Synthesis of Nucleosides`s Analogues and their Application as Chemotherapeutic Agents

Application of the chemical-enzyme approach which is a combination of chemical synthesis and enzyme reaction has allowed to develop original effective methods of synthesis both new compounds and known nucleoside antibiotics which have been inaccessible earlier. Among them preparations for the treatment of oncohaematological diseases like: Cytarabin, Leukladin (Cladribine), Fludarabel, ara-adenosine (Vidarabine), ara-guanosine and produced from the last by chemical method a new medicine for the treatment of T-cellular lymphomas – Nelarabine. Results on the comparative study of antileukemic activity of purine nucleosides using the model of the lymphoid leukemia L1210 are presented. It is shown that the model of mouse lymphoid leukemia L1210 in vivo is not useful for results extrapolation for human if specific activity of modified nucleoside shows itself in therapy of hair-cellular leucosis (HCL), acute myeloid leukemia (AML) and especially for T-cellular leucosis. From commercially available derivative of 2'-fluoro-arabinofuranose developed an original method for the synthesis of antitumor drug Clofarabine for treatment of acute lymphoblastic leukaemia (ALL) in pediatric patients. Highly effective technology producing pharmaceutical substance Pemetrexed has been developed. At present new chemical-therapeutic agent Pemetrexed, which is structural analog of folic acid containing 7-deasaguanine is introduced into clinic practice. It is first agent specially developed for treatment of malignant pleural mesothelioma. It is worth to note that possibilities of the Pemetrexed’s usage for treatment of other tumor diseases are not exhausted still. It is interesting to develop new method of synthesis of modified pyrimidine nucleoside Azacytidine possesses both cytostatic action and ability to inhibit DNA methyltransferases

ВЛИЯНИЕ ПАРАМЕТРОВ ПОТЕНЦИАЛА СМЕЩЕНИЯ И ОРИЕНТАЦИИ ПОДЛОЖКИ НА ХАРАКТЕРИСТИКИ ОСАЖДАЕМОГО ПОКРЫТИЯ: РОЛЬ РАСПЫЛЕНИЯ

Теоретически исследуется влияние процессов атомного распыления на величину внутренних напряжений и скорость роста покрытия, получаемого методом плазменно-ионного осаждения с использованием импульсного потенциала смещения на подложке и при различных углах падения ионов на осаждаемую поверхность. Формула для расчета внутренних напряжений в осаждаемом покрытии, полученная в рамках модели нелокального термоупругого пика иона с учетом процессов атомного распыления, использовалась для расчета напряжений в покрытиях TiN и CrN, осаждаемых из потоков ионов Ti+ и Cr+, соответственно. Величина напряжений для рассмотренных покрытий коррелирует с модулем упругости материала покрытия. Максимум кривой напряжений уменьшается и смещается в область более высоких потенциалов с ростом угла падения. Такое поведение обусловлено процессом распыления квазистабильных междоузельных дефектов, определяющих уровень напряжений в осаждаемом покрытии. Предложена формула для скорости осаждения покрытия, учитывающая распыление атомов покрытия при произвольных потенциале смещения и угле падения ионов. Показано, что распыление резко снижает скорость осаждения покрытий и делает невозможным осаждение покрытий TiN и CrN в режиме постоянного потенциала при потенциалах на подложке, превышающих 1,7 кВ и 0,7 кВ, соответственно, и при нормальном падении ионов. Распыление оказывает наибольшее влияние на внутреннее напряжение и скорость роста покрытия при осаждении ионов под наклонными углами падения α = 45°...70° . Результаты расчетов сравниваются с имеющимися экспериментальными данными

Синтез фторсодержащих аналогов 5-азацитидина

Synthesis of new 2'(3')-fluorinated analogues of 5-azacitidine has been performed by condensation of silylated 5-azacito-zine with blocked fluorodeoxy pentofuranosides. Deblocking of intermediate nucleosides produced target 2'-desoxy-2'-fluor-5-azacitidine and 3'-desoxy-3'-fluor-5-azacitidine in high yields. Structure of synthesized compounds has been proved by spectral methods.Осуществлен синтез новых 2'(3')-фторсодержащих аналогов 5-азацитидина методом конденсации 4,6- (бис )триметилсилильного производного 5-азацитозина с соответствующими блокированными фторпроизвод-ными сахаров. Деблокирование промежуточных нуклеозидов давало целевые 2'-дезокси-2'-фтор-5-азацитидин и 3'-дезокси-3'-фтор-5-азацитидин с высокими выходами. Структура синтезированных соединений доказана совокупностью спектральных методов исследования

