Synthesis of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines and investigation of their fungistatic activity

A series of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines has been synthesized through oxidation reaction of the corresponding 3,6-disubstituted 1,2,4,5-tetrazines bearing amidine fragments. It is shown that the heterocyclic systems obtained can be modified easily at C(3) position in the reactions with aliphatic alcohols and amines. Also, the reactivity of [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines towards CH-active compounds has been studied. The obtained triazolo[1,5-b]annulated 1,2,4,5-tetrazines proved to be active in micromolar concentrations in vitro against filamentous anthropophilic and zooanthropophilic dermatophyte fungi (Trichophyton, Microsporum and Epidermofiton), which cause skin and its appendages (hair, nails) diseases. © 2022 Korotina et al.; licensee Beilstein-Institut.Ministry of Education and Science of the Russian Federation, Minobrnauka: 075-15-2020-777; Ural Branch, Russian Academy of Sciences, UB RASThis work was supported by the Ministry of Education and Science of the Russian Federation (Agreement No. 075-15-2020-777).Analytical studies were carried out using equipment of the Center for Joint Use “Spectroscopy and Analysis of Organic Compounds”, located in Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences. This work was supported by the Ministry of Education and Science of the Russian Federation (Agreement No. 075-15-2020-777)

Inner Polar Rings and Disks: Observed Properties

A list of galaxies with inner regions revealing polar (or strongly inclined to the main galactic plane) disks and rings is compiled from the literature data. The list contains 47 galaxies of all morphological types, from E to Irr. We consider the statistics of the parameters of polar structures known from observations. The radii of the majority of them do not exceed 1.5 kpc. The polar structures are equally common in barred and unbarred galaxies. At the same time, if a galaxy has a bar (or a triaxial bulge), this leads to the polar disk stabilization - its axis of rotation usually coincides with the major axis of the bar. More than two thirds of all considered galaxies reveal one or another sign of recent interaction or merging. This fact indicates a direct relation between the external environment and the presence of an inner polar structure.Comment: 12 pages, 3 figures, accepted to Astrophysical Bulletin. Minor changes and corrections are still possibl

Image-Subtraction Photometry of the Globular Cluster M3: identification of new double-mode RR Lyrae stars

We have applied the image subtraction method to the M3 dataset previously analyzed by Corwin & Carney (2001; CC01). The new analysis produced light curves and periods for 15 variables, bringing to 222 the total number of RR Lyrae stars in CC01 M3 dataset. We have identified three new candidate double-mode (RRd) variables (V13, V200, and V251) in M3. Of the newly discovered RRd's V13 is unusual in that it has the fundamental as the dominant pulsation mode. Two of the new candidate RRd's (V13 and V200) have period ratios as low as 0.738-0.739. They lie separated from all previously known RRd's in the Petersen diagram, in positions implying a large spread in mass and/or, less likely, in heavy element mass fraction, among the M3 horizontal branch (HB) stars. We explore mass transfer and helium enhancement as possible explanations for the apparent spread in HB masses. We also note that the masses derived from the RRd analyses now favor little mass loss on the red giant branch. V200 has changed its dominant pulsation mode from fundamental to first overtone, while V251 has changed its dominant mode from first overtone to fundamental in the interval 1992 to 1993. Together with M3-V166 this is the first time that RRd variables are observed to switch their dominant pulsation modes while remaining RRd's. The phenomenon is found to occur in a one year time-span thus suggesting that these stars are undergoing a rapid evolutionary phase, and that both redward and blueward evolution may take place among the HB stars in M3. The unusual behavior of the M3 RRd's is discussed and compared to that of the RRd's identified so far in globular clusters and in the field of our and other Local Group galaxies. We find lack of correlation between the presence of RRd variables and any of the cluster structural parameters.Comment: 38 pages, 16 figures, AJ in pres

Eribulin-trastuzumab combination in HER2-positive metastatic breast cancer: updated results from a Russian observational study

