RESUMEN
Endolichenic fungi are a rich source of natural products with a wide range of potent bioactivities. Herein, syntheses of the two naturally occurring α-pyrones dothideopyrone E and F are presented. These natural products were isolated from a culture of the endolichenic fungus Dothideomycetes sp. EL003334. The outlined strategy includes a Fu-Suzuki akyl-alkyl cross-coupling, a MacMillan α-oxyamination, and a Sato's pericyclic cascade process to construct the 4-hydroxy-2-pyrone ring system. All the obtained data on the synthesized compounds matched with that of the isolated material.
Asunto(s)
Ascomicetos , Productos Biológicos , Ascomicetos/metabolismo , Pironas/metabolismo , Estructura MolecularRESUMEN
Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV-Vis and LC-MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.
Asunto(s)
Ácidos Docosahexaenoicos , Espectrometría de Masas en Tándem , Cromatografía Liquida , Ácidos Grasos , Estructura MolecularRESUMEN
A stereodivergent strategy has been devised to access the diene motif found in biologically active compounds from the Piperaceae family. Herein the first total syntheses of 2E,4E configured piperchabamide E (2) and its enantiomer (ent-2), as well as 2E,4Z configured scutifoliamide B (3), are narrated. The mainstay in the adopted approach is the gram-scale conversion of quaternized pyridine in a practical three-step sequence to access isomerically pure conjugated bromodiene esters 2E,4E8 and 2E,4Z9 by differential crystallization. Even though the developed oxidation protocol forms the basis of the entailed divergent strategy, the geometrical integrity of the involved bromodiene motive can be controlled by the choice of solvent. Thus, while oxidation of pure bromodienal 2E,4Z7 in methanol yields equal amounts of bromodiene esters 2E,4E8 and 2E,4Z9, only bromodiene ester 2E,4Z10 is formed in isopropanol. Subseqently, capitalizing on a stereoretentive Suzuki cross-coupling and direct amidation of the corresponding esters, the featured natural products can be accessed in five and six steps, respectively. The somewhat surprising (R)-configured amine portion, which has been assigned to piperchabamide E (2), is facilitated by a Curtius rearrangement. Following this, the actual amine portion is shown to be (S)-configured.
Asunto(s)
Productos BiológicosRESUMEN
Cyclooxygenase-2 and several lipoxygenases convert polyunsaturated fatty acids into a large variety of products. During inflammatory processes, these enzymes form several distinct families of specialized pro-resolving lipid mediators possessing potent anti-inflammatory and pro-resolving effects. These mediators have attracted a great interest as leads in drug discovery and have recently been the subject of biosynthetic pathway studies using docosahexaenoic and n-3 docosapentaenoic acid as substrates. Herein we present enzymatic studies with cyclooxygenase-2 and 5-, 12- and 15-lipoxygenase enzymes using 3-oxa n-3 DPA as a synthetic mimic of n-3 docosapentaenoic acid. Structural elucidation based on data from RP-HPLC UV and LC/MS-MS experiments enabled the identification of novel enzymatically formed products. These findings constitute the basis for further biosynthetic studies towards understanding the mechanisms regulating substrate utilization in the biosynthesis of specialized pro-resolving lipid mediators.
Asunto(s)
Araquidonato 12-Lipooxigenasa/metabolismo , Araquidonato 15-Lipooxigenasa/metabolismo , Araquidonato 5-Lipooxigenasa/metabolismo , Ciclooxigenasa 2/metabolismo , Ácidos Grasos Insaturados/metabolismo , Animales , Humanos , Ratones , Glycine max/enzimología , Glycine max/metabolismo , Especificidad por SustratoRESUMEN
The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant up-regulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1n-3 DPA or resolvin (Rv)D5n-3 DPA protected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1n-3 DPA and augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1n-3 DPA and RvD5n-3 DPA decreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil-endothelial interactions under flow: PD1n-3 DPA and RvD5n-3 DPA reduced cell adhesion onto TNF-α-activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut.
Asunto(s)
Colitis/prevención & control , Ácidos Docosahexaenoicos/farmacología , Enfermedades Inflamatorias del Intestino/metabolismo , Intestinos/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Casos y Controles , Colitis/inducido químicamente , Ácidos Docosahexaenoicos/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Mucosa Intestinal/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Mesenterio/irrigación sanguínea , Mesenterio/efectos de los fármacos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Peritonitis/inducido químicamente , Peritonitis/prevención & control , Daño por Reperfusión/prevención & controlRESUMEN
Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca2+- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.
