New 30-norlupane derivatives through chemical-microbial semi-synthesis of betulinic acid and their neuroprotective effect

Xu, Shaohua; Chen, Hailan; Yang, Zhisheng; Lyu, Liwei; Fan, Yong; Sha, Mei; Zhang, Jian; Xu, Wei; Lin, Yu

doi:10.1016/j.bmcl.2020.127407

Cited by 8 publications

(4 citation statements)

References 26 publications

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“…1 H and 13 C NMR data of new compounds 3 , 5 , 6 , and 9 – 21 are included in Tables – . Known compounds were identified as 3-oxo-7β-hydroxy-lup-20(29)-en- 28-oic acid ( 2 ), 3-oxo-7β,15α-dihydroxy-lup-20(29)-en-28-oic acid ( 4 ), 3-oxo-30- hydroxy-lup-20(29)-en-28-oic acid ( 7 ), 3-oxo-7β,30-dihydroxy-lup-20(29)-en-28-oic acid ( 8 ), and 3,20-dioxo-7β-hydroxy-30-norlupane-28-oic acid ( 22 ), by comparison of spectroscopic data with data reported in the literature.…”

Section: Resultsmentioning

confidence: 99%

Biotransformation of Betulonic Acid by the Fungus Rhizopus arrhizus CGMCC 3.868 and Antineuroinflammatory Activity of the Biotransformation Products

Song

Chu

et al. 2021

J. Nat. Prod.

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Biotransformation of betulonic acid (1) by Rhizopus arrhizus CGMCC 3.868 resulted in the production of 16 new (3, 5, 6, and 9–21) and five known compounds. Structures of the new compounds were established by analysis of spectroscopic data. Hydroxylation, acetylation, oxygenation, glycosylation, and addition reactions involved the C-20–C-29 double bond. Antineuroinflammatory activities of the obtained compounds in NO production were tested in lipopolysaccharides-induced BV-2 cells. Compared with the substrate betulonic acid, biotransformation products 3, 8, 9, 14, and 21 exhibited an improved inhibitory effect, with IC50 values of 10.26, 11.09, 5.38, 1.55, and 4.69 μM, lower than that of the positive control, N G-monomethyl-l-arginine.

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Section: Resultsmentioning

confidence: 99%

Biotransformation of Betulonic Acid by the Fungus Rhizopus arrhizus CGMCC 3.868 and Antineuroinflammatory Activity of the Biotransformation Products

Song

Chu

et al. 2021

J. Nat. Prod.

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“…The latter is a fluorinated analog of the approved anti-malarial drug artesunate ( 33 ), with potentially improved DMPK properties owing to the presence of F at the metabolically prone C-7 carbon. 33 The above results taken together (Schemes 6–8) highlight the broad potentials of chemoenzymatic C–H hydroxylation of natural products 34 as a rich enabling technology to introduce new diversity handles (OH groups), which can be exploited for potentiation of biological activities, unravelling new biological profiles, introduction of fluorine in natural products and even, for chemoproteomic studies.…”

Section: Drug Discovery Approachesmentioning

confidence: 85%

C–H modification of natural products: a minimalist enabling tactic for drug discovery, API processing and bioconjugation

2023

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“…Several preclinical studies have shown that BA is endowed with potent neuroprotective activities by targeting different pathways [3][4][5][6][7][8]. In addition, BA has been widely used to develop novel semi-synthetic derivatives with improved pharmacological attributes [2,9]. We have recently described that some triterpenoid hydroxamate derivatives including betulinic acid hydroxamate (BAH) activate the hypoxia inducing factor (HIF) pathway and therefore represent promising small molecules for the development of new drug candidates against inflammatory diseases [10,11].…”

Section: Introductionmentioning

confidence: 99%

Betulinic Acid Hydroxamate is Neuroprotective and Induces Protein Phosphatase 2A-Dependent HIF-1α Stabilization and Post-transcriptional Dephosphorylation of Prolyl Hydrolase 2

Prados¹,

Correa-Sáez

Unciti-Broceta³

et al. 2021

Neurotherapeutics

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Huntington’s disease (HD) is a neurodegenerative disorder characterized by unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia. The activation of the hypoxic response pathway through the pharmacological inhibition of hypoxia-inducing factor (HIF) prolyl-hydroxylases (PHDs) is a promising approach for neurodegenerative diseases, including HD. Herein, we have studied the mechanism of action of the compound Betulinic acid hydroxamate (BAH), a hypoximimetic derivative of betulinic acid, and its efficacy against striatal neurodegeneration using complementary approaches. Firstly, we showed the molecular mechanisms through which BAH modifies the activity of the PHD2 prolyl hydroxylase, thus directly affecting HIF-1α stability. BAH treatment reduces PHD2 phosphorylation on Ser-125 residue, responsible for the control of its hydrolase activity. HIF activation by BAH is inhibited by okadaic acid and LB-100 indicating that a protein phosphatase 2A (PP2A) is implicated in the mechanism of action of BAH. Furthermore, in striatal cells bearing a mutated form of the huntingtin protein, BAH stabilized HIF-1α protein, induced Vegf and Bnip3 gene expression and protected against mitochondrial toxin-induced cytotoxicity. Pharmacokinetic analyses showed that BAH has a good brain penetrability and experiments performed in a mouse model of striatal neurodegeneration induced by 3-nitropropionic acid showed that BAH improved the clinical symptoms. In addition, BAH also prevented neuronal loss, decreased reactive astrogliosis and microglial activation, inhibited the upregulation of proinflammatory markers, and improved antioxidant defenses in the brain. Taken together, our results show BAH’s ability to activate the PP2A/PHD2/HIF pathway, which may have important implications in the treatment of HD and perhaps other neurodegenerative diseases.

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New 30-norlupane derivatives through chemical-microbial semi-synthesis of betulinic acid and their neuroprotective effect

Cited by 8 publications

References 26 publications

Biotransformation of Betulonic Acid by the Fungus Rhizopus arrhizus CGMCC 3.868 and Antineuroinflammatory Activity of the Biotransformation Products

Biotransformation of Betulonic Acid by the Fungus Rhizopus arrhizus CGMCC 3.868 and Antineuroinflammatory Activity of the Biotransformation Products

C–H modification of natural products: a minimalist enabling tactic for drug discovery, API processing and bioconjugation

Betulinic Acid Hydroxamate is Neuroprotective and Induces Protein Phosphatase 2A-Dependent HIF-1α Stabilization and Post-transcriptional Dephosphorylation of Prolyl Hydrolase 2

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