Odessa's Intellectuals In the 1920s: the activities of the All-Ukrainian Committee for the Promotion of Scientists

У статті аналізуються усі сфери суспільного життя в Україні у перше десятиліття більшовицького режиму. Досліджується основні напрямків діяльності Всеукраїнського комітету сприяння вченим у 1920 рр. у великому науковому центрі України – Одесі.В статье анализируются все сферы общественной жизни в Украине в первое десятилетие большевистского режима. Исследуется основные направления деятельности Всеукраинского комитета содействия ученым в 1920 в большом научном центре Украины - Одессе.The article analyzes all spheres of public life in Ukraine in the first decade of the Bolshevik regime. The main directions of activity of the All-Ukrainian Committee for the Facilitation of Scientists in 1920 in the large scientific center of Ukraine - Odessa were investigated

2-Substitution of Adenine Nucleotide Analogues Containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation: Enhanced Potency as P2Y 1 Receptor Antagonists

Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of P2Y1 receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829–842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y1 receptor and by using the radiolabeled antagonist [3H]2-chloro-N6-methyl-(N)-methanocarba-2′-deoxyadenosine 3′,5′-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y1 receptor was an (N)-methanocarba N6-methyl-2-iodo analogue 12, which displayed a Ki value in competition for binding of [3H]5 of 0.79 nM and a KB value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y1 receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(1-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y1 receptors. An enzymatic method of synthesis of the 3′,5′-bisphosphate from the corresponding 3′-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored

DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms

Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multidomain protein that includes a Rho GTPase Activating Protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the anti-tumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-δ1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC

Polymorphism in anti-hyperammonemic agent N-carbamoyl-<scp>l</scp>-glutamic acid

Solid form screen of anti-hyperammonemic drug carglumic acid (CGA) resulted in two polymorphs, Form-I and Form-II. The crystal structure of Form-I is sustained by an acid catemer synthon, whereas Form-II has an acid–amide heterosynthon. Slurry grinding, thermal stress, stability measurements, and DVS analysis confirm the thermodynamic stability of Form-I.</p

Tetramorphs of the Antibiotic Drug Trimethoprim: Characterization and Stability

Trimethoprim (TMP) is a well-known antifolate drug and one of the most widely used broad-spectrum antibiotics. TMP was first approved by the United States FDA in combination with sulfamethoxazole (SMZ) in 1973, and three polymorphs of TMP (named Form I, II, and III) and a hydrate form were reported in 1978. However, a complete characterization and molecular level analysis of polymorphic structures are not available. We report herein four polymorphs (Forms 1–4) of TMP and a hemihydrate form with complete structural and thermal characterization. The polymorphs were isolated in the pure state by different techniques such as antisolvent method, freeze-drying, and spray drying. Polymorphs 1 and 2 of our study match with Forms I and II reported, and polymorphs 3 and 4 are novel. The X-ray crystal structure of a novel TMP Form 2 is now reported nearly four decades after the first crystal structure of Form 1 was determined by neutron diffraction (J. Am. Chem. Soc. 1976, 98, 2074−2078). The crystal structure of Form 1 has two types of R₂²(8) motifs, and Form 2 has a third type R₂²(8) and R₃²(8) motif of N–H···N_arom hydrogen bonds. The polymorphs were characterized by FT-IR and Raman spectroscopy, differential scanning calorimetry (DSC), ¹⁵N ss-NMR, field emission scanning electron microscopy, powder X-ray diffraction, and also dynamic vapor sorption. Thermodynamic stability, phase transformations, and Hirshfeld surfaces are also discussed. The polymorphs were tested under accelerated International Conference on Harmonization (ICH) conditions of 40 °C and 75% RH for stability, and found that all the solid forms were stable for three months except TMP Form 3, which converted to Form 2. Slurry grinding and thermal experiments suggest that TMP Form 1 is the most stable modification among TMP crystal forms

Cocrystals of the Tuberculosis Drug Isoniazid: Polymorphism, Isostructurality, and Stability

Isoniazid (INH) is a key drug ingredient in the fixed dose combination for the treatment of tuberculosis (TB). INH is highly soluble in aqueous medium and also stable in pure form, but it undergoes degradation when it is part of the FDC due to cross reactions. In continuation of our studies to improve the physiochemical properties of INH, we performed a cocrystal screen with pharmaceutically acceptable molecules selected from the generally regarded as safe (GRAS). Cocrystals with acidic conformers, such as vanillic acid (VLA), ferulic acid (FRA), caffeic acid (CFA), as well as with hydroxyl coformer resorcinol (RES), are reported. INH–VLA and INH–FRA are dimorphic, and INH–CFA is trimorphic. Form-1 of INH–FRA and INH–VLA are two-dimensional isostructural. All cocrystal structures are sustained by the expected acid–pyridine synthon, except the isostructural cocrystals which have the hydroxyl–pyridine synthon. The cocrystal forms were tested in accelerated ICH conditions of 40 °C and 75% RH for stability, and it was found that all the solid forms are stable for a test period of six months, except the INH–RES cocrystal. Slurry conditions and grinding experiments suggest that Form-2 of INH–FRA and INH–VLA have good stability, and Form-1 of INH–CFA is the most stable crystalline form of INH

High Solubility Crystalline Pharmaceutical Forms of Blonanserin

Blonanserin (BLN) is an antipsychotic drug having poor aqueous solubility. In continuation of our preliminary work (CrystEngComm 2012, 14, 2367−2372), the aim of this study was to improve physicochemical properties of the drug, such as solubility, dissolution rate, and stability. Novel crystalline forms of BLN were obtained by liquid-assisted grinding with pharmaceutically acceptable coformers such as succinic acid (SUC), suberic acid (SBA), nicotinic acid (NIA), methanesulfonic acid (MSA), and toluenesulfonic acid (TsOH). Four salts of blonanerin [BLNH⁺–SUC^– (1:1), BLNH⁺–NIA^– (1:1), BLNH⁺–TsO^– (1:1), and BLNH⁺–MSA^– (1:1)], a salt hydrate BLNH⁺–MSA^––H₂O (1:1:1), and a cocrystal BLN–SBA (1:0.5) are reported in this paper. All multicomponent phases were characterized by IR, Raman, and ¹³C ss-NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and their structures were confirmed by single crystal X-ray diffraction. The crystal structures are sustained by ionic N⁺–H···O^– H-bonds except in the BLN–SBA cocrystal, which has a neutral COOH···N­(tertiary amine) H-bond. These novel salts exhibited a faster intrinsic dissolution rate (IDR) compared to the parent drug BLN, and they exhibited good stability (2 months) under accelerated ICH conditions of 75% RH at 40 °C, except BLN⁺–MSA^– anhydrate. The BLNH⁺–MSA^––H₂O salt hydrate exhibited the highest solubility (464 times) and dissolution rate (126 times) in 60% EtOH–water medium together with good stability