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Three compounds were obtained from Sabia parviflora Wall., and their structures were identified through nuclear magnetic resonance (NMR) spectroscopy, particularly 2-dimensional (2D)-NMR. The molecular masses were determined using quadrupole-time-of-flight-mass spectrometry. Electronic circular dichroism spectra were used to determine the absolute configuration of compound 1. The 3 new compounds were identified as 2,2,7,7-tetramethyl-8S,10-dihydroxy-2,7,8,9-tetrahydro-2H-naphtha[2,3-b]pyran-6-one-10- O - β -D-glucopyranoside, (2Z)-4-(3-carboxy-4-hydroxyphenyl)-2-methylbut-2-enoic acid, and (2Z)-5-(3-carboxy-4-hydroxyphenyl)-5-oxo-2-methylpent-2-enoic acid. The liver protective activities of these compounds were tested by HepG2 and LO2 cell lines, which were induced using free fatty acids. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities. [ABSTRACT FROM AUTHOR]

This study reports the design and synthesis of NO-donating polymer to generate biodegradable polymeric micelle containing paclitaxel (NO/PTX) as a nanomedicine delivery system aimed to enhance the solubility and anti-cancer activity of paclitaxel (PTX). NO/PTX showed greater NO-releasing performance than nitroglycerin, displaying excellent tolerance in KM mice, and exhibited a two-fold stronger antiproliferative activity than PTX in vitro against HCT116, SW480, and SGC-7901 cell lines. In vivo tumor growth inhibition assay results indicated that NO/PTX displayed lightly stronger activities against tumor growth than PTX at a dose of 10 mg kg−1, while the anti-tumor effect of NO/PTX was significantly improved than that of PTX and Genexol®-PM groups at a dose of 15 mg kg−1 (the inhibition rate: 67% vs. 53% and 41%). In addition, NO/PTX showed an improved area under the plasma concentration-time curve and drug deposition in tumors in comparison to PTX. Wound healing assay and western blot analysis of EMT-related markers suggested that NO/PTX could inhibit the potential of HCT116 migration. Western blot analysis also demonstrated that NO/PTX dampened efflux activity of P-gp and up-regulated apoptosis-related proteins. Overall, these promising results suggested that the synergism between PTX and NO-donating micelles could contribute to the potent anti-cancer activity of NO/PTX. [ABSTRACT FROM AUTHOR]

A series of Pulsatilla saponin D (PSD) and α-hederin derivatives bearing NO donors were designed, synthesized and evaluated for anticancer activities in vitro and in vivo. Among them, most of the target compounds exhibited strong antiproliferative activities against the tested cancer cell lines, and derivatives 5a, 5b and 5c exhibited high levels of NO release. Furthermore, compound 5c treated with a dose of 15 mg kg−1 showed a more potent tumor inhibitory effect than that of Taxol (27.44% vs. 23.26%). In addition, compound 5c blocked the cell cycle at the S phase and induced cancer cell apoptosis in a concentration-dependent manner. [ABSTRACT FROM AUTHOR]

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0–2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction). [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) has a high mortality rate due to liver metastasis. The insulin‐like growth factor‐1 receptor (IGF‐1R) is highly expressed in UM and has been shown to be associated with hepatic metastases. Targeting IGF signalling may be considered as a promising approach to inhibit the process of metastatic UM cells. Pristimerin (PRI) has been demonstrated to inhibit the growth of several cancer cells, but its role and underlying mechanisms in the IGF‐1‐induced UM cell proliferation are largely unknown. The present study examined the anti‐proliferative effect of PRI on UM cells and its possible role in IGF‐1R signalling transduction. MTT and clonogenic assays were used to determine the role of PRI in the proliferation of UM cells. Flow cytometry was performed to detect the effect of PRI on the cell cycle distribution of UM cells. Western blotting was carried out to assess the effects of PRI and IGF‐1 on the IGF‐1R phosphorylation and its downstream targets. The results indicated that IGF‐1 promoted the UM cell proliferation and improved the level of IGF‐1R phosphorylation, whereas PRI attenuated the effect of IGF‐1. Interestingly, PRI could not only induce the G1 phase accumulation and reduce the G2 phase induced by IGF‐1, but also could stimulate the expression of p21 and inhibit the expression of cyclin D1. Besides, PRI could attenuate the phosphorylations of Akt, mTOR and ERK1/2 induced by IGF‐1. Furthermore, the molecular docking study also demonstrated that PRI had potential inhibitory effects on IGF‐1R. Taken together, these results indicated that PRI could inhibit the proliferation of UM cells through down‐regulation of phosphorylated IGF‐1R and its downstream signalling. [ABSTRACT FROM AUTHOR]

