity of the methyl 1,2,3-triazine-5-carboxylate and 5-cyano-1,2,3-triazine core heterocycles.

The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry.

Covering: 2000 up to 2020This review presents select recent advances in the medicinal chemistry of complex natural products that are prepared by total synthesis. The underlying studies highlight enabling divergent synthetic strategies and methods that permit the systematic medicinal chemistry studies of key analogues bearing deep-seated structural changes not readily accessible by semisynthetic or biosynthetic means. Select and recent examples are detailed where the key structural changes are designed to improve defined properties or to overcome an intrinsic limitation of the natural product itself. In the examples presented, the synthetic efforts provided supernatural products, a term first introduced by our colleague Ryan Shenvi (Synlett, 2016, 27, 1145-1164), with properties superseding the parent natural product. The design principles and approaches for creating the supernatural products are highlighted with an emphasis on the properties addressed that include those that improve activity or potency, increase selectivity, enhance durability, broaden the spectrum of activity, improve chemical or metabolic stability, overcome limiting physical properties, add mechanisms of action, enhance PK properties, overcome drug resistance, and/or improve in vivo efficacy. Some such improvements may be regarded by some as iterative enhancements whereas others, we believe, truly live up to their characterization as supernatural products. Most such efforts are also accompanied by advances in synthetic organic chemistry, inspiring the development of new synthetic methodology and providing supernatural products with improved synthetic accessibility.

Maxamycins: Durable Antibiotics Derived by Rational Redesign of Vancomycin.

Since its discovery, vancomycin has been used in the clinic for >60 years. Because of their durability, vancomycin and related glycopeptides serve as the antibiotics of last resort for the treatment of protracted bacterial infections of resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant (MDR) Streptococcus pneumoniae. After 30 years of use, vancomycin resistance was first observed and is now widespread in enterococci and more recently in S. aureus. The widespread prevalence of vancomycin-resistant enterococci (VRE) and the emergence of vancomycin-resistant S. aureus (VRSA) represent a call to focus on the challenge of resistance, highlight the need for new therapeutics, and provide the inspiration for the design of more durable antibiotics less prone to bacterial resistance than even vancomycin.Herein we summarize progress on efforts to overcome vancomycin resistance, first addressing recovery of its original durable mechanism of action and then introducing additional independent mechanisms of action intended to increase the potency and durability beyond that of vancomycin itself. The knowledge of the origin of vancomycin resistance and an understanding of the molecular basis of the loss of binding affinity between vancomycin and the altered target ligand d-Ala-d-Lac provided the basis for the subtle and rational redesign of the vancomycin binding pocket to remove the destabilizing lone-pair repulsion or reintroduce a lost H-bond while not impeding binding to the unaltered ligand d-Ala-d-Ala. Preparation of the modified glycopeptide core structure was conducted by total synthesis, providing binding pocket-modified vancomycin aglycons with dual d-Ala-d-Ala/d-Lac binding properties that directly address the intrinsic mechanism of resistance to vancomycin. Fully glycosylated pocket-modified vancomycin analogues were generated through a subsequent two-step enzymatic glycosylation, providing a starting point for peripheral modifications used to introduce additional mechanisms of action. A well-established vancosamine N-(4-chlorobiphenyl)methyl (CBP) modification as well as newly discovered C-terminal trimethylammonium cation (C1) or guanidine modifications were introduced, providing two additional synergistic mechanisms of action independent of d-Ala-d-Ala/d-Lac binding. The CBP modification provides an additional stage for inhibition of cell wall synthesis that results from direct competitive inhibition of transglycosylase, whereas the C1/guanidine modification induces bacteria cell permeablization. The synergistic behavior of the three independent mechanisms of action combined in a single molecule provides ultrapotent antibiotics (MIC = 0.01-0.005 µg/mL against VanA VRE). Beyond the remarkable antimicrobial activity, the multiple mechanisms of action suppress the rate at which resistance may be selected, where any single mechanism of action is protected by the action of others. The results detailed herein show that rational targeting of durable vancomycin-derived antibiotics has generated compounds with a "resistance against resistance", provided new candidate antibiotics, and may serve as a generalizable strategy to combat antibacterial resistance.

Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification.