Stabilization of the floating sternocostal segment of the chest with multiple bilateral fractures of the ribs and the manubrium of the sternum

Among patients with floating rib fractures without pneumo- and hemopneumothorax or after their elimination, the most severe disorders of ventilation and circulation occur in patients with multiple bilateral rib fractures and a fracture of the sternum manubrium with the formation of a floating sternocostal segment of the chest. At the same time, the suction aero- and hemodynamic function of the chest is disturbed, there is pressure on the heart and large vessels. As a result, the efficiency of external respiration progressively decreases, the respiratory muscles are exhausted, which requires an urgent transfer to artificial ventilation of the lungs. The article presents a clinical case of successful treatment of such a chest injury using the author’s technique (Patent No. 2621871 of the Russian Federation). The extrathoracic silicone reinforced splint has two horizontal branches that go around the mammary glands. The splint is attached to the floating sternocostal segment with ligatures passed behind the sternum and laterally – to stable sections of the ribs along the posterior axillary line on both sides. The tire reliably holds the sternocostal segment from paradoxical movements. The tire is removed after 3  weeks. By this time, fibrous calluses are formed in places of fractures of bones and cartilage, and the swelling of the chest wall subsides. Superficial bedsores in the places of fixation of the splint are epithelialized under the scab within 7–8 days. The patient was examined a year later, her condition was satisfactory, she had no complaints, there was no chest deformity. The technique is less traumatic, it is indicated for patients with polytrauma and in other cases

СИНТЕЗ 2′-ДЕЗОКСИ-2′-ФТОР-D-АРАБИНОНУКЛЕОЗИДОВ 6-ЗАМЕЩЕННОГО ТИМИНА

New 6-fluorothymine 2′-deoxy-2′-fluoro-D-arabinofuranosyl nucleosides were prepared by the silyl method starting from persilylated 6-fluorothymine and 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide. A mixture of benzoylated N(1)-β- and α-anomeric 6-fluorothymine 2′-fluorodeoxy arabinonucleosides was obtained by refluxing in CHCl3 witha 34  % yield. 6-Substituted (OMe, NH2) thymine 2′-deoxy-2′-fluoro-D-arabinonucleosides were prepared by the treatment of individually protected N(1)-α/β-D-arabinosides with methanolic ammonia. It is shown that mild deprotection of the benzoyl groups of intermediate 6-fluorothymine β-nucleoside using LiOH monohydrate in a mixture of acetonitrile-water resulted in the target nucleoside in good yields (82  %). An approach to the synthesis of 2′-fluoro-6,3′-O-α-D-anhydronucleosides was developed as a result of the intramolecular substitution reaction of the fluorine atom at the C(6)-position of the heterocycle by the C(3′)-hydroxyl group of an intermediate deprotected nucleoside during the removal of the protective groups of 6-fluorothymine N(1)-α-arabinonucleoside under the basic reaction conditions. The structures of all synthesized nucleosides were proved by UV-, NMR-, CD- and mass-spectroscopy.Исследования в области химии фторнуклеозидов являются актуальным направлением современной биоорганической и медицинской химии компонентов нуклеиновых кислот. Настоящая работа посвящена синтезу 2′-дезокси-2′-фтор-D-арабинофуранозил нуклеозидов 6-замещенного тимина с целью изучения их биологической активности. Конвергентный синтез пиримидиновых C(2′)-α/β-фторзамещенных нуклеозидов осуществлен путем конденсации 2,4-бис-О-триметилсилильного производного 6-фтортимина с 3,5-ди-O-бензоил-2-дезокси-2-фтор-α-D-арабино-фуранозил бромидом. Конденсация 1-α-бромсахара и персилильного производного 6-фтортимина при кипячении в хлороформе приводила к образованию смеси блокированных N(1)-α/β-D-нуклеозидов 6-фтортимина, которые выделены колоночной хроматографией на силикагеле с выходом 29 и 5  % соответственно. Стандартная процедура деблокирования индивидуальных бензоилированных α/β-нуклеозидов 6-фтортимина аммиаком в метаноле приводилак замещению атома фтора в 6-положении гетероцикла с образованием 2′-дезокси-2′-фтор-β/α-D-арабинозидов 6-амино- и 6-метокситимина. Показано, что дебензоилирование промежуточного С(2′)-β-арабинозида 6-фтортиминапод действием моногидрата гидроксида лития в смеси ацетонитрил–вода приводило к целевому нуклеозиду с высоким выходом (82  %). Разработан подход к синтезу 2′-фтор-6,3′-O-α-D-ангидронуклеозидов путем реакции внутримолекулярной  циклизации в результате удаления защитных групп бензоильного производного 2′-фтор-α-D-арабинофуранозил-6-фтортимина в основных условиях. Структура синтезированных нуклеозидов установлена на основании данных УФ-, ЯМР-, КД- и масс-спектроскопии

