Single- and double-chained truncated jaspine B analogues: asymmetric synthesis, biological evaluation and theoretical study of an unexpected 5-endo-dig process

An optimized synthesis of jaspine B analogues bearing an n-octyl or a p-fluorophenethyl lipophilic appendage was developed. Key to the approach was the use of acetylenic nucleophiles for the stereocontrolled introduction of the side chain and the implementation of a novel cyclization procedure to build the tetrahydrofuran ring. Three N-substituted amine or amide derivatives were also accessed. The biological activity of these four jaspine B analogues was shown to strongly depend on the nature of both the N-substituent and the aliphatic moiety connected to the tetrahydrofuran ring. Gratifyingly, the truncated jaspine B derivative proved to be a pro-apoptotic inhibitor of the conversion of ceramide into sphingomyelin. Finally, the efficient formation of a fused bis-furan derivative according to a 5-endo-dig process was observed under saponification conditions. On the basis of a theoretical study, a mechanistic pathway was delineated highlighting the Lewis acidity of the K⁺ ion as the driving force for this transformation in a strongly alkaline medium.     

Effective Dynamics for a Kinetic Monte–Carlo Model with Slow and Fast Time Scales

We consider several multiscale-in-time kinetic Monte Carlo models, in which some variables evolve on a fast time scale, while the others evolve on a slow time scale. In the first two models we consider, a particle evolves in a one-dimensional potential energy landscape which has some small and some large barriers, the latter dividing the state space into metastable regions. In the limit of infinitely large barriers, we identify the effective dynamics between these macro-states, and prove the convergence of the process towards a kinetic Monte Carlo model. We next consider a third model, which consists of a system of two particles. The state of each particle evolves on a fast time-scale while conserving their respective energy. In addition, the particles can exchange energy on a slow time scale. Considering the energy of the first particle, we identify its effective dynamics in the limit of asymptotically small ratio between the characteristic times of the fast and the slow dynamics. For all models, our results are illustrated by representative numerical simulations.     

Analogues of Miyachi, cowling-price and Morgan theorems for compact extensions of ℝ n

Let K be a compact subgroup of automorphisms of ? ⁿ . We formulate and prove an analogue of Miyachi’s theorem for the semi-direct product K ? ? ⁿ . This allows us to solve the sharpness problems in the theorem of Cowling-Price and in the L ^p ? L ^q analogue of Morgan theorem for any compact extension of ? ⁿ . These upshots are proved using the representations theory and the Plancherel formula for the group Fourier transform.     

Periodicity of pricing and marketing efforts in a distribution channel

Most research about cooperative (coop) advertising programs in channels relies on the assumption that manufacturers and retailers decide of pricing and marketing efforts simultaneously. This paper evaluates this central assumption and investigates the optimal periodicity (sequence of move) of pricing and marketing efforts (ME) decisions for a distribution channel. We develop a game theoretic model that accounts for pricing at each level of the channel, for the manufacturer’s ME mix strategies (a direct ME to consumers and coop advertising program offered to the retailer) and the retailer’s ME as well. We obtain solutions for a bilateral channel under different vertical interaction scenarios; when the channel is led by the manufacturer, the retailer or when channel members decide simultaneously of each of their marketing mix decisions (vertical Nash). We compare the effect of pricing and ME decision periodicity on outputs for each channel member. The main findings suggest that simultaneous decision-making of pricing and ME is optimal only for high enough levels of the manufacturer’s ME effects. For very highly effective marketing efforts, sequential play of pricing and ME allows channel members to implement equilibrium strategies and achieve maximum profits that would not be achieved with simultaneous decision-making. This highlights the importance of relaxing the simultaneous play assumption of pricing and ME in a distribution channel.     

A dynamic model for advertising and pricing competition between national and store brands

We study the relationship between the pricing and advertising decisions in a channel where a national brand is competing with a private label. We consider a differential game that incorporates the carryover effects of brand advertising over time for both the manufacturer and the retailer and we account for the complementary and competitive roles of advertising. Analysis of the obtained equilibrium Markov strategies shows that the relationship between advertising and pricing decisions in the channel depends mainly on the nature of the advertising effects. In particular, the manufacturer reacts to higher competitive retailer’s advertising levels by offering price concessions and limiting his advertising expenditures. The retailer’s optimal reaction to competitive advertising effects in the channel depends on two factors: (1) the price competition level between the store and the national brands and (2) the strength of the competitive advertising effects. For example, in case of intense price competition between the two brands combined with a strong manufacturer’s competitive advertising effect, the retailer should lower both the store and the national brands’ prices as a reaction to higher manufacturer’s advertising levels. For the retailer, the main advantage from boosting his competitive advertising investments seems to be driven by increased revenues from the private label. The retailer should however limit his investments in advertising if the latter generates considerable competitive effects on the national brand’s sales.     