Asunto(s)
Ácidos Docosahexaenoicos/química , Ácidos Grasos Omega-3/química , Ácidos Grasos Insaturados/química , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos Insaturados/uso terapéutico , Aceites de Pescado/química , Aceites de Pescado/metabolismo , Humanos , Activación del Canal Iónico/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/química , Canales de Potasio de Gran Conductancia Activados por el Calcio/química , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismoRESUMEN
Recently, the identity of the marine hydrindane natural product (-)-mucosin was revised to the trans-fused structure 6, thereby providing a biogenetic puzzle that remains to be solved. We are now disseminating some of our insights with regard to the possible machinery delivering the established architecture. Aspects with regard to various modes of cyclization in terms of concerted versus stepwise processes are held up against the enzymatic apparatus known to be working on arachidonic acid (8). To provide a contrast to the tentative polyunsaturated fatty acid biogenesis, the structural pattern featured in (-)-mucosin (6) is compared to some marine hydrinane natural products of professed polyketide descent. Our appraisal points to a different origin and strengthens the hypothesis of a polyunsaturated fatty acids (PUFA) as the progenitor of (-)-mucosin (6).
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Ácido Araquidónico/química , Productos Biológicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Indanos/químicaRESUMEN
The two ar-bisabol sesquiterpenoids (+)-sielboldianin A (1) and (+)-sielboldianin B (2) were isolated from the stem bark of the plant Fraxinus sielboldiana and belong to a medicinally interesting class of natural products used in traditional Chinese medicine. Herein the total synthesis of the proposed structure of (+)-sielboldianin A (1) is reported using an organocatalyzed enantioselective bromolactonization protocol. X-ray analysis of a key intermediate together with specific rotation values and NOESY data of the synthesized product enabled the revision of the absolute configuration of the natural product (+)-sielboldianin A to (7 R,10 R). Studies on the antioxidant effects using two cell-based assays were conducted. These studies revealed that the enantiomer of 1 exhibited antioxidant effects with IC50 values of 18 ± 3 µM in a cellular lipid peroxidation antioxidant activity assay. Moreover, (-)-1 showed strong protective effects against reactive oxygen species in a cell-based antioxidant activity assay (IC50 = 31 ± 5 µM). In addition, the two ar-sesquiterpenoids (-)-boivinianin B and (-)-gossoronol showed no effect in either assay. No cytotoxic activity in the K562 cancer cell line was observed for the three sesquiterpenoids tested (IC50 > 50 µM).
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Productos Biológicos/química , Productos Biológicos/farmacología , Terpenos/química , Terpenos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Línea Celular Tumoral , Células Hep G2 , Humanos , Células K562 , Peroxidación de Lípido/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/metabolismo , EstereoisomerismoRESUMEN
Inflammation and its natural resolution are host-protective responses triggered by infection or injury. The resolution phase of inflammation is regulated by enzymatically produced specialized pro-resolving mediators. We recently identified a new class of peptide-conjugated specialized pro-resolving mediators that carry potent tissue regenerative actions that belong to the protectin family and are coined protectin conjugates in tissue regeneration (PCTR). Herein, with the use of microbial-induced peritonitis in mice and liquid chromatography-tandem mass spectrometry-based lipid mediator metabololipidomics, we found that PCTR1 is temporally regulated during self-resolving infection. When administered at peak of inflammation, PCTR1 enhanced macrophage recruitment and phagocytosis of Escherichia coli, decreased polymorphonuclear leukocyte infiltration, and counter-regulated inflammation-initiating lipid mediators, including prostaglandins. In addition, biologically produced PCTR1 promoted human monocyte and macrophage migration in a dose-dependent manner (0.001 to 10.0 nmol/L). We prepared PCTR1 via organic synthesis and confirmed that synthetic PCTR1 increased macrophage and monocyte migration, enhanced macrophage efferocytosis, and accelerated tissue regeneration in planaria. With human macrophage subsets, PCTR1 levels were significantly higher in M2 macrophages than in M1 phenotype, along with members of the resolvin conjugates in tissue regeneration and maresin conjugate families. In contrast, M1 macrophages gave higher levels of cysteinyl leukotrienes. Together, these results demonstrate that PCTR1 is a potent monocyte/macrophage agonist, regulating key anti-inflammatory and pro-resolving processes during bacterial infection.
Asunto(s)
Infecciones por Escherichia coli/microbiología , Macrófagos/citología , Monocitos/efectos de los fármacos , Fagocitosis/fisiología , Animales , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/farmacología , Escherichia coli/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Masculino , Ratones , Fagocitosis/efectos de los fármacosRESUMEN
Asymmetric bromolactonization reactions of δ-unsaturated carboxylic acids have been investigated in the presence of 10 chiral squaramide hydrogen-bonding organocatalysts. The best catalyst enabled the cyclization of several 5-arylhex-5-enoic acids into the corresponding bromolactones with up to 96% ee and in high to excellent chemical yields. The reported catalysts are prepared in a straightforward manner in two steps from dimethyl squarate. The utility of the developed protocol was demonstrated in highly enantioselective syntheses of the sesquiterpenoids (-)-gossoronol and (-)-boivinianin B. Both natural products were obtained in ≥99% enantiomeric excess.
