The GPR40 novel agonist SZZ15-11 improves non-alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet-induced obese mice.

AIM: Non-alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15-11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15-11 in fatty liver treatment. METHODS: In vivo, diet-induced obese (DIO) mice received SZZ15-11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40-knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15-11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells. RESULTS: SZZ15-11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15-11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15-11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibited acetyl-CoA carboxylase activity. Furthermore, SZZ15-11 promotes AMPK activity via [cAMP]i accumulation. CONCLUSION: This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.

The Asymmetric Total Synthesis of (-)-Eurothiocin A and Its Enantiomer.

The first asymmetric total synthesis of (-)-eurothiocin A was achieved in 14 linear steps with 2% overall yield from the commercially available materials. A Sharpless asymmetric dihydroxylation reaction was utilized as the key step to construct the stereogenic center. Additionally, (+)- and (±)-eurothiocin A were also synthesized.

Asymmetric Total Synthesis of Griseofamine B and Its Three Stereoisomers.

The first total synthesis of griseofamine B is described starting from l-4-bromo tryptophan methyl ester hydrochloride via five steps and in 18% overall yield. Its three stereoisomers were also synthesized following the same procedure with the yields of 5%, 19%, and 5%, respectively. In vitro antibacterial activities were also evaluated. All four compounds exhibited less potent activity than griseofamine A.

Circular RNAs acting as ceRNAs mediated by miRNAs may be involved in the synthesis of soybean fatty acids.

Soybean oil is composed of fatty acids and glycerol. The content and composition of fatty acids partly determine the quality of soybean seeds. Circular RNAs (circRNAs) are endogenous non-coding RNAs that competitively bind to microRNAs (miRNAs) through miRNA recognition elements, thereby acting as sponges to regulate the expression of target genes. Although circRNAs have been identified previously in soybean, only their expression has been investigated without exploration of the competitive endogenous RNAs (ceRNAs) network of circRNAs-miRNAs-mRNAs. In this study, circRNAs in immature pods of a low linolenic acid soybean Mutant 72' (MT72) and the wild-type control 'Jinong 18' (JN18) were systematically identified and analyzed at 30 and 40 days after flowering using high-throughput sequencing technology. We identified 6377 circRNAs, of which 114 were differentially expressed. Gene ontology and KEGG pathway analyses of targeted mRNAs in the ceRNAs network indicated that the differentially expressed circRNAs may be involved in fatty acid transport, suggesting that circRNAs may play a post-transcriptional regulatory role in soybean oil synthesis. This study provides a foundation for future exploration of the function of circRNAs in soybean and presents novel insights to guide further studies of plant circRNAs.

Design, synthesis and cytotoxicity of novel hexacyclic saframycin-ecteinascidin analogs.

Two series of novel hexacyclic skeletons and their thirty-four derivatives were prepared from l-tryptophan and l-DOPA. The cytotoxicities of these compounds were tested against four human cancer cell lines HCT-116, HepG2, BGC-823 and A2780. Compounds with the tetrahydro-ß-carboline moiety in the left-half of the hexacyclic skeleton showed more potent cytotoxicity with IC50 values in the range of 10-7-10-9 M. Compound 20 with the 4-methoxybenzamide side chain showed potent cytotoxicity towards HepG2 with an IC50 value of 1.32 nM. Compounds 29 and 30 with 2-pyridine amide and (2E)-3-(3-thifluoromethyl-phenyl)acrylic amide side chains showed selective cytotoxicity towards A2780 with IC50 values of 1.73 nM and 7 nM, respectively.

Synthesis and cytotoxicity of (-)-homo-renieramycin G and its derivatives.

(-)-Homo-renieramycin G and its twenty derivatives were prepared from l-tyrosine methyl ester via a multi-step route. Their cytotoxicities were tested against four human cancer cell lines (A549, HeLa, KB and BGC-823). (-)-Renieramycin G and (-)-homo-renieramycin G showed comparable cytotoxicity against these four cancer cell lines, which indicated that the expansion of ring C from the six-membered 1,4-piperazinone to the seven-membered 1,4-diazepanone had no obvious impact on the cytotoxicity. Compound 42 with methyl side chain and compounds 38-41 with heterocyclic aromatic side chains at C-23 exhibited the most potent cytotoxicity with the IC50 values at the level of 10-6 M.