CИНТЕЗ НОВЫХ 6-АЗАПИРИМИДИНОВЫХ 2′(3′)-ФТОРДЕЗОКСИНУКЛЕОЗИДОВ

Fluorinated nucleosides have been shown to possess interesting physicochemical and biological properties. Bioisosteric replacement of a hydroxy group or a hydrogen atom by fluorine atom(s) is a classic approach in medicinal chemistryto improve the pharmacological properties of a biologically active molecule. Essential modifications that led to the discovery of fluorinated nucleosides with biological activity are substitutions at 2′- and 3′-positions deoxy-furanosyl moiety. Novel 6-azathymine 2′(3′)-fluorodeoxy nucleosides have been prepared by the silyl method starting from persilylated 6-azathymine and 1-O-acetyl-2,5-di-O-benzoyl-3-deoxy-3-fluoro-α,β-D-ribofuranose or 3,5-di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabino-furanosyl bromide. Debenzoylation of protected 6-azathymine 2′(3′)-fluorodeoxy nucleosides with methanolic ammonia resulted in the corresponding fluorinated nucleosides in good yields. Along with the main products of the deprotection, their 5′-O-benzoyl derivatives were isolated. Conversion of the 6-azathymine 2′(3′)-fluorodeoxy nucleosides into 5-methyl-6-azacytosine 2′(3′)-fluorodeoxy nucleosides was accomplished via the corresponding 4-thioderivatives. The structures of all synthesized nucleosides were proved by UV-, NMR- and mass-spectroscopy. Novel 6-azapyrimidine 2′(3′)-fluorodeoxy nucleosides are of interest as potential antiviral and anticancer agents.Биоизостерическая замена в молекуле биологически активного соединения – один из подходов, используемых в медицинской химии для создания более эффективных и безопасных лекарств. Введение атома фтора в биологически активные молекулы оказывает существенное влияние на их физико-химические и биологические свойства. Основные модификации, которые привели к обнаружению  фторпроизводных нуклеозидов с биологической активностью, включают замены во 2′- и 3′-положениях дезоксифуранозного цикла. В данной работе исследован подходк синтезу 1-(β-D-рибофуранозил)-6-азатимина и его новых 2′(3′)-фторсодержащих нуклеозидных аналогов путем конденсации 2,4-бис-О-триметилсилильного производного 6-азатимина с 1-О-ацетил-2,3,5-три-О-бензоил-β-D-рибофуранозой, 1-O-ацетил-2,5-ди-O-бензоил-3-дезокси-3-фтор-α,β-D-рибофуранозой или 3,5-ди-O-бензоил-2-дезокси-2-фтор-α-D-арабинофуранозил бромидом и последующим удалением защитных групп промежуточных N(1)-β-нуклеозидов под действием нуклеофильного агента. Наряду с основными продуктами реакции деблокированиявыделены их 5′-О-бензоильные производные. 2′(3′)-Фтордезоксинуклеозидные аналоги 5-метил-6-азацитозина получены прямым превращением 6-азатиминового фрагмента блокированных фтордезоксинуклеозидов в 6-азацитозиновый через соответствующие 4-тиопроизводные. Структура синтезированных нуклеозидов установлена на основании данных УФ-, ЯМР- и масс-спектроскопии. Таким образом, разработаны эффективные методы получения новых 2′(3′)-фторсодержащих нуклеозидных аналогов 6-азатимина и 5-метил-6-азацитозина, которые могут представлять интерес в качестве потенциальных противовирусных или противоопухолевых агентов

Дизайн, синтез и биологические свойства ингибиторов ВСR-ABL тирозинкиназы, применяемых для лечения хронического миелолейкоза

