Review on abyssomicins:Inhibitors of the chorismate pathway and folate biosynthesis

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure–activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure–activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop-o-benzyl-desmethylabyssomicin C constitute promising candidates for such programs

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Spermine in semen of male sea lamprey acts as a sex pheromone.

Semen is fundamental for sexual reproduction. The non-sperm part of ejaculated semen, or seminal plasma, facilitates the delivery of sperm to the eggs. The seminal plasma of some species with internal fertilization contains anti-aphrodisiac molecules that deter promiscuity in post-copulatory females, conferring fitness benefits to the ejaculating male. By contrast, in some taxa with external fertilization such as fish, exposure to semen promotes spawning behaviors. However, no specific compounds in semen have been identified as aphrodisiac pheromones. We sought to identify a pheromone from the milt (fish semen) of sea lamprey (Petromyzon marinus), a jawless fish that spawns in lek-like aggregations in which each spermiating male defends a nest, and ovulatory females move from nest to nest to mate. We postulated that milt compounds signal to ovulatory females the presence of spawning spermiating males. We determined that spermine, an odorous polyamine initially identified from human semen, is indeed a milt pheromone. At concentrations as low as 10-14 molar, spermine stimulated the lamprey olfactory system and attracted ovulatory females but did not attract males or pre-ovulatory females. We found spermine activated a trace amine-associated receptor (TAAR)-like receptor in the lamprey olfactory epithelium. A novel antagonist to that receptor nullified the attraction of ovulatory females to spermine. Our results elucidate a mechanism whereby a seminal plasma pheromone attracts ready-to-mate females and implicates a possible conservation of the olfactory detection of semen from jawless vertebrates to humans. Milt pheromones may also have management implications for sea lamprey populations

In Vitro and In Vivo Activities of PD 0305970 and PD 0326448, New Bacterial Gyrase/Topoisomerase Inhibitors with Potent Antibacterial Activities versus Multidrug-Resistant Gram-Positive and Fastidious Organism Groups

PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (μg/ml) for PD 0305970 capable of inhibiting ≥90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC(90)s were generally twofold higher versus these same organism groups. Comparative quinolone MIC(90) values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD(50)s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD(50)s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD(50) = 3.2 mg/kg) and was 22-fold more potent than levofloxacin

Алгоритм расчета необходимого продовольственного потенциала региона и его реализация

У роботі викладено необхідність розробки стратегії забезпечення населення продовольством на основі аналізу сучасного економічного стану сільськогосподарського виробництва та випуску продукції в регіоні.The need for the strategy of the population provision with food considering modern economic situation with agricultural production is shown. Analysis of food production in the region is conducted

Stereoselective Synthesis of (<i>S</i>)-3-(Methylamino)-3-((<i>R</i>)-pyrrolidin-3-yl)propanenitrile

(<i>S</i>)-3-(Methylamino)-3-((<i>R</i>)-pyrrolidin-3-yl)­propanenitrile (<b>1</b>) is a key intermediate in the preparation of PF-00951966, a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of <b>1</b> in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru­(II) complex to afford β-hydroxy amide <b>11b</b> in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S_N2 substitution reaction with methylamine to provide diamine <b>14</b> with inversion of configuration at the 1′-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REG&gamma; activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REG&gamma; protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM