Inhibitory effect of 4,4′-dihydroxy-α-truxillic acid derivatives on NO production in lipopolysaccharide-induced RAW 264.7 macrophages and exploration of structure–activity relationships

Liu, Shan Xiang; Jin, Hui; Shan, Lei; Zeng, Hua Wu; Chen, Bing Yang; Sun, Qing Wen; Zhang, Wensheng

doi:10.1016/j.bmcl.2013.01.091

Cited by 18 publications

(16 citation statements)

References 19 publications

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“…>240°C; 1 H NMR (300 MHz, acetone-d 6 ) δ 3.32 (d, J = 9.2 Hz, 2 H), 3.85 (m, 8 H), 4.39 – 4.28 (m, 2 H), 6.72 – 6.86 (m, 4 H), 6.98 (m, 2 H); 13 C NMR (125 MHz, acetone-d 6 ) δ41.29, 46.96, 55.35, 111.59, 114.59, 120.21, 130.98, 145.54, 147.13, 172.56; FIA m/z : calcd for C 20 H 20 O 8 H + , 389.1, found, 389.1. These data are consistent with literature values [42].…”

Section: Methodssupporting

confidence: 94%

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SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins

Elmes

Tong

et al. 2018

European Journal of Medicinal Chemistry

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Fatty acid binding proteins (FABPs) serve as critical modulators of endocannabinoid signaling by facilitating the intracellular transport of anandamide and whose inhibition potentiates anandamide signaling. Our previous work has identified a novel small-molecule FABP inhibitor, α-truxillic acid 1-naphthyl monoester (SB-FI-26, 3) that has shown efficacy as an antinociceptive and anti-inflammatory agent in rodent models. In the present work, we have performed an extensive SAR study on a series of 3-analogs as novel FABP inhibitors based on computer-aided inhibitor drug design and docking analysis, chemical synthesis and biological evaluations. The prediction of binding affinity of these analogs to target FABP3, 5 and 7 isoforms was performed using the AutoDock 4.2 program, using the recently determined co-crystal structures of 3 with FABP5 and FABP7. The compounds with high docking scores were synthesized and evaluated for their activities using a fluorescence displacement assay against FABP3, 5 and 7. During lead optimization, compound 3l emerged as a promising compound with the Ki value of 0.21 μM for FABP 5, 4-fold more potent than 3 (Ki, 0.81 μM). Nine compounds exhibit similar or better binding affinity than 3, including compounds 4b (Ki, 0.55 μM) and 4e (Ki, 0.68 μM). Twelve compounds are selective for FABP5 and 7 with >10 μM Ki values for FABP3, indicating a safe profile to avoid potential cardiotoxicity concerns. Compounds 4f, 4j and 4k showed excellent selectivity for FABP5 and would serve as other new lead compounds. Compound 3a possessed high affinity and high selectivity for FABP7. Compounds with moderate to high affinity for FABP5 displayed antinociceptive effects in mice while compounds with low FABP5 affinity lacked in vivo efficacy. In vivo pain model studies in mice revealed that exceeding hydrophobicity significantly affects the efficacy. Thus, among the compounds with high affinity to FABP5 in vitro, the compounds with moderate hydrophobicity were identified as promising new lead compounds for the next round of optimization, including compounds 4b and 4j. For select cases, computational analysis of the observed SAR, especially the selectivity of new inhibitors to particular FABP isoforms, by comparing docking poses, interaction map, and docking energy scores has provided useful insights.

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Section: Methodssupporting

confidence: 94%

“…127-128°C 1 H NMR (300 MHz, CDCl 3 ) δ0.24 (s, 6 H), 1.00 (s, 9 H), 6.33 (d, J = 15.9 Hz, 1 H), 6.87 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8.6 Hz, 2 H), 7.76 (d, J = 15.9 Hz, 1H); FIA m/z : calcd for C 15 H 22 O 3 SiH + , 279.1, found, 279.1. These data are consistent with literature values [42].…”