A novel specific peroxisome proliferator-activated receptor γ (PPARγ) modulator YR4-42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet-induced obese mice.

AIMS: To evaluate a novel tetrahydroisoquinoline derivative YR4-42 as a selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti-diabetic effects in vitro and in vivo. MATERIALS AND METHODS: Using two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ binding affinity and transactivation action of YR4-42 were evaluated using biochemical and cell-based reporter gene assays. The capacity of YR4-42 to recruit coactivators of PPARγ was also assessed. The effects of YR4-42 on adipogenesis and glucose consumption and PPARγ Ser273 phosphorylation were investigated in 3T3-L1 adipocytes. The effects of YR4-42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high-fat diet-induced obese (DIO) C57BL/6J mice. The expression of PPARγ target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo. RESULTS: In vitro biochemical and cell-based functional assays showed that YR4-42 has much weaker binding affinity, transactivation, and recruitment to PPARγ of the coactivators thyroid hormone receptor-associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1-α (PGC1α) compared to full agonists. In 3 T3-L1 adipocytes, YR4-42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α-mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ Ser273 phosphorylation-dependent genes. Furthermore, in DIO mice, oral administration of YR4-42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4-42 also improved hyperlipidaemia-associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4-42 appeared to selectively modulate PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4-42 selectively targets PPARγ-regulated genes mapped to glucose and lipid metabolism in DIO mice. CONCLUSIONS: We conclude that YR4-42 is a novel anti-diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4-42 should be further investigated in preclinical and clinical studies.

Synthesis and cytotoxicity of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A.

A series of novel imidazo[4,5-d]azepine compounds derived from marine natural product ceratamine A were designed and synthesized in 7 steps. Most compounds exhibited comparable cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780) to natural product ceratamine A. Compound 1k, bearing methoxy group at C-14, C-15 and C-16, showed the best in vitro cytotoxicity, which was better than ceratamine A. The structure and activity relationships study showed that the benzyloxymethyl group on N-3 played an important role on the cytotoxicity.

Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings.

A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different ß-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 µM, cLogP = 1.3; TAK-875: EC50 = 5.1 µM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.

A concise synthesis of (E)-3-aryl-2,3,4,5-tetrahydro-1H-3-benzazonines by aryne induced [2,3] Stevens rearrangement of 1,2,3,4-tetrahydroisoquinolines.

A mild and transition-metal-free approach for the synthesis of (E)-3-aryl-2,3,4,5-tetrahydro-1H-3-benzazonines via [2,3] Stevens rearrangement of 1,2,3,4-tetrahydroisoquinolines with arynes is described. This protocol provides straightforward access to (E)-3-aryl-2,3,4,5-tetrahydro-1H-3-benzazonines in moderate to good yields with excellent diastereoselectivity. A broad range of functional groups, involving nitrile, esters, ketone and aryl halide, were well tolerated in this reaction.

Synthesis and cytotoxic activities of a series of novel N-methyl-bisindolylmaleimide amide derivatives.

A novel series of N-methyl-bisindolylmaleimides were synthesized and evaluated for their inhibitory activities against nine tumor cell lines. Some of the compounds showed an interesting activity against the tested cell lines. The most potent compounds 5e and 5j displayed antiproliferative activity with 50% inhibitory concentration values in the µM range against some tested cell lines.

[Design, synthesis and antidiabetic activity of novel tetrahydrocarboline PPAR regulators].

A series of novel tetrahydrocarboline derivatives was designed and synthesized in order to discover more potent peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual regulators. The structures of these compounds were confirmed by 1H NMR and HR-MS; their PPAR-regulating activities were evaluated in vitro. Compounds 6h, 6n, 6p and 6q exhibited more potent PPARalpha agonistic activities than the control drug WY14643, while compounds 60, 6g, 6i and 6q exhibited more potent PPARgamma agonistic activities than the control drug rosiglitazone. Compound 6q was discovered as a potent PPARalpha/gamma dual agonist and deserves further investigation.