Synthesis and characterization of a tetramethyl furanone functionalized diiminedioxime,a potential ligand for Cu radiopharmaceuticals,and its copper(II) and nickel(II) complexes

As part of our on-going effort to develop ⁶⁴Cu-based radiopharmaceuticals for PET (positron emission tomography) imaging of multidrug resistance in cancer, we prepared a tetramethylfuranone-functionalized diiminedioxime ligand, TMFPreH (TMFPreH = 4-[3-(4-hydroxyimino-2,2,5,5-dimethyl-dihydro-furan-3-ylideneamino)-propylimino]-2,2,5,5-tetramethyl-dihydrofuran-3(2H)-one oxime) and its Cu(II) and Ni(II) complexes. When the copper(II) complex was prepared from Cu(ClO₄)₂ in ethanol, it was isolated as a Cu(II)-bridged dimer, but when it was prepared from Cu(OAc)₂ and heated in acetone, an unusual example of an acetone adduct of the ligand is formed by reduction of one of the imine double bonds by the solvent. The Ni(II) complex is square pyramidal with the perchlorate counterion at the apex.     

A Spectrofluorimetric Sequential Injection Method for the Determination of Penicillamine Using Fluorescamine in the Presence of β-cyclodextrins

A simple, robust and sensitive sequential injection spectrofluorimetric method for the determination of penicillamine (PA) in pharmaceutical formulations is developed. The method is based on the formation of a highly fluorescent derivative when penicillamine is reacted with fluorescamine (FL) in borate buffer of pH 9.3. The derivative produced is monitored at an emission wavelength of 495 nm using an excitation wavelength of 355 nm. The optimum conditions for the determination of PA with FL were: 3 mM FL, pH 9.3, 5 mM methyl-β-cyclodextrin, sample volume of 75 μL and reagent volume of 75 μL. Furthermore, the effect of various media on the fluorescence intensity of the PA–FL derivative was studied and methyl-β-cyclodextrin was found to give the largest enhancement. A linear dynamic range for the determination of PA of 5–80 ppm was obtained with a sampling frequency of 50 h⁻¹ and a relative standard deviation of less than 2.5%. The method was applied to the determination of PA in pharmaceutical formulations with reasonable recoveries ranging from 101.0–103.1%, indicating that no interference is observed from concomitants usually present in dosage forms.     

Synthesis of Silver Nanoparticles from Extracts of Wild Ginger (Zingiber zerumbet) with Antibacterial Activity against Selective Multidrug Resistant Oral Bacteria

Antibiotic resistance rate is rising worldwide. Silver nanoparticles (AgNPs) are potent for fighting antimicrobial resistance (AMR), independently or synergistically. The purpose of this study was to prepare AgNPs using wild ginger extracts and to evaluate the antibacterial efficacy of these AgNPs against multidrug-resistant (MDR) Staphylococcus aureus, Streptococcus mutans, and Enterococcus faecalis. AgNPs were synthesized using wild ginger extracts at room temperature through different parameters for optimization, i.e., pH and variable molar concentration. Synthesis of AgNPs was confirmed by UV/visible spectroscopy and further characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy analysis (EDXA), and Fourier-transform infrared spectroscopy (FTIR). Disc and agar well diffusion techniques were utilized to determine the in vitro antibacterial activity of plant extracts and AgNPs. The surface plasmon resonance peaks in absorption spectra for silver suspension showed the absorption maxima in the range of 400–420 nm. Functional biomolecules such as N–H, C–H, O–H, C–O, and C–O–C were present in Zingiber zerumbet (Z. zerumbet) (aqueous and organic extracts) responsible for the AgNP formation characterized by FTIR. The crystalline structure of ZZAE-AgCl-NPs and ZZEE-AgCl-NPs was displayed in the XRD analysis. SEM analysis revealed the surface morphology. The EDXA analysis also confirmed the element of silver. It was revealed that AgNPs were seemingly spherical in morphology. The biosynthesized AgNPs exhibited complete antibacterial activity against the tested MDR bacterial strains. This study indicates that AgNPs of wild ginger extracts exhibit potent antibacterial activity against MDR bacterial strains.     

Identification of Novel Natural Inhibitors to Human 3-Phosphoglycerate Dehydrogenase (PHGDH) for Cancer Treatment

Targeting the serine biosynthesis pathway enzymes has turned up as a novel strategy for anti-cancer therapeutics. 3- Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme that catalyzes the conversion of 3-Phosphoglyceric acid (3-PG) into 3-Phosphohydroxy pyruvate (3-PPyr) in the first step of serine synthesis pathway and perform a critical role in cancer progression. PHGDH has been reported to be overexpressed in different types of cancers and emerged as a novel target for cancer therapeutics. During this study, virtual screening tools were used for the identification of inhibitors of PHGDH. A library of phenolic compounds was docked against two binding sites of PHGDH using Molegro Virtual Docker (MVD) software. Out of 169 virtually tested compounds, Salvianolic acid C and Schizotenuin F possess good binding potential to co-factor binding site of PHGDH while Salvianolic acid I and Chicoric acid were identified as the best binding compounds toward the substrate binding site of PHGDH. The top selected compounds were evaluated for different physiochemical and ADMET properties, the obtained results showed that none of these hit compounds violated the Pfizer Rule and they possess acceptable ADMET profiles. Further, a commercially available hit compound, Chicoric acid, was evaluated for its anti-cancer potential against PHGDH-expressing gastric cancer cell lines (MGC-803 and SGC-7901) as well as cell lines with low expression of PHGDH (MCF-7 and MDA-MB2-31), which demonstrated that Chicoric acid possesses selective cytotoxicity toward PHGDH expressing cancer cell lines. Thus, this study has unveiled the potential of phenolic compounds, which could serve as novel candidates for the development of PHGDH inhibitors as anti-cancer agents.