Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage

Khlebnicova, Tatyana S.; Piven, Yu. A.; Baranovsky, A. V.; Лахвич, Ф. А.; Шишкина, Светлана В.; Zicāne, Daina; Tetere, Z.; Ravina, I.; Kumpiņš, Viktors; Rijkure, I.; Mieriņa, Inese; Peipiņš, Uldis; Turks, Māris

doi:10.1016/j.steroids.2016.08.002

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…Positions 3 and 28 of BA skeleton are easily functionalized through esterification reactions and, consequently, many studies involving this transformation have been reported [17,22,27,31,34,35,36,37,38,39,40,41,42,43,44,45,46,47]. The used methodologies involve: (i) The reaction of 17-COOH group of BA 1 with alkyl halides in the presence of a base (mainly, K 2 CO 3 ), or (ii) the reaction of BA-based acyl chloride intermediate with alcohols, or even (iii) the reaction of 3-OH group of BA 1 with acid anhydrides in the presence of a catalyst [usually, 4-(dimethylamino)pyridine (DMAP)] (Scheme 11).…”

Section: Simple Transformationsmentioning

confidence: 99%

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Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

et al. 2019

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Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23-hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA/BN/BoA/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA/HBA derivatives and polymer‒BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others.

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Section: Simple Transformationsmentioning

confidence: 99%

“…Khlebnicova et al synthesized novel BA‒indazolone hybrids 66 with an oxime ester linkage [37]. A series of BoA‒indazolone hybrids 62 were obtained in 33%–83% yield via alcoholysis of the BoA-based acyl chloride intermediate 7 with 6,7-dihydro-1 H -indazol-4(5 H )-one oximes (Scheme 11).…”

Section: Simple Transformationsmentioning

confidence: 99%

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

et al. 2019

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“…BoA has two major functional groups, 3-=O and 28-COOH, which are susceptible to functionalization by transformations such as amination, esterification, sulfonation, hydroxylation, and alkylation. And many of these derivatives ( Figure 1 ) are known to possess various types of biological activities ( Saxena et al, 2006 ; Dangroo et al, 2017 ; Eignerova et al, 2017 ; Gupta et al, 2017 ; Khlebnicova et al, 2017 ; Mzhelskaya et al, 2017 ; Khlebnicova et al, 2019 ; Popov et al, 2019 ; Sousa et al, 2019 ; Hoenke et al, 2020 ; Yang et al, 2020 ). A previous study demonstrated that BoA derivatives with fused azole and triazine displayed impressive cytotoxic activity against several cancer cell lines ( Dinh Ngoc et al, 2014 ; Grishko et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and cytotoxic evaluation of novel betulonic acid-diazine derivatives as potential antitumor agents

Shu

Han

et al. 2022

Front. Chem.

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With the purpose to improve antiproliferative activity, 26 new betulonic acid-diazine derivatives were designed and synthesized from betulinic acid. The anticancer activity of these semi-synthetic compounds was evaluated by MTT assay in both tumor cell lines and normal cell line. The results indicated that majority of new compounds exhibited improved antitumor activity compared with the parent compound betulonic acid. Compound BoA2C, in particular, had the most significant action with IC50 value of 3.39 μM against MCF-7 cells, while it showed lower cytotoxicity on MDCK cell line than cisplatin. Furthermore, we discovered that BoA2C strongly increased MCF-7 cell damage mostly by influencing arginine and fatty acid metabolism. In addition, the structure-activity relationships were briefly discussed. The results of this study suggested that the introduction of different diazines at C-28 could selectively inhibit different kinds of cancer cells and might be an effective way to synthesize potent anticancer lead compound from betulonic acid.

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“…In our continuing search for bioactive hybrid compounds [ 27 - 29 ], we present in the article the synthesis and in vivo investigation of anti-inflammatory and analgesic effects of nine betulinic acid-azaprostanoid hybrids including hybrids with 7-azaprostanoids 1 - 6 and hybrids with 13-azaprostanoids 7 - 9 (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

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

Khlebnicova

Piven

Лахвич

et al. 2020

AIAAMC

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Background: Prevention and treatment of chronic inflammatory diseases requires 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, immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes. Objective: Development of 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 a transformation of betulin via Jones' oxidation into betulonic acid, a reductive amination of the latter and coupling obtained 3β-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 a pain ̶ the acetic acid-induced abdominal writhing and the hot-plate 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 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 agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β-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 measure with the azaprostanoid scaffold, but the last one 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.

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Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage

Cited by 15 publications

References 47 publications

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

Design, synthesis and cytotoxic evaluation of novel betulonic acid-diazine derivatives as potential antitumor agents

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

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