Introduction. The standard of 1st line treatment of HER2+ metastatic breast cancer (mBC) is double blockade with trastuzumab and pertuzumab + taxane, 2nd line – Trastuzumab-emtazine. There are no standards for further treatment, as well as the optimal drug sequence. Expansion of the arsenal of therapeutic possibilities and the use of new combinations will certainly improve the results of treatment of this category of patients and increase their life expectancy.Aim. We sought to describe treatment patterns of  eribulin  and clinical outcomes of  metastatic HER2-positive breast cancer treated with eribulin  plus trastuzumab combination in  academic institutions and community oncology practices across the Russian Federation.Materials and methods. Patients treated with eribulin anytime between Jan, 2014 and Sep, 2019 with a diagnosis of MBC were identified by 23 providers from Russia. Providers retrospectively reviewed the health records and abstracted selected data points into an electronic case report form for each eligible patient.Results. 100 HER2-positive pts received eribulin in combination with trastuzumab. Median age was 55 (31–80) yrs and ECOG status 0–3. 67% pts had visceral metastases. Eribulin was administered as 1st and 2nd line to 23 (23%) pts, 3rd line to 31 (31%) pts, 4th line and later to 46 (46%). Median number of cycles was 5 (2–27). ORR was 12%, SD – 72%, SD > 6 months – 23%, PD – 16%. Clinical efficacy rate achieved in 35%. Median PFS was 5.07 months (95% CI 4.021–6.119). According to the ER-status the response to eribulin and trastuzumab was different. ORR was 18.8%, SD 72.9% in pts with ER-positive MBC (n = 48) and 5.8% and 71.2% respectively in ER-negative MBC (n = 52). Median PFS was 6.97 months (95% CI 3.924–10.016) in pts with ER-positive MBC and 4.67 months (95% CI 3.841–5.499) in ER-negative MBC (р = 0.3). The combination was well tolerated: dose reductions were required in 12% pts, withdrawal due to toxicity in 4% pts. The most common type of toxicity was hematological with neutropenia Gr III-IV in 14 (14%) pts. Peripheral neuropathy Gr III was observed in 5 (5%) pts. No cardiotoxicity was detected.Conclusions. This is the real-life data of clinical outcomes for patients receiving eribulin plus trastuzumab for HER2-positive MBC throughout the Russian Federation. Our experience with eribulin plus trastuzumab demonstrates that this combination may be a potential effective treatment option for HER-2 positive MBC patients

The efficacy of the combination of eribulin and trastuzumab in advanced HER2-positive breast cancer: the results of Russian observational study

The article presents the experience of 19 Russian medical institutions on the use of eribulin in combination with trastuzumab in various treatment lines of metastatic HER2+ breast cancer in routine clinical practice. Aim. The main objective of this retrospective observational study was to evaluate the efficacy and tolerability of eribulin and trastuzumab combo in HER2+ breast cancer patients pretreated with anthracyclines and taxanes. The analysis included 60 patients who received at least 2 cycles of eribulin in combination with trastuzumab. 2 patients (3.3%) received treatment as the 1st line, as the 2nd 14 (23.3%), as the 3rd 16 (26.7%), and as the 4th and more 28 (46.7%). Materials and methods. Complete response was achieved in 2 (3.3%) patients, partial response in 9 (15%), stable disease in 33 (55%), stabilization for more than 6 months in 11 (18.3%), disease progression was detected in 16 (26.7%) patients. The objective response rate was 18.3% in the whole group, the clinical benefit rate 36.7%. Results. The objective response rate in the group of the luminal subtype (ER/PR+HER2+) was 26.9%, in HER2-overexpressed subtype (ER-PR-HER2+) 8.8% and 64.7%, respectively, disease progression was recorded 2.3 times more often 35.3% versus 15.5% in the luminal subtype group. The median progression-free survival in patients with HER2+ breast cancer was 4.95 months (95% confidence interval CI 3.048.29 months), in luminal subtype 6.38 months (95% CI 3.338.54 months), in non-luminal 4.44 months (95% CI 2.47.96 months); p=0.306. The treatment was well tolerated, the spectrum of adverse events corresponded to the eribulin toxicity profile. Conclusions. The uniqueness of this study lies in the fact that on a large clinical material from the standpoint of real clinical practice, a very promising treatment regimen that is not used routinely in a number of countries has been studied, its effectiveness and satisfactory tolerance have been confirmed

The structure and evolution of M51-type galaxies

We discuss the integrated kinematic parameters of 20 M51-type binary galaxies. A comparison of the orbital masses of the galaxies with the sum of the individual masses suggests that moderately massive dark halos surround bright spiral galaxies. The relative velocities of the galaxies in binary systems were found to decrease with increasing relative luminosity of the satellite. We obtained evidence that the Tully-Fisher relation for binary members could be flatter than that for local field galaxies. An enhanced star formation rate in the binary members may be responsible for this effect. In most binary systems, the direction of orbital motion of the satellite coincides with the direction of rotation of the main galaxy. Seven candidates for distant M51-type objects were found in the Northern and Southern Hubble Deep Fields. A comparison of this number with the statistics of nearby galaxies provides evidence for the rapid evolution of the space density of M51-type galaxies with redshift Z. We assume that M51-type binary systems could be formed through the capture of a satellite by a massive spiral galaxy. It is also possible that the main galaxy and its satellite in some of the systems have a common cosmological origin.Comment: 8 pages, 4 figures, to be published in Astronomy Letter

Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals

4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 μg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking. © 2022 by the authors.FFSN-2021-0005; Russian Foundation for Basic Research, РФФИ: 20-03-00312; Russian Science Foundation, RSF: 21-13-00390This work was financially supported by the Russian Science Foundation (grant No 21-13-00390 for V.I.S.): the synthesis and analysis of compounds, antimicrobial evaluation, cytotoxicity, analgesic and anti-inflammatory activity, mechanism of analgesia, molecular docking; by the Russian Foundation for Basic Research (grant No 20-03-00312 for Y.V.B.): esterase profile of compounds; antioxidant activity in ABTS and FRAP tests were performed in the frame of IPAC RAS State Targets Project FFSN-2021-0005

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201