lignans and diphenyl

We previously synthesized two retinoid X receptor (RXR) agonists, 4'-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid ethyl ester (4'OHE) and 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid ethyl ester (6OHE), based on the structure of magnaldehyde B, a natural product obtained from Magnolia obovata. 4'OHE and 6OHE exhibited different selectivities for peroxisome proliferator-activated receptor (PPAR)/RXR heterodimers. To examine the regulatory effects of these compounds in adipogenesis, 3T3-L1 mouse preadipocytes were treated with a differentiation cocktail with or without test compounds to induce differentiation, and subsequently treated with test compounds in insulin-containing medium every alternate day. Lipid droplets were stained with Oil Red O to examine lipid accumulation. In addition, adipogenesis-related gene expression was measured using RT-qPCR and immunoblotting. The results showed that a PPARγ agonist, 4'OHE, which exerts agonistic effects on PPARγ and RXRα, enhanced adipogenesis similar to rosiglitazone. However, unlike GW501516, a PPARδ agonist, 6OHE and its hydrolysis product (6OHA), which exert agonistic effects on PPARδ and RXRα, suppressed adipogenesis. In a manner similar to 6OHE and 6OHA, bexarotene, an RXR agonist, suppressed adipocyte differentiation, and its anti-adipogenic effect was reversed by an RXR antagonist. Furthermore, 6OHA and bexarotene inhibited the increase in Pparγ2 and Cebpa mRNA levels 2 days after the induction of differentiation. We demonstrated the adipogenic effect of 4'OHE and anti-adipogenic effects of 6OHE and 6OHA in 3T3-L1 cells. Previously, RXR agonists have been reported to positively regulate the differentiation of mesenchymal stem cells into adipocytes, but our current data showed that they inhibited the differentiation of preadipocytes, at least 3T3-L1 cells, into adipocytes.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Bexarotene; Cell Differentiation; Lignans; Mice; PPAR delta; PPAR gamma; Propionates; Retinoid X Receptors

Obesity is a complex disease defined as an excessive amount of body fat. It is considered a risk factor for several pathologies; therefore, there is an increasing interest in its treatment. Pancreatic lipase (PL) plays a key role in fat digestion, and its inhibition is a preliminary step in the search for anti-obesity agents. For this reason, many natural compounds and their derivatives are studied as new PL inhibitors. This study reports the synthesis of a library of new compounds inspired by two natural neolignans, honokiol (1) and magnolol (2) and bearing amino or nitro groups linked to a biphenyl core. The synthesis of unsymmetrically substituted biphenyls was achieved through an optimisation of the Suzuki-Miyaura cross-coupling reaction followed by the insertion of allyl chains, thus furnishing the O- and/or N-allyl derivatives, and finally, a sigmatropic rearrangement yielding in some cases, the C-allyl analogues. Magnolol, honokiol and the twenty-one synthesised biphenyls were evaluated for their in vitro inhibitory activity toward PL. Three compounds (15b, 16 and 17b) were more effective inhibitors than the natural neolignans (magnolol IC

Topics: Biphenyl Compounds; Lignans

Six new biphenyl-type neolignans (1-6), and eighteen known compounds (7-24) were isolated from the EtOH extract of Magnolia officinalis. Their structures were determined by 1D and 2D NMR, and by HRMS. The anti-tumor activities of the isolated compounds were evaluated on HepG2, HCT-116, H1975 and HUVEC cell lines. Among the isolated compounds, nine compounds (3, 5, 7, 8, 12, 14, 20, 22, and 24) showed moderate cytotoxicities, and compound 23 showed the best cytotoxicity with IC

Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; China; HCT116 Cells; Hep G2 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Magnolia; Molecular Structure; Phytochemicals; Plant Bark

Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Products; Biphenyl Compounds; Cell Line; Dose-Response Relationship, Drug; Heterocyclic Compounds; Lignans; Lipopolysaccharides; Mice; Molecular Structure; Nitric Oxide; Structure-Activity Relationship

Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand-target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.

Topics: Biphenyl Compounds; Crystallography, X-Ray; Dimerization; Drug Discovery; HEK293 Cells; Humans; Ligands; Lignans; Molecular Docking Simulation; PPAR gamma; Protein Binding; Retinoid X Receptor alpha

The cannabinoid CB(2) receptor is known to modulate osteoclast function by poorly understood mechanisms. Here, we report that the natural biphenyl neolignan 4'-O-methylhonokiol (MH) is a CB(2) receptor-selective antiosteoclastogenic lead structure (K(i) < 50 nM). Intriguingly, MH triggers a simultaneous G(i) inverse agonist response and a strong CB(2) receptor-dependent increase in intracellular calcium. The most active inverse agonists from a library of MH derivatives inhibited osteoclastogenesis in RANK ligand-stimulated RAW264.7 cells and primary human macrophages. Moreover, these ligands potently inhibited the osteoclastogenic action of endocannabinoids. Our data show that CB(2) receptor-mediated cAMP formation, but not intracellular calcium, is crucially involved in the regulation of osteoclastogenesis, primarily by inhibiting macrophage chemotaxis and TNF-α expression. MH is an easily accessible CB(2) receptor-selective scaffold that exhibits a novel type of functional heterogeneity.

Topics: Animals; Biphenyl Compounds; Calcium; Cannabinoid Receptor Modulators; Cell Line; Cell Migration Inhibition; Cells, Cultured; Cyclic AMP; Humans; Lignans; Macrophages; Mice; Monocytes; Osteoclasts; Osteogenesis; Plant Extracts; Plants; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

A set of ten derivatives of methylhonokiol, an anti-inflammatory active biphenyl-type neolignan from Magnolia grandiflora, has been evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified prostaglandin H synthase (PGHS)-1 and PGHS-2 enzymes as well as for their 5-lipoxygenase (5-LOX) mediated LTB(4) formation inhibitory activity using an assay with activated human polymorphonuclear leukocytes. The derivatization reactions included methylation, acetylation, hydrogenation, epoxydation and isomerization. Five of the derivatives are new to science. The most active compound against COX-1 and COX-2 was methylhonokiol with IC(50) values of 0.1 microM, whereas the most active compound against LTB(4) formation was (E)-3'-propenyl-5-(2-propenyl)-biphenyl-2,4'-diol with an IC(50) value of 1.0 microM. Structure-activity relationship studies showed that the polarity of the derivatives plays a crucial role in their activity towards COX-1/2 enzyme and 5-LOX mediated LTB(4) formation.

Topics: Arachidonate 5-Lipoxygenase; Biphenyl Compounds; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Leukocytes; Leukotriene B4; Lignans; Magnolia; Prostaglandin-Endoperoxide Synthases; Structure-Activity Relationship

The circular dichroism (CD) is an excellent method for determining the absolute stereochemistry of organic compounds. The CD spectra of four biphenyl compounds were determined by using CD spectrometer, and two pairs of symmetrical CD spectra were obtained. The absolute configuration of biphenyl bond was confirmed by the Cotton effect according to the CD rule. The CD spectrum of compound 3 shows a negative Cotton effect at 256 nm, and a positive Cotton effect at 220 nm, which predicts an S-configuration of biphenyl according to an experimental CD rule. Conversely, the CD spectrum of compound 3' displays a positive Cotton effect at 256 nm, and a negative Cotton effect at 219 nm, which predicts an R-configuration of biphenyl. And the regularity of oxazoline-mediated Ullmann reaction was obtained, too.

Topics: Biphenyl Compounds; Circular Dichroism; Cyclooctanes; Lignans; Polycyclic Compounds; Spectrum Analysis