A series of ester and amide derivatives of triterpenoid saponin Pulsatilla saponin D (PSD) were designed, synthesized, and evaluated for their antiproliferative activity. Compounds 1 and 6 displayed 1.7–8.3 times more potent cytotoxicity (IC50 = 1.2–4.7 and 1.7–4.5 μM, respectively) against five human tumor cell lines (SMMC-7721, MCF-7, NCI-H460, A549, and HCT-116) in vitro and lower acute toxicity to mice in vivo than did PSD. Furthermore, compound 6 was observed to show potent tumor growth inhibition against mice H22 hepatocellular cells (49.8% at 20 mg/kg) and induce cell cycle at G1 phase and apoptosis in HCT-116 cells. [ABSTRACT FROM AUTHOR]

• The authors designed novel GPR119 agonists bearing various core moiety from lipophilic cycloolefin fused pyrimidines to polar tetrahydropyridopyrimidines and found that the less polar cyclohexene fused compounds displayed the most potent activity. A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16 , 19 , 26 , 28 , 42) bearing endo - N -Boc-nortropane amine and fluoro-substituted aniline exhibited better EC 50 values (0.27–1.2 μM) though they appeared to be partial agonists. [ABSTRACT FROM AUTHOR]

We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC 50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC 0–2h ) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC 0–2h at the dose of 300 mg/kg. [ABSTRACT FROM AUTHOR]

Several phenylbutenoid dimer ( PBD) analogs were synthesized and evaluated for their inhibitory activities against nitric oxide ( NO) production and TNF-α release. The PBD analogs were synthesized via Diels-Alder and subsequent Schlosser reactions as key steps. Among the tested compounds, two analogs ( 8c, 8f) exhibited much stronger inhibitory activity against LPS-stimulated NO production and TNF-α release in RAW 264.7 cells than that of wogonin. [ABSTRACT FROM AUTHOR]

A practical total synthesis of racemic nyasol (7) was explored. The α-hydroxyketo compound3was prepared from commercially available starting materials in two steps. Chelation-controlled reduction of the α-hydroxyketo compound3with Zn(BH4)2gave the anti-1,2-diol compound4as the major product (anti/syn = 11.5:1). Stereospecific elimination reaction of a 1,3-cyclic thionocarbonate intermediate (5) exclusively yielded the Z-alkene compound6. Our total synthesis is very concise (seven steps), uses commercially available starting materials, and offers good overall yield (40%). [ABSTRACT FROM PUBLISHER]

Straightforward and facile synthesis of a bioactive component A fromZingiber cassumunarRoxb. is described. The phenylbutenoid dimer A was reported to possess anti-inflammatory and cytotoxic activities. The optically active cyclohexene ring fragment was obtained via the highly diastereo- and enantioselective Diels–Alder reaction of chiral acryloyloxazolidinones (1aand1b) and 1-(4-hydroxy-3-methoxyphenyl)butadiene (2). The enantiomeric excess of Diels–Alder adducts3aand3bwere determined via high-performance liquid chromatotography of the corresponding bis-acetate (6). The greatest enantiomeric excess (99.9% ee) was obtained when the 4-phenyloxazolidin-2-one (1a) chiral auxiliary was used in combination with TiCl4. The optically pure bioactive compound A was prepared from the optically active Diels–Alder adduct (3a) in two additional steps. [ABSTRACT FROM PUBLISHER]