Asunto(s)
Productos Biológicos/síntesis química , Bromo/química , Lactonas/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Catálisis , Cromatografía Líquida de Alta Presión , Ciclización , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , EstereoisomerismoRESUMEN
Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, 5), we provide direct evidence that the four novel mediators 1-4 are all biosynthesized from the pivotal intermediate 5. The UV and LC/MS-MS results from synthetic 13R-HDPA (5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure 5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in 5. Incubation of 5 with isolated human neutrophils gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1-4.
Asunto(s)
Ácido Eicosapentaenoico/análogos & derivados , Ácidos Grasos Insaturados/síntesis química , Animales , Cromatografía Liquida , Ácidos Docosahexaenoicos , Ácido Eicosapentaenoico/síntesis química , Ácido Eicosapentaenoico/química , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/metabolismo , Humanos , Inflamación/metabolismo , Mediadores de Inflamación , Macrófagos/metabolismo , Estructura Molecular , Neutrófilos/metabolismo , Resonancia Magnética Nuclear Biomolecular , EstereoisomerismoRESUMEN
Three different protocols for the syntheses of hydroxyalkylnitramines are presented and compared. Safety issues regarding the synthesis of nitramines are also discussed.
Asunto(s)
Compuestos de Anilina/síntesis química , Técnicas de Química Sintética , Nitrobencenos/síntesis química , Carbamatos/química , Dióxido de Carbono/química , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Ácido Nítrico/química , Espectrometría de Masa por Ionización de Electrospray , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Transformation of quaternary pyridinium compounds into functionalized conjugated dienes can be adapted to natural product synthesis with great effect. Most conspicuously, the transformation has been employed in the preparation of polyenic structures. However, in a more convoluted application, polycyclic systems have arisen from elaboration of the diene motif. The goal of the present account is to survey the utility of dienals derived from pyridinium salts as the means to establish molecular architecture featured in natural products.
Asunto(s)
Aldehídos/química , Productos Biológicos/química , Polienos/química , Compuestos de Piridinio/química , Estructura MolecularRESUMEN
Lipid mediators have attracted great interest from scientists within the chemical, medicinal, and pharmaceutical research community. One such example is leukotriene B4 which has been the subject of many pharmacological studies. Herein, we report a convergent and stereoselective synthesis of this potent lipid mediator in 5% yield over 10 steps in the longest linear sequence from commercial starting materials. The key steps were a stereocontrolled acetate-aldol reaction with Nagao's chiral auxiliary and a Z-selective Boland reduction. All spectroscopic data were in agreement with those previously reported.
Asunto(s)
Leucotrieno B4/síntesis química , Aldehídos/síntesis química , Aldehídos/química , Alquinos/síntesis química , Alquinos/química , Leucotrieno B4/biosíntesis , Leucotrieno B4/químicaRESUMEN
The n-3 polyunsaturated fatty acids act as substrates during the resolution phase of acute inflammation for the biosynthesis of specialized pro-resolving lipid mediators. One premier example is the C22-dihydroxy-polyunsaturated fatty acid protectin D1 (1). The human 15-lipoxygenase type I, via stereoselective processes and with docosahexaenoic acid as the substrate, enables the formation of this specialized pro-resolving lipid mediator. Herein, based on results from LC/MS-MS metabololipidomics, support is presented for the apprehended biosynthesis of 1 in human macrophages occurring via the intermediate 16S,17S-epoxyprotectin (5). Stereochemically pure 5 was obtained using the Katsuki-Sharpless epoxidation protocol, establishing the chirality at the C16 and C17 atoms, one Z-selective reduction, and E- and Z-stereoselective Wittig reactions. In addition, information on the nonenzymatic aqueous hydrolysis products and the half-life of 16S,17S-epoxyprotectin (5) is presented.
Asunto(s)
Ácidos Docosahexaenoicos/biosíntesis , Macrófagos/metabolismo , Antígenos CD59 , Catálisis , Cromatografía Liquida , Ácidos Docosahexaenoicos/química , Ácidos Grasos Insaturados/metabolismo , Humanos , Inflamación/metabolismo , Estructura Molecular , EstereoisomerismoRESUMEN
The first total synthesis of the lipid mediator MaR1n-3 DPA (5) has been achieved in 12 % overall yield over 11â steps. The stereoselective preparation of 5 was based on a Pd-catalyzed sp(3) -sp(3) Negishi cross-coupling reaction and a stereocontrolled Evans-Nagao acetate aldol reaction. LC-MS/MS results with synthetic material matched the biologically produced 5. This novel lipid mediator displayed potent pro-resolving properties stimulating macrophage efferocytosis of apoptotic neutrophils.
