Synthesis of nigranoic acid and manwuweizic acid derivatives as HDAC inhibitors and anti-inflammatory agents

Ni, Dongxuan; Wang, Qi; Li, Yiming; Cui, Yi-Man; Shen, Tian-Ze; Li, Xiao-Li; Sun, Han‐Dong; Zhang, Xing-Jie; Zhang, Ruihan; Xiao, Wei‐Lie

doi:10.1016/j.bioorg.2021.104728

Cited by 8 publications

(4 citation statements)

References 27 publications

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“…An example is the preparation of 1.8 g of E -11 (77% yield, 3:97 Z / E ), precursor to mintlactone; 1.0 mol % catalyst loading sufficed for these gram-scale CM reactions. The catalytic approach can be used for accessing the derived enoic acids, as highlighted by the one-pot transformation of lanosterol acetate to 3- epi -anwuweizic acid (Scheme b), precursor to other bioactive triterpenoids, including manwuweizic acid (see Scheme a). , …”

Section: Resultsmentioning

confidence: 99%

“…Innumerable bioactive natural products contain an α,β-unsaturated carbonyl moiety, and a key subset within this class is composed of Z -trisubstituted α-methyl enoates; examples include the anti-inflammatory agent polycerasoidol, the anticancer agent gambogic acid, the HNE inhibitor nigranoic acid ester, and the HDAC inhibitor manwuweizic acid (Scheme a). Enoates are regularly used in regio-, diastereo-, and/or enantioselective transformations as well .…”

Section: Introductionmentioning

confidence: 99%

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Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis

et al. 2023

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Catalytic cross-metathesis (CM) reactions that can generate trisubstituted alkenes in high stereoisomeric purity are important but remain limited in scope. Here, CM reactions are introduced that generate Z-trisubstituted α-methyl, α,β-unsaturated, alkyl and aryl esters, thiol esters, and acid fluorides. Transformations are promoted by a Mo bis-aryloxide, a monoaryloxide pyrrolide, or a monoaryloxide chloride complex; air-stable and commercially available paraffin tablets containing a Mo complex may also be used. Alkyl, aryl, and silyl carboxylic esters as well as thiol esters and acid fluoride reagents are either purchasable or can be prepared in one step. Products were obtained in 55–95% yield and in 88:12–>98:2 Z/E ratio (typically >95:5). The applicability of the approach is highlighted by a two-step conversion of citronellol to an isomintlactone precursor (1.7 g, 73% yield, and 97:3 Z/E) and a single-step transformation of lanosterol acetate to 3-epi-anwuweizic acid (72% yield and 94:6 Z/E). Included are the outcomes of DFT studies, regarding several initially puzzling catalyst activity trends, providing the following information: (1) it is key that a disubstituted Mo alkylidene, generated by a competing homo-metathesis (HM) pathway, can re-enter the productive CM cycle. (2) Whereas in a CM cycle the formation of a molybdacyclobutane is likely turnover-limiting, the collapse of related metallacycles in a HM cycle is probably rate-determining. It is therefore the relative energy barrier required for these steps that determines whether CM or HM is dominant with a particular complex.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis

et al. 2023

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“…Moreover, one of the reasons for the destruction of tissue structure is the excessive production of inflammatory cytokines ( Zhang et al., 2019 ; Smith et al., 2021 ). HDAC inhibitors vorinostat, butyrate and tubastatin A showed promising therapeutic potential in the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, contact hypersensitivity and inflammatory bowel diseases, due to their ability to regulate inflammatory cells and cytokines through several G protein–coupled receptors (GPCRs) ( Ran and Zhou, 2019 ; Li et al., 2021 ; Ni et al., 2021 ). We found that the mRNA expression levels of TNF-α, IL-1β and IL-6 were significantly increased after 7 days of infection, while the expression of the three inflammatory factors was decreased upon intraocular injection of LBH589.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

Zhang¹,

Li²,

Huang³

et al. 2022

Front. Cell. Infect. Microbiol.

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Ocular toxoplasmosis (OT) is retinochoroiditis caused by Toxoplasma gondii infection, which poses a huge threat to vision. However, most traditional oral drugs for this disease have multiple side effects and have difficulty crossing the blood-retinal barrier, so the new alternative strategy is required to be developed urgently. Histone deacetylases (HDAC) inhibitors, initially applied to cancer, have attracted considerable attention as potential anti-Toxoplasma gondii drugs. Here, the efficacy of a novel HDAC inhibitor, Panobinostat (LBH589), against T. gondii has been investigated. In vitro, LBH589 inhibited the proliferation and activity of T. gondii in a dose-dependent manner with low toxicity to retinal pigment epithelial (RPE) cells. In vivo, optical coherence tomography (OCT) examination and histopathological studies showed that the inflammatory cell infiltration and the damage to retinal architecture were drastically reduced in C57BL/6 mice upon treatment with intravitreal injection of LBH589. Furthermore, we have found the mRNA expression levels of inflammatory cytokines were significantly decreased in LBH589–treated group. Collectively, our study demonstrates that LBH589 holds great promise as a preclinical candidate for control and cure of ocular toxoplasmosis.

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“…Ky-2, a hybrid compound HDACi, downregulates LPS-induced NLRP3, caspase-1 p 20, and IL-1β in THP-1 cells that may regulate M1 macrophage polarization via inhibiting NLRP3 inflammasome activation (Kaneko et al, 2018). In J774A.1 cells, hydroxamic acid derivatives of nigranoic acid and manwuweizic acid moderately enhance HDAC1/2/4/6 inhibition activity, which inhibits IL-1β maturation and caspase-1 cleavage, and Ni et al suggest that the synthesis of HDACi may block NLRP3 inflammasome activation (Ni et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

et al. 2021

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Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI.Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage.Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression.Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.

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Synthesis of nigranoic acid and manwuweizic acid derivatives as HDAC inhibitors and anti-inflammatory agents

Cited by 8 publications

References 27 publications

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis

In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

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