A series of halogenated 1,5-diarylimidazole compounds were synthesized and their inhibitory effects on LPS-induced PGE2 production in RAW 264.7 cells were evaluated. A wide variety of 2,4-, 4-, and 2-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles were synthesized for SAR study via two different pathways. Overall, 4-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles, regardless of the species of halogen, exhibited very strong inhibitory activities of PGE2 production. Among them, 4-chloro-5-(4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole (3, IC50 3.3 nM ± 2.93), and 4-chloro-5-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)imidazole (13, IC50 5.3 nM ± 0.23) showed the best results. [ABSTRACT FROM AUTHOR]

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel. [ABSTRACT FROM AUTHOR]

• A series of tetrahydropyridopyrimidine derivatives targeting GPR119 and DPP-4 were designed and synthesized. • Compound 51 was revealed to show both GPR119 agonistic and DPP-4 inhibitory activities. • Compound 51 demonstrated potent hypoglycemic effect compared with vildagliptin. • The 3D binding mode of 51 with DPP-4 was generated. Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC 50 = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC 0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators. [ABSTRACT FROM AUTHOR]

Three series of novel thienopyrimidine derivatives 9a–l, 15a–l, and 18a–h were designed and synthesized, and their IC50 values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC50 values of 12.32 ± 0.96, 11.30 ± 1.19, 14.69 ± 1.32, and 9.80 ± 0.93 µM, respectively. The inhibitory activities of compounds 9a and 15a against PI3Kα and mTOR kinase were further evaluated. Compound 9a exhibited PI3Kα kinase inhibitory activity with IC50 of 9.47 ± 0.63 µM. In addition, docking studies of compounds 9a and 15a were also investigated. [ABSTRACT FROM AUTHOR]

An abstract of the article "Practical Synthesis of (±)-Nyasol (I)" by Yuanying Fang and Haeil Park is presented.

Graphical abstract Highlights • Twenty-eight coumarin-dithiocarbamate hybrids were designed and synthesized. • 8g was identified as a potent and balanced inhibitor for AChE and MAO-B. • 8g showed no acute toxicity in mice and could penetrate the BBB. • 8g could significantly reverse scopolamine-induced memory deficit in vivo. Abstract A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC 50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold. [ABSTRACT FROM AUTHOR]

A series of novel coumarin-based N -hydroxycinnamamide derivatives were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds showed potent HDAC inhibitory activity and significant antiproliferative activity against human cancer cell lines MCF-7, HepG2, HeLa and HCT-116. Among them, compound 14f displayed the most potent HDAC inhibition, especially against HDAC1 with IC 50 value of 0.19 μM, which was better than that of SAHA (IC 50 = 0.23 μM). It also showed the strongest antiproliferative activity towards HeLa cells and more than 26-fold selectivity for HDAC1 compared with HDAC6. Molecular docking studies revealed the possible binding modes of compound 14f into the two isoforms and provided a reasonable explanation for the selectivity. In addition, compound 14f could inhibit colony formation, upregulate the acetylation level of histone H3, and induce apoptosis and cell cycle arrest at G2/M phase in HeLa cells. Taken together, these results highlighted that compound 14f might be a promising HDAC inhibitor for cancer therapy. [ABSTRACT FROM AUTHOR]