Asunto(s)
Antiinflamatorios/síntesis química , Ácidos Docosahexaenoicos/síntesis química , Antiinflamatorios/farmacología , Catálisis , Ácidos Docosahexaenoicos/farmacología , Humanos , Macrófagos/efectos de los fármacos , EstereoisomerismoRESUMEN
The rates of CH3NHNO2 and (CH3)2NNO2 reaction with OH radicals were determined relative to CH3OCH3 and CH3OH at 298 ± 2 K and 1013 ± 10 hPa in purified air by long path FTIR spectroscopy, and the rate coefficients were determined to be k(OH+CH3NHNO2) = (9.5 ± 1.9) × 10(-13) and k(OH+(CH3)2NNO2) = (3.5 ± 0.7) × 10(-12) (2σ) cm(3) molecule(-1) s(-1). Ozone was found to react very slowly with the two nitramines, k(O3+nitramine) < 10(-21) cm(3) molecule(-1) s(-1). Product formation in the photo-oxidation of CH3NHNO2 and (CH3)2NNO2 was studied by FTIR, PTR-ToF-MS, and quantum chemistry calculations; the major products in the OH-initiated degradation are the corresponding imines, CH2âNH and CH3NâCH2, and N-nitro amides, CHONHNO2 and CHON(CH3)NO2. Atmospheric degradation mechanisms are presented.
Asunto(s)
Compuestos de Anilina/química , Atmósfera/química , Dimetilaminas/química , Radical Hidroxilo/química , Metilaminas/química , Nitrobencenos/química , Teoría Cuántica , Ozono/químicaRESUMEN
The polyunsaturated lipid mediator PD1n-3 DPA (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1n-3 DPA (5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data of its methyl ester 6, confirmed the structure of 5 to be (7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-7,11,13,15,19-pentaenoic acid. The proposed biosynthetic pathway, with the involvement of an epoxide intermediate, was supported by results from trapping experiments. In addition, LC-MS/MS data of the free acid 5, obtained from hydrolysis of the synthetic methyl ester 6, matched data for the endogenously produced biological material. The natural product PD1n-3 DPA (5) demonstrated potent anti-inflammatory properties together with pro-resolving actions stimulating human macrophage phagocytosis and efferocytosis. These results contribute new knowledge on the n-3 DPA structure-function of the growing numbers of specialized pro-resolving lipid mediators and pathways.
Asunto(s)
Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos Insaturados/química , Animales , Antiinflamatorios/química , Cromatografía Liquida , Ácidos Docosahexaenoicos/química , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/química , Ácido Eicosapentaenoico/farmacología , Humanos , Macrófagos/metabolismo , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Protectin D1 (PD1 (3)), a C22-dihydroxylated polyunsaturated fatty acid biosynthesized from all-Z-docosahexaenoic acid, belongs to the new family of endogenous mediators referred to as specialized pro-resolving lipid mediators. PD1 (3) is a natural product that displays potent anti-inflammatory properties together with pro-resolving actions including inhibition of polymorphonuclear leukocyte (PMN) infiltration and promotion of macrophage phagocytosis and efferocytosis. Given its potent endogenous actions, this compound has entered several clinical development programs. Little has been reported on the metabolism of PD1 (3). The synthesis and biological evaluations of the ω-22 monohydroxylated metabolite of PD1 (3), named herein 22-OH-PD1 (6), are presented. LC-MS/MS data of the free acid 6, obtained from hydrolysis of the synthetic methyl ester 7, matched data for the endogenously produced 22-OH-PD1 (6). Compound 6 exhibited potent pro-resolving actions by inhibiting PMN chemotaxis in vivo and in vitro comparable to its precursor PD1 (3) and decreased pro-inflammatory mediator levels in inflammatory exudates. The results reported herein provide new knowledge of the metabolism of the protectin class of specialized pro-resolving mediators.
Asunto(s)
Ácidos Docosahexaenoicos/síntesis química , Ácidos Docosahexaenoicos/farmacología , Antiinflamatorios/farmacología , Quimiotaxis/efectos de los fármacos , Ácidos Docosahexaenoicos/química , Ésteres , Ácidos Grasos Insaturados/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Estructura Molecular , Neutrófilos/efectos de los fármacos , Espectrometría de Masas en TándemRESUMEN
Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.