Section: Methodssupporting

confidence: 94%

SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins

Elmes

Tong

et al. 2018

European Journal of Medicinal Chemistry

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“…The inflammatory response is an important protective reaction to injury, irritation and infection and is characterised by redness, heat, swelling, loss of function and pain [1]. In the inflammatory state, activated immune cells, such as macrophages secrete large amounts of proinflammatory cytokines, nitric oxide (NO), and prostaglandin E 2 (PGE 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the inflammatory state, activated immune cells, such as macrophages secrete large amounts of proinflammatory cytokines, nitric oxide (NO), and prostaglandin E 2 (PGE 2 ). However, high levels of NO and PGE 2 in a chronic inflammation state can result in various pathological conditions [1-4]. For this reason, regulation of the production of NO and PGE 2 in macrophages are current research topics for the development of new anti-inflammatory agents.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effects of apo-9′-fucoxanthinone from the brown alga, Sargassum muticum

et al. 2013

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BackgroundThe marine environment is a unique source of bioactive natural products, of which Sargassum muticum (Yendo) Fensholt is an important brown algae distributed in Jeju Island, Korea. S. muticum is a traditional Korean food stuff and has pharmacological functions including anti-inflammatory effects. However, the active ingredients from S. muticum have not been characterized.MethodsBioguided fractionation of the ethanolic extract of S. muticum, collected from Jeju island, led to the isolation of a norisoprenoid. Its structure was determined by analysis of the spectroscopic data. In vitro anti-inflammatory activity and mechanisms of action of this compound were examined using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells through ELISA assays and Western blot analysis.ResultsApo-9′-fucoxanthinone, belonging to the norisoprenoid family were identified. Apo-9′-fucoxanthinone effectively suppressed LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. This compound also exerted their anti-inflammatory actions by down-regulating of NF-κB activation via suppression of IκB-α in macrophages.ConclusionsThis is the first report describing effective anti-inflammatory activity for apo-9’-fucoxanthinone′-fucoxanthnone isolated from S. muticum. Apo-9′-fucoxanthinone may be a good candidate for delaying the progression of human inflammatory diseases and warrants further studies.

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“…This simultaneously exposed a key alcohol moiety for further functionalization. Steglich esterification (20) with TBS-protected p-coumaric acid (S8) (21) provided triester 24 (S8, DMAP, DCC, CH2Cl2, 23-40 °C, 20 h, 69%), which, after reduction (LiBH4, Et2O, 23 °C, 3 h, 64%), deprotection (TBAF, THF, 23 °C, 5 min, 90%), and oxidation (SO3•py, Et3N, DMSO/CH2Cl2, 0 °C, 2.5 h, 58%), was converted to the target dialdehyde 25 (9 steps from commercial, 9% overall yield, see Figures S1-S10 for spectra). It is notable that many intermediates en route to dialdehyde 25 (e.g.…”

Section: Introductionmentioning

confidence: 99%

Sporopollenin-inspired design and synthesis of robust materials

Glinkerman

Lin

et al. 2021

Preprint

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Sporopollenin is a mechanically robust and chemically inert biopolymer that constitutes the outer protective exine layer of plant spores and pollen grains. Recent investigation of the molecular structure of pine sporopollenin revealed unique monomeric units and inter-unit linkages distinct from other previously known biopolymers, which could be harnessed for new material design. Here, we report the bioinspired synthesis of a series of sporopollenin analogues. This exercise confirms large portions of the previously proposed pine sporopollenin structural model, while the measured chemical, thermal, and mechanical properties of the synthetic sporopollenins indicate favorable attributes of a new kind of robust material. This study explores a new design framework of robust materials inspired by natural sporopollenins, and provides insights and reagents for future elucidation and engineering of sporopollenin biosynthesis in plants.

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Inhibitory effect of 4,4′-dihydroxy-α-truxillic acid derivatives on NO production in lipopolysaccharide-induced RAW 264.7 macrophages and exploration of structure–activity relationships

Cited by 18 publications

References 19 publications

SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins

SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins

Anti-inflammatory effects of apo-9′-fucoxanthinone from the brown alga, Sargassum muticum

Sporopollenin-inspired design and synthesis of robust materials

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