In this paper, we intended to fabricate ultra-small nanocrystals (below 50 nm) by formation of hydrogen bonds between model drug and stabilizer. The absorption mechanisms, pharmacokinetic performance in rats and therapeutic effect for myocardial ischemia were studied after in vitro characterization. Poor water solubility and low bioavailability hinder the clinical application of about 70% of newly synthesized compounds. Nanocrystal technology has become a preferred way to improve bioavailability by improving solubility. However, it remains challenging to produce nanocrystals with ultra-small particle sizes to further enhance the extent of bioavailability. Herein, we constructed ultra-small puerarin nanocrystals (Pue-NCs) (20–40 nm) via formation of hydrogen bond during HPH. We confirmed the formation of hydrogen bonds by 1H NMR and FTIR, and observed the distribution of polymer chains by SEM and TEM. The absorption mechanisms were studied in Caco-2 cell monolayers, and the results showed that the major transport mechanism for puerarin was passive diffusion, meanwhile, for Pue-NCs, the passive transport and micropinocytosis-mediated endocytosis coexisted. The absolute bioavailability of Pue-NCs was 35.28%, which was 11.54 folds compared to that of puerarin. Therapeutic equivalence was demonstrated between Pue-NCs and puerarin injection at 50 mg/kg and 15 mg/kg, respectively, in isoproterenol-induced myocardial ischemia model. This study provides a novel strategy for preparing ultra-small nanocrystals by HPH to increase bioavailability of poorly soluble drugs. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports., Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1 H )-quinolinone and dithiocarbamate., Methods: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo., Results: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC 50 =0.28 µM to eeAChE; IC 50 =0.34 µM to hAChE; IC 50 =2.81 µM to hMAO-B; IC 50 =0.91 µM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 µM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.)., Conclusion: This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Guo et al.)

Farnesoid X receptor (FXR) is an important regulator of bile acid, lipid, amino acid, and glucose homeostasis, hepatic inflammation, regeneration, and fibrosis. FXR has been recognized as a promising drug target for various metabolic diseases such as lipid disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic kidney disease. A large number of FXR ligands have been developed by pharmaceutical companies and academic institutions, and several candidates have progressed into clinical trials in the past decade. However, it is continually a challenge to discover drugs targeting FXR due to side effects associated with long-term administration. In this perspective, we summarize the research progress on medicinal chemistry of FXR modulators from 2018 to the present by discussing the diverse structures of synthetic FXR modulators including steroidal and non-steroidal ligands, their structure-activity relationships (SARs), and their therapeutic applications.

Introduction : Type 2 diabetes is a rapid-growing complex chronic metabolic disease characterized by hyperglycemia due to lessened insulin secretion, insulin resistance and hepatic glucose overproduction. GPR119 is a class A of G protein-coupled receptor, expressed on certain enteroendocrine L and K cells in the small intestine and by β-cells within the islets of Langerhans of the pancreas. Activation of GPR119 stimulates the secretion of glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose-dependent release of insulin in pancreatic β-cells. Area covered : This review summarized the reported patents on GPR119 agonists from 2014 to present. The authors described the structural features of these novel synthetic molecules and compared their biological activities (including in vitro and in vivo ) as potent GPR119 agonists for the treatment of diabetes. Expert opinion : GPR119 agonists remain the advantage of stimulating both insulin and incretin release in a glucose-dependent manner over other hypoglycemic agents, although some GPR119 agonist clinical candidates have been discontinued in Phase І or Phase II. GPR119 agonists will succeed to be developed as anti-diabetic drugs after accumulated scaffolds of agonists are discovered and the crystallographic structure of GPR119 is elucidated. The synergic effect of GPR119 agonist and DPP-4 inhibitor will also elicit a benefit for the new therapeutic of diabetes.

Antimicrobial peptides (AMPs) are promising antibacterial agents often hindered by their undesired hemolytic activity. Inspired by gramicidin S (GS), a well-known cyclodecapeptide, we synthesized a panel of antibacterial cyclopeptidomimetics using β,γ-diamino acids (β,γ-DiAAs). We observed that peptidomimetic CP-2 displays a bactericidal activity similar to that of GS while possessing lower side-effects. Moreover, extensive studies revealed that CP-2 likely kills bacteria through membrane disruption. Altogether, CP-2 is a promising membrane-active antibiotic with therapeutic potential., (© 2020 Wiley-VCH GmbH.)