A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against selection or induction of resistance, and introduces a synergistic mechanism of action independent of d-Ala-d-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compounds examined that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive but especially vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of d-Ala-d-Ala/d-Lac binding and display superb antimicrobial potencies (MIC 0.6-0.15 µg/mL, VanA VRE). For the first time, we demonstrate that the synergistic behavior of the peripheral modifications examined requires the presence of both the CBP and guanidine modifications in a single molecule versus their combined use as an equimolar mixture of singly modified compounds. Finally, we show that a prototypical member of the series, G3-CBP-vancomycin (15), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, possesses improved and especially attractive in vivo pharmacokinetic (PK) properties, and displays excellent in vivo efficacy and potency against an especially challenging multidrug-resistant (MRSA) and VanA vancomycin-resistant (VRSA) Staphylococcus aureus bacterial strain.

C1-CBP-vancomycin: Impact of a Vancomycin C-Terminus Trimethylammonium Cation on Pharmacological Properties and Insights into Its Newly Introduced Mechanism of Action.

C1-CBP-vancomycin (3) was examined alongside CBP-vancomycin for susceptibility to acquired resistance upon serial exposure against two vancomycin-resistant enterococci strains where its activity proved more durable and remarkably better than many current therapies. Combined with earlier studies, this observation confirmed an added mechanism of action was introduced by incorporation of the trimethylammonium cation and that C1-CBP-vancomycin exhibits activity against vancomycin-resistant organisms through two synergistic mechanisms of action, both independent of d-Ala-d-Ala/d-Lac binding. New insights into this added mechanism of action, induced cell membrane permeabilization, can be inferred from studies that show added exogenous lipoteichoic acid reduces antimicrobial activity, rescues bacteria cell growth inhibition, and blocks induced cell permeabilization properties of C1-CBP-vancomycin, suggesting a direct binding interaction with embedded teichoic acid is responsible for the added mechanism of action and enhanced antimicrobial activity. Further studies indicate that the trimethylammonium cation does not introduce new liabilities in common pharmacological properties of the analogue and established that 3 is well tolerated in mice, displays substantial PK improvements over both vancomycin and CBP-vancomycin, and exhibits in vivo efficacy against a challenging multidrug-resistant and vancomycin-resistant S. aureus strain that is representative of the resistant pathogens all fear will emerge in the general population.

Total Synthesis and Stereochemical Assignment of Streptide.

Streptide (1) is a peptide-derived macrocyclic natural product that has attracted considerable attention since its discovery in 2015. It contains an unprecedented post-translational modification that intramolecularly links the ß-carbon (C3) of a residue 2 lysine with the C7 of a residue 6 tryptophan, thereby forming a 20-membered cyclic peptide. Herein, we report the first total synthesis of streptide that confirms the regiochemistry of the lysine-tryptophan cross-link and provides an unambiguous assignment of the stereochemistry (3R vs 3S) of the lysine-2 C3 center. Both the 3R and the originally assigned 3S lysine diastereomers were independently prepared by total synthesis, and it is the former, not the latter, that was found to correlate with the natural product. The approach enlists a powerful Pd(0)-mediated indole annulation for the key macrocyclization of the complex core peptide, utilizes an underdeveloped class of hypervalent iodine(III) aryl substrates in a palladium-catalyzed C-H activation/ß-arylation reaction conducted on a lysine derivative, and provides access to material with which the role of streptide and related natural products may be examined.

Synthesis, Characterization, and Cycloaddition Reactivity of a Monocyclic Aromatic 1,2,3,5-Tetrazine.

Herein we disclose the synthesis and full characterization of the first monocyclic aromatic 1,2,3,5-tetrazine, 4,6-diphenyl-1,2,3,5-tetrazine. Initial studies of its cycloaddition reactivity, mode, regioselectivity, and scope illustrate that it participates as the 4π-component of well-behaved inverse electron demand Diels-Alder reactions where it preferentially reacts with electron-rich or strained dienophiles. It was found to exhibit an intrinsic reactivity comparable to that of the isomeric 3,6-diphenyl-1,2,4,5-tetrazine, display a single mode of cycloaddition with reaction only across C4/N1 (no N2/N5 cycloaddition observed), proceed with a predictable regioselectivity (dienophile most electron-rich atom attaches to C4), and manifest additional reactivity complementary to the isomeric 1,2,4,5-tetrazines. It not only exhibits a remarkable cycloaddition reactivity, surprisingly good stability (e.g., stable to chromatography, long-term storage, presence of H2O even as reaction co-solvent), and broad cycloaddition scope, but it also displays powerful orthogonal reactivity with the 1,2,4,5-tetrazines. Whereas the latter reacts at extraordinary cycloaddition rates with strained dienophiles (tetrazine ligation), the new and isomeric 1,2,3,5-tetrazine displays similarly remarkable cycloaddition rates and efficiencies with amidines (1,2,3,5-tetrazine/amidine ligation). The crossover reactivities (1,2,4,5-tetrazines with amidines and 1,2,3,5-tetrazines with strained dienophiles) are sufficiently low to indicate they may be capable of use concurrently without competitive reactions.