Design, synthesis of griseofamine A derivatives and development of potent antibacterial agents against MRSA.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA), one of the most important multidrug-resistant bacteria in clinic, has become a serious global health issue. In this study, we designed and synthesized a series of griseofamine A derivatives and evaluated their antibacterial profiles. In vitro assays found that compound 9o10 showed a remarkable improvement of antibacterial activity toward MRSA (MIC = 0.0625 µg/mL), compared with griseofamine A (MIC = 8 µg/mL) and vancomycin (MIC = 0.5 µg/mL) with low hemolysis and cytotoxicity. Its rapid bactericidal property was also confirmed by time-kill curve assay. Furthermore, compound 9o10 displayed weak drug resistance frequency. In in vivo experiment, compound 9o10 exhibited more potent antibacterial efficacy than vancomycin and excellent biosafety (LD50 > 2 g/kg). Preliminary mechanism study revealed compound 9o10 might involve antibacterial mechanisms contributing to membrane damage. Taken together, compound 9o10 possessed excellent inhibitory activity against MRSA in vitro and in vivo with low toxicity and drug resistance frequency, making it a promising hit compound for further development against MRSA infections.

Total synthesis of microtubule-stabilizing agent ceratamine A.

The total synthesis of ceratamine A, a natural microtubule-stabilizing agent with unusual cellular effects, has been accomplished starting from 5-methoxybenzimidazole in 10 steps in an overall yield of 12.7%. The key steps in the synthesis involved the Schmidt rearrangement to construct the azepine ring, the alkylation of lactam to introduce the C-5 benzylic side chain, and the highly economical SNAr reaction to install the C-2 methylamine residue.

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine.

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.

Synthesis and cytotoxicity of (-)-renieramycin G analogs.

(-)-Renieramycin G and fifteen C-22 analogs were prepared employing l-tyrosine as the chiral starting material. These analogs, along with (-)-renieramycin G itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, A2780, MCF-7, A549, BGC-823, Ketr3, KB, Hela cells. The IC(50) values of most of these analogs were at the level of µM. Among these analogs, 2-thiophenecarboxylate ester derivative 17 exhibited potent cytotoxic activity against KB cell line with the IC(50) of 20 nM. From this study, it could be concluded that the C-22 side chain played an important role in the cytotoxic potency and specificity of this class of (-)-renieramycin G derivatives.

[Design, synthesis, and PPARalpha/gamma agonistic activity of novel tetrahydroisoquinoline derivatives].

A series of tetrahydroisoquinoline derivatives were prepared and their peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonistic activities were evaluated to obtain more potent PPAR agonist. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Three compounds exhibited higher agonistic activities of PPARgamma than that of the comparison, six compounds exhibited higher agonistic activities of PPARalpha than that of the comparison, and compound 8a was discovered as a highly potent PPARalpha/gamma agonist that is much more active than that of WY14643 and rosiglitazone. The development of potent PPAR agonists may offer a new choice for the treatment of diabetes.

Design, synthesis and biological evaluation of exiguamine A analogues as IDO1 inhibitors.

A series of exiguamine A analogues were designed and synthesized via 15 steps. Their inhibitory activities against IDO1 were tested and the structure-activity relationships were studied. Most compounds exhibited potent IDO1 inhibitory activities with IC50 values at the level of 10-7-10-8 M. Compound 21f was the most potent IDO1 inhibitor with an IC50 value of 65.3 nM, which was comparable with the positive control drug epacadostat (IC50 = 46 nM). Moreover, compound 21f showed higher selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO) and no cytotoxicity at its effective concentration, rending it justifiable for further optimization and evaluation.

Quantitative structure-activity relationship studies of threo-methylphenidate analogs.

Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value.

Synthesis and antitumor activity of bisindolylmaleimide and amino acid ester conjugates.

A series of novel bisindolylmaleimide and natural amino acid ester conjugates were synthesized and evaluated for their inhibitory activity against six tumor cell lines. Some compounds displayed interesting cytotoxic profiles. The most active compound 8e showed inhibitory activity against several human cancer cell lines.