The Low-Molecular-Weight Ligands of the Gonadotropin Receptors as the New Generation of the Regulators of the Reproductive Functions and Steroidogenesis

In clinic, the luteinizing (LH) and follicle-stimulating (FSH) hormones and human chorionic gonadotropin (hCG) are used to treat reproductive dysfunctions and in assisted reproductive technology. They are the αβ-heterodimeric complexes and specifically bind to ectodomain of G protein-coupled LH and FSH receptors. This leads to activation of many signaling cascades; some of which are responsible for steroidogenesis, folliculogenesis, and spermatogenesis, while the others, such as β-arrestin pathways, trigger the downregulation of gonadotropin receptors. A low selectivity of the intracellular signaling of gonadotropins and a large number of their isoforms are the main causes of undesirable effects of gonadotropins, limiting their clinical applications. Unlike gonadotropins, the low-molecular-weight (LMW) ligands interact with an allosteric site located in the transmembrane domain of the LH and FSH receptors and selectively activate the certain signaling pathway, preventing a number of side effects of gonadotropins. The LMW ligands are characterized by activity of the full and inverse agonists and neutral antagonists, as well as the positive and negative modulators, and they have the in vivo activity, including when administered orally. This review focuses on the advances in the development of LMW allosteric ligands of the LH and FSH receptors and the prospects for their use in reproductive medicine

ПОЗДНЕГОЛОЦЕНОВОЕ ОСАДКОНАКОПЛЕНИЕ В АКТИВНЫХ ГЕОЛОГИЧЕСКИХ СТРУКТУРАХ ЧУКОТСКОГО МОРЯ

The article presents the detailed analysis results considering bottom sediments from the Chukchi Sea. Two core samples, b16 and НС–8 were taken from the northern Herald Canyon 150 km northeast from NE Wrangel Island. Core b16 has been studied in more detail. According to the 210Pb measurements, the recent sedimentation rate amounts to 0.9 mm/y–1 at the sampling point. In the bottom layer of the core sample, the minimum concentrations of biogenic components (SiO2bio, Corg, Ntot, and Br) and the increased concentrations of cold-water diatom species Thalassiosira antarctica may result from low biological productivity during the Maunder Minimum. A correlation with recent global warming (11–22 years) is shown by the increased concentrations of SiO2bio, Corg, Ntot, and Br and the decreased values of magnetic susceptibility and X-ray density in the top layer (1–2 cm) of the same core sample. The results of our geochemical and diatom analysis support the available literature data and confirm that the Late Holocene sedimentation in the Chukchi Sea takes place in the zone wherein the water transits from the Pacific to the Arctic Ocean.Представлены результаты комплексного исследования вещественного состава донных осадков, вскрытых двумя кернами в северной части каньона Геральд Чукотского моря. Одна из полученных колонок была выбрана для более детального исследования. Скорость современного осадконакопления в точке отбора этого керна, измеренная по 210Pb, составляет 0.9 мм/год. Минимальные концентрации биогенных компонентов (SiO2биог., Сорг., Nобщ., Br) и увеличение содержаний холодноводного вида диатомей Thalassiosira antarctica в нижнем слое колонки, вероятно, объясняются низкой биологической продуктивностью во время минимума Маундера. Повышенные концентрации SiO2биог, Сорг, Nобщ, Br, пониженные значения магнитной восприимчивости и рентгеновской плотности в самом верхнем интервале разреза (до 1–2 см) соответствуют последним 11–22 годам глобального потепления климата. Результаты геохимического и диатомового анализов подтверждают имеющиеся в литературе данные о том, что позднеголоценовая седиментация в Чукотском море происходит в зоне транзита тихоокеанских вод в Северный Ледовитый океан

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications

The Chan–Evans–Lam <i>N</i>‑Arylation of 2‑Imidazolines

<i>N</i>-Arylation of 2-imidazolines with arylboronic acids promoted by copper­(II) acetate in DMSO provides an attractive alternative to the earlier reported transition metal-catalyzed approaches employing (hetero)­aryl halides as it taps into the vast reagent space of commercially available boronic acids and proceeds at ambient temperature. Many of the resulting compounds are distinctly lead-like, thus positioning the method developed well within the toolbox of lead-oriented synthesis

Multicomponent Reactions Involving Diazo Reagents: A 5-Year Update

This review summarizes recent developments in multicomponent reactions of diazo compounds. The role of diazo reagent and the type of interaction between components was analyzed to structure the discussion. In contrast to previous reviews on related topics mostly focused on metal catalyzed transformations, a substantial amount of organocatalytic or catalyst-free methodologies is covered in this work

Preparation and Synthetic Applications of Five-to-Seven-Membered Cyclic &alpha;-Diazo Monocarbonyl Compounds

The reactivity of cyclic &alpha;-diazo monocarbonyl compounds differs from that of their acyclic counterparts. In this review, we summarize the current literature available on the synthesis and synthetic applications of three major classes of cyclic &alpha;-diazo monocarbonyl compounds: &alpha;-diazo ketones, &alpha;-diazo lactones and &alpha;-diazo lactams

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

Diazocarbonyl compounds have found numerous applications in many areas of chemistry. Among the most developed fields of diazo chemistry is the preparation of azoles from diazo compounds. This approach represents a useful alternative to more conventional methods of the synthesis of azoles. A comprehensive review on the preparation of various azoles (oxazoles, thiazoles, imidazoles, pyrazoles, triazoles, and tetrazoles) from diazocarbonyl and related compounds is presented for the first time along with discussion of advantages and disadvantages of «diazo» approaches to azoles