Exploration of the site-specific nature and generalizability of a trimethylammonium salt modification on vancomycin: A-ring derivatives.

Vancomycin analogues bearing an A-ring trimethylammonium salt modification were synthesized and their antimicrobial activity against vancomycin-resistant Enterococci (VRE) was evaluated. The modification increased antimicrobial potency and provided the capability to induce bacteria cell membrane permeabilization, but both properties were weaker than that found with our earlier reported similar C-terminus modification. The results provide further insights on the additive effect and generalizability of the structural and site-specific nature of a peripheral quaternary trimethylammonium salt modification of vancomycin.

N-Terminus Alkylation of Vancomycin: Ligand Binding Affinity, Antimicrobial Activity, and Site-Specific Nature of Quaternary Trimethylammonium Salt Modification.

A series of vancomycin derivatives alkylated at the N-terminus amine were synthesized, including those that contain quaternary trimethylammonium salts either directly at the terminal amine site or with an intervening three-carbon spacer. The examination of their properties provides important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogues through an added mechanism of action. The N-terminus modifications disclosed herein were well-tolerated, minimally altering model ligand binding affinities (d-Ala-d-Ala) and antimicrobial activity, but did not induce membrane permeabilization that was observed with a similar C-terminus modification. The results indicate that our earlier observations with the C-terminus modification are sensitive to the site as well as structure of the trimethylammonium salt modification and are not simply the result of nonspecific effects derived from introduction of a cationic charge.

Corona[5]arenes Accessed by a Macrocycle-to-Macrocycle Transformation Route and a One-Pot Three-Component Reaction.

Corona[5]arenes, a novel type of macrocyclic compound that is composed of alternating heteroatoms and para-arylenes, were synthesized efficiently by two distinct methods. In a macrocycle-to-macrocycle transformation approach, S6 -corona[3]arene[3]tetrazine underwent sequential SN Ar reactions with HS-C6 H4 -X-C6 H4 -SH (X=S, CH2 , CMe2 , SO2 , and O) to produce the corresponding corona[3]arene[2]tetrazines. Different corona[3]arene[2]tetrazine compounds were also constructed in a straightforward manner by a one-pot three-component reaction of HS-C6 H4 -X-C6 H4 -SH (X=S, CH2 , CMe2 , SO2 , and O) with diethyl 2,5-dimercaptoterephthalate and 2 equiv of 3,6-dichlorotetrazine under very mild conditions. All corona[5]arenes adopted 1,2,4-alternate conformational structures in the crystalline state yielding similar nearly regular pentagonal cavities. Both the cavity size and the electronic property of the acquired macrocycles were fine-tuned by the nature of the bridging element X.

Combined Effects of Flow Diverting Strategies and Parent Artery Curvature on Aneurysmal Hemodynamics: A CFD Study.

PURPOSE: Flow diverters (FD) are increasingly being considered for treating large or giant wide-neck aneurysms. Clinical outcome is highly variable and depends on the type of aneurysm, the flow diverting device and treatment strategies. The objective of this study was to analyze the effect of different flow diverting strategies together with parent artery curvature variations on altering intra-aneurysmal hemodynamics. METHODS: Four ideal intracranial aneurysm models with different parent artery curvature were constructed. Computational fluid dynamics (CFD) simulations of the hemodynamics before and after applying five types of flow diverting strategies (single FD, single FD with 5% and 10% packing density of coils, two FDs with 25% and 50% overlapping rate) were performed. Changes in pressure, wall shear stress (WSS), relative residence time (RRT), inflow velocity and inflow volume rate were calculated and compared. RESULTS: Each flow diverting strategy resulted in enhancement of RRT and reduction of normalized mean WSS, inflow volume rate and inflow velocity in various levels. Among them, 50% overlapped FD induced most effective hemodynamic changes in RRT and inflow volume rate. The mean pressure only slightly decreased after treatment. Regardless of the kind of implantation of FD, the mean pressure, inflow volume rate and inflow velocity increased and the RRT decreased as the curvature of the parent artery increased. CONCLUSIONS: Of all flow diverting strategies, overlapping FDs induced most favorable hemodynamic changes. Hemodynamics alterations post treatment were substantially influenced by parent artery curvature. Our results indicate the need of an individualized flow diverting strategy that is tailored for a specific aneurysm.