Imatinib, a selective BCR-ABL tyrosine kinase inhibitor has significantly improved efficacy of chronic myelogenous leukemia treatment. This review focuses on discovery and development of imatinib, methods of its synthesis and further structure optimization opportunities.Эффективность лечения хронического миелолейкоза существенно повысилась после введения в клиническую практику иматиниба - селективного ингибитора BCR-ABL тирозинкиназы. Описаны история разработки иматиниба, методы его синтеза и направления дальнейшей оптимизации структуры

Photo- and X-ray induced cytotoxicity of CeF3-YF3-TbF3 Nanoparticle-Polyvinylpyrrolidone -"Radachlorin" composites for combined photodynamic therapy

The Ce0.5Y0.35Tb0.15F3 nanoparticles with a CeF3 hexagonal structure were synthesized using the co-precipitation technique. Сonjugated with Radachlorin using polyvinylpyrrolidone coating as well as without Radachlorin were detecte

Examining immune arms in mice immunized with site-specific influenza virus mutants

Site-specific mutants as candidates for live influenza vaccines were resulted from directly introducing into the genome of the pathogenic influenza virus A/WSN/33 (H1N1) strain ts mutations derived from the genes encoding the polymerase complex proteins from some cold-adapted strains serving as attenuation donor. Here we present the data of a comparative study examining immune system arms in mice immunized intranasally with influenza virus mutants and classical cold-adapted reassortant obtained by crossing cold-adapted strain Donor A/Krasnodar/101/35/59 (H2N2) with strain A/WSN/33 (H1N1) bearing surface antigens (hemagglutinin and neuraminidase) similar to mutants. Immunophenotyping mononuclear leukocytes from immunized mice indicated at moderate suppressive effect after using site-specific mutant and the HA reassortant viruses on some immune cell subsets. All viruses in immunized mice resulted in activation of certain lymphocyte subsets including MHC II-positive cells, CD45+/CD19+ B lymphocytes and natural killer cells (CD16/32+/CD3–). Timescale and magnitude of activation markedly differed for each cell subsets. Mice immunized with mutants M26 and U2 peaked with count of CD16/32+/CD3– expressing cells on day 2 after the second immunization compared with control (p < 0.05) that may suggest about an important role for NK cells in activating immune response. In contrast, no significant changes were observed during the study in percentage of CD4+/CD25+/Fox P3 regulatory T cells, CD4+ T helpers and CD8+ cytotoxic cells, except for a sharply decreased count of activated CD4+/CD25+ cells (4-fold) on day 7 after immunization with mutant virus M26. Moreover, mutants U2 and M26 more moderately increased percentage of TLR2- and TLR4-positive cells. The viruses studied ambiguously affected count of TLR9-expressing cells in immunized animals. All viruses increased phagocytic activity in monocytes, but not neutrophils. Despite the moderate activation of innate and adaptive immunity arms, site-specific mutants more profoundly affected humoral reactions inducing increased antibody titers, so that immunogenicity of mutant viruses was higher than that of the cold-adapted reassortant. Thus, the findings hold a promise of using site-specific mutants as live influenza vaccines

Effects of reproductive technologies and SPF status on some physiological and behavioral characteristics in rats with arterial hypertension (ISIAH strain)

Modern standards of Laboratory Animal Science include working with laboratory animals of high quality, in particular, with specific pathogen free (SPF) mice and rats. On the other hand, assisted reproductive technologies (ART) are widely used in modern medicine for human infertility treatment as well as for genome resource banking. In the present study, a comparison of body weight, blood pressure (BP) and behavior in the «elevated plus maze» (EPM) test was made between three groups of ISIAH (inherited stress induced arterial hypertension) rats: a group of animals that were born and raised in a conventional animal facility and two groups from an SPF animal facility (one with animals born naturally and another with animals resulting from ART). There were no changes in BP between the groups, but the behavior of ISIAH differed depending on rearing conditions. In particular, grooming time, as well as the number of defecations and the number of urinations during the test were decreased in both groups of ISIAH rats born in the SPF animal facility as compared to ISIAH rats born in the conventional animal facility. The behavior of the ISIAH rat offspring resulting from ART was different from that of the naturally born group: the EPM test revealed reduced anxiety in the former. The results of the present study indicate that the rearing conditions as well as reproductive technologies affect some behavioral characteristics in adult ISIAH rats, although they develop arterial hypertension in all the conditions used in this study