Betulinic Acid-Azaprostanoid Hybrids: Synthesis and Pharmacological Evaluation as Anti-inflammatory Agents.

BACKGROUND: Prevention and treatment of chronic inflammatory diseases require effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes. OBJECTIVE: The study aimed to develop structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids. METHODS: A series of betulinic acid-azaprostanoid hybrids was synthesized. The synthetic pathway included the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 3ß-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of pain - the acetic acid-induced abdominal writhing and the hotplate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U- 87 MG) and non-cancer humane cell lines. RESULTS: In the immunogenic inflammation model, the substances showed a pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All the agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3ß- amino-3-deoxybetulinic acid and doxorubicin. CONCLUSION: The results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some cases with the azaprostanoid scaffold, but the latter makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.

Fluorine-containing lupane triterpenoid acid derivatives: Design, synthesis and biological evaluation as potential anti-inflammatory agents.

A series of novel fluorine-containing lupane triterpenoid acid derivatives with fluoroaromatic amide moieties at the C-28 position (1-8) or with 2-(fluoroacyl)cyclopentane-1,3-dione fragments at the C-3 position (9-18) of lupane skeleton was synthesized. A simple synthesis of novel lupane triterpenoid hybrids with 2-(fluoroacyl)-2-cyclopenten-1-one moieties was developed. An interaction of 2-acyl-3-chlorocyclopent-2-en-1-ones, obtained from corresponding cyclic ß-triketones, with methyl 3-amino-3-deoxybetulinate gave 3ß-isomers (9-13) and 3α-isomers (14-18) of target hybrids, which were isolated as individual compounds. Anti-inflammatory properties of selected synthesized compounds were studied in vivo using the histamine-, concanavalin A- and sheep erythrocytes immunization-induced mouse paw edema models. The antioxidant activity was investigated in vivo on the model of tetracycline-induced hepatitis. Majority of synthesized fluorine-containing lupane triterpenoid acid derivatives exhibited significant anti-inflammatory and antioxidant effects. Among studied compounds, 3ß-hybrid 11 with 2-perfluorobutanoyl-2-cyclopenten-1-one moiety was the most potent bioactive compound.

[Morphometrical evaluation of fetuses and newborns kidneys status developing under maternal iron deficiency anemaia conditions].

OBJECTIVE: Introduction: Kidneys in fetuses and newborns play an important role in the homeostasis regulation and are the most vulnerable to the action of damaging factors from the mother organism, therefore it is important to timely assess their morphofunctional state. The aim: The purpose of the study was to reveal the morphometrical features of fetuses and newborns kidneys from mothers, whose pregnancy was complicated by iron deficiency anemia of varying degrees of severity. PATIENTS AND METHODS: Materials and methods: The material of the study was the tissue of kidneys of mature fetuses and newborns from mothers with physiological pregnancy (28 cases), as well as from mothers whose pregnancy was complicated by iron deficiency anemia of varying degrees of severity (85 cases). Morphometrical examination was performed during which the nephrogenic zone thickness, the specific volumes of renal corpuscles, tubules and stroma were determined. The absolute number of renal corpuscles, the specific volumes of immature and mature renal corpuscles and tubules were counted. RESULTS: Results: Maternal iron deficiency anemia of mild degree of severity in the offspring kidneys leads to an increase of the nephrogenic zone thickness; does not affect the absolute number of renal corpuscles; in fetuses in the cortical layer does not affect the specific volume of renal corpuscles, in the cortical and medullary layers decreases the specific volume of tubules and increases the specific volume of stroma, while in newborns in the cortical layer does not affect the specific volumes of renal corpuscles and tubules, increases the specific volume of stroma, in the medullary layer reduces the specific volume of tubules and increases the specific volume of stroma; increases the specific volumes of immature renal corpuscles, tubules and reduces the specific volumes of mature renal corpuscles, tubules. Maternal iron deficiency anemia of moderate and severe degree of severity in the offspring kidneys leads to an increase of the nephrogenic zone thickness; reduces the absolute number of renal corpuscles; decreases the specific volume of renal corpuscles in the cortical layer, reduces the specific volume of tubules and increases the specific volume of stroma in the cortical and medullary layers; increases the specific volumes of immature renal corpuscles, tubules and decreases the specific volumes of mature renal corpuscles and tubules. CONCLUSION: Conclusions: Quantitative changes of the structural elements in the fetuses and newborns kidneys from mothers with iron deficiency anemia, characterized by a decrease of the parenchymal component with the presence a significant number of immature structures in it and an increase of the stromal component, will lead to kidneys dysfunction in such children.

[Morphological characteristics of kidneys connective tissue of mature fetuses and newborns from mothers, whose pregnancy was complicated by preeclampsia of varying degrees of severity].

OBJECTIVE: Introduction: The kidneys connective tissue condition in the antenatal period affects the formation of tissues and it changes with the development of various general pathological processes in this organ. The aim of the study was to identify the morphological features of kidneys connective tissue of fetuses and newborns from mothers whose pregnancy was complicated by preeclampsia of varying degrees of severity. PATIENTS AND METHODS: Materials and methods: The material of the study was the tissue of kidneys of mature fetuses and newborns from mothers with physiological pregnancy (28 cases), as well as from mothers whose pregnancy was complicated by preeclampsia of varying degrees of severity (78 cases). Immunohistochemical study was performed by an indirect Coons method according to M. Brosman's technique using monoclonal antibodies to collagen type I, III and IV. RESULTS: Results: The kidneys connective tissue of fetuses and newborns developing under the maternal preeclampsia conditions is characterized by the qualitative and quantitative changes that indicate the development of sclerotic processes in this organ, the severity of which increase with the age and with the increase of the maternal preeclampsia severity. Qualitative changes are characterized by an increase of the fibrous component, thickening of the bundles of connective tissue fibers, and a decrease in the distance between them. Quantitative changes are characterized by a pronounced predominance of collagen fibers over elastic fibers, almost total absence in some field of view elastic fibers and the violation of the content of collagen type I, III and IV. CONCLUSION: Conclusion: Maternal preeclampsia underlies the development of qualitative and quantitative changes in kidneys connective tissue of fetuses and newborns, which as a result will lead to disruption of the functions of these organs in such children.