Evaluation of Antiinflammatory Activity of 4'-О-Methylhonokiol Derivatives in a Neuroinflammation Model

Сивак, К. В.; Stosman, K. I.; Muzhikyan, Arman; Alexandrov, A. G.; Viktorov, N. B.; Vaulina, D. D.; Gomzina, N. A.

doi:10.1134/s1068162019040113

Cited by 2 publications

(3 citation statements)

References 13 publications

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“…In preliminary tests, unlabeled MPbP showed promising anti‐inflammatory activity investigated in an LPS‐induced neuroinflammation model in mice . In particular, histological analysis of brain tissue showed that MPbP administration (5 mg/kg) reduced the number of damaged neurons located in the DG zone of hippocampus.…”

Section: Figurementioning

confidence: 99%

Radiosynthesis of a Novel ¹¹C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

et al. 2020

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Cyclooxygenase type 2 (COX‐2) is an attractive biomarker for the visualization of neuroinflammation processes by positron emission tomography (PET). Neolignan 4’‐O‐methylhonokiol (MH) is known to have high anti‐inflammatory activity and inhibits the expression of COX‐2. We synthesized 4′‐[11C]methoxy‐5‐propyl‐1,1′‐biphenyl‐2‐ol ([11C]MPbP), a compound based on the MH structure and labeled with carbon‐11 (T1/2=20.4 min) and studied its distribution in rats treated with lipopolysaccharide (LPS). It was shown that the new ligand has significant inhibitory activity against COX‐2 (IC50=0.14 μM) and sufficient lipophilicity (logD7.4=2.46±0.12) for penetration the blood brain barrier (BBB). [11C]MPbP was obtained by 11C‐methylation using [11C]CH3I with decay‐corrected radiochemical yield of 20% based on [11C]CH3I with molar activity 10–15 GBq/μmol, high radiochemical purity (> 99%) and low level of chemical impurities (<1 μg/ml). The radioligand did not undergo any noticeable decomposition in human plasma for 40 min. The results of ex vivo biodistribution in rats demonstrated that [11C]MPbP crossed the BBB and the observed radioactivity uptake in brain of rats with LPS‐induced neuroinflammation was 4 times higher than in intact animals. Further studies of compounds with the MH scaffold are planned for their possible application in PET, including in vivo assessment in animal neuroinflammation models.

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Section: Figurementioning

confidence: 99%

Radiosynthesis of a Novel ¹¹C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

et al. 2020

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“…The labeling precursor 15 (4 -hydroxy-2-((1,1-dimethylethyloxycarbonyl)oxy)-5-propyl-1,1biphenyl-2-ol) was obtained from 3 (2-iodo-4-propylphenyl tert-butyl carbonate) in a yield of 44%, and F-IV (4 -(2-fluoroethoxy)-2-hydroxy-5-propyl-1,1 -biphenyl) was obtained from 15 in a yield of 16% according to the previously described procedures [18,35].…”

Section: Synthesis Of Structural Analogs Of Honokiol With a 4 -O-(2-fluoroethyl) Moiety (F-i -F-iv)mentioning

confidence: 99%

“…Tert-butyl 4 -hydroxy-3 -methoxy-5-propyl-1,1 -biphenyl-2-yl carbonate (8): This compound was prepared by the same procedure as described for 5 using 2-iodo-4-propylphenyl tertbutyl carbonate 3 [35] and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. The yield of light-yellow oil was 46%.…”

Section: -(2-fluoroethoxy)-3 -Methoxy-5-propyl-2-hydroxy-11 -Biphenyl (F-iii)mentioning

confidence: 99%

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

et al. 2021

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Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [11C]MPbP (4′-[11C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [18F]F-IV in a rodent model of neuroinflammation. [18F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by 18F-fluoroethylation of the precursor with Boc-protecting group (15) with [18F]2-fluoro-1-bromoethane ([18F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [18F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [11C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [18F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.

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Evaluation of Antiinflammatory Activity of 4'-О-Methylhonokiol Derivatives in a Neuroinflammation Model

Cited by 2 publications

References 13 publications

Radiosynthesis of a Novel ¹¹C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

Radiosynthesis of a Novel ¹¹C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

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Evaluation of Antiinflammatory Activity of 4'-О-Methylhonokiol Derivatives in a Neuroinflammation Model

Cited by 2 publications

References 13 publications

Radiosynthesis of a Novel 11C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

Radiosynthesis of a Novel 11C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

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Radiosynthesis of a Novel ¹¹C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

Radiosynthesis of a Novel ¹¹C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation