Search

[Display omitted] • D-π-A fluorescent probes were reasonably designed and developed through systematic changes in electron-donor and-acceptor groups. • Probes M−H−SO 3 with a hydrophilic sulfonate group displayed sufficient selectivity for discrimination of HSA from BSA. • Probe M−H−SO 3 can bind to the IB site of HSA, yielding a substantial fluorescent enhancement. • The probe M−H−SO 3 can be used for detecting human serum albumin in urine samples. HSA (human serum albumin), a most abundant protein in blood serum, plays a key role in maintaining human health. Abnormal HSA level is correlated with many diseases, and thus has been used as an essential biomarker for therapeutic monitoring and biomedical diagnosis. Development of small-molecule fluorescent probes allowing the selective and sensitive recognition of HSA in in vitro and in vivo is of fundamental importance in basic biological research as well as medical diagnosis. Herein, we reported a series of new synthesized fluorescent dyes containing D-π-A constitution, which exhibited different optical properties in solution and solid state. Among them, dye M−H−SO 3 with a hydrophilic sulfonate group at electron-acceptor part displayed selectivity for discrimination of HSA from BSA and other enzymes. Upon binding of dye M−H−SO 3 with HSA, a significant fluorescence enhancement with a turn-on ratio about 96-fold was triggered. The detection limit was estimated to be ∼ 40 nM. Studies on the interaction mechanism revealed that dye M−H−SO 3 could bind to site III of HSA with a 1:1 binding stoichiometry. Furthermore, dye M−H−SO 3 has been applied to determine HSA in real urine samples with good recoveries, which provided a useful method for HSA analysis in biological fluids. [ABSTRACT FROM AUTHOR]

[Display omitted] • Apigenin analogs (L1–L27) were designed and synthesized. • The synthetic molecules were screened for α-glucosidase inhibitory activities. • Compound L22 was found to be the most active compound. • L22 presented in vivo hypoglycemic activity in STZ-induced diabetic mice. This study investigated the inhibitory potential of a series of synthesized compounds (L1-L27) on α-glucosidase. Among them, compound L22 showed significant inhibitory effect. Through enzymatic kinetics studies, we demonstrated that L22 acts via a non-competitive inhibition mode with a K i value of 2.61 μM, highlighting its high affinity for the enzyme. Molecular docking studies revealed the formation of hydrogen bonds between L22 and α-glucosidase and diverse interactions with neighboring amino acid residues. Furthermore, molecular dynamics simulations confirmed the stability of the L22-α-glucosidase complex. In a mouse model of type 2 diabetes, treatment with L22 significantly lowered fasting blood glucose levels, and reduced insulin resistance, suggesting its potential as a therapeutic agent for type 2 diabetes. Furthermore, L22 showed a protective effect against oxidative stress in the liver and alleviated liver and pancreatic abnormalities. These results provide valuable insights into the mechanism of action of L22 and its potential applications to treat type 2 diabetes, and improve liver health. [ABSTRACT FROM AUTHOR]

[Display omitted] • Six C-3′-C-6″ type of biflavonoids were isolated from S. trichoclada. • RF-A showed the strongest activity against MCF-7 cells among all isolated compounds. • RF-A induced the accumulation of ROS and Lipid peroxidation in MCF-7 cells. • RF-A induced ferroptosis in MCF-7 cells via the upregulation of VDAC2 protein. Breast cancer is one of the major malignant tumors in females, and currently, recurrence and metastasis are the main obstacles preventing effective breast cancer treatment. Biflavonoids of secondary metabolites from plants are excellent anticancer agents to fight sensitive and resistant breast cancer cell lines. In this study, six C-3′-C-6″ biflavonoids, including one new robustaflavone A (1 , RF-A) and five known robustaflavone derivatives (2 – 6) , were isolated from Selaginella trichoclada for the first time. We aimed to evaluate the inhibitory effects of compounds 1 – 6 against human breast cancer MCF-7 cells. Among the six compounds, RF-A showed the strongest activity, decreasing cell viability with an IC 50 value of 11.89 μΜ. Furthermore, RF-A strikingly induced MCF-7 nonapoptotic cell death through ferroptosis by enhancing the expression of VDAC2 channels and reducing the expression of Nedd4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production. The results suggested that RF-A has potential as a novel breast cancer treatment through its regulation of the mitochondrial VDAC2 and Nedd4 pathways. [ABSTRACT FROM AUTHOR]

• The structure of polyhydroxy serratene triterpenoids is quite novel. • All compounds revealed selective cytotoxicities against MCF-7 cells. • Biosynthetic pathways of compounds were proposed. • UV spectrums provide some references for the structure of serratene triterpenoids. Phytochemical investigation of the 70% aqueous EtOH extract of Lycopodium complanatum led to six new polyhydroxy serratene triterpenoids (serrat A-F, 1 – 6), along with a known analogue (7). Their structures and configurations were elucidated by data analysis of HRESIMS, 1D and 2D NMR, in combination with comparisons of reported experimental spectroscopic data. All the isolates were evaluated cytotoxic activities against HepG2 cells, MCF-7 cells and series human lung cancer cell lines A549, Calu-6, NCI-H441, NCI-H226 and NCI-H1975. The results indicated that certain compounds inhibited proliferation of human cancer cells. Moreover, all compounds possessed selective cytotoxic activities on MCF-7 cells. Further, possible biosynthesis pathways of these compounds were proposed. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Ten new withanolides and three artificial withanolides were isolated from the aerial parts of Tubocapsicum anomalum. • A chemical conversion from 16 α ,17 α –epoxywithanolides to Δ13,14–16 α –hydroxywithanolides was achieved by Wagner–Meerwein rearrangement. • Cytotoxicity of all isolated compounds 1 – 18 were evaluated in vitro. Abstract Ten new withanolides (1 – 10) and three artificial withanolides (11 – 13) were isolated from the aerial parts of Tubocapsicum anomalum , together with five known analogues (14 – 18). Their structures were determined on the basis of extensive spectroscopic and chemical methods. They include seven acnistin–type (1 – 4 , 11 , 14 and 15), three withajardin–type (5 – 7), and eight normal–type (8 – 10 , 12 , 13 and 16 – 18) withanolides. Of normal–type withanolides, a chemical conversion from the 16 α ,17 α –epoxywithanolide (16) to Δ13,14–16 α –hydroxywithanolide (18) was achieved by Wagner–Meerwein rearrangement. All isolates were evaluated for their cytotoxicity against four human tumor cell lines (HCT–116, HepG2, MCF–7 and A375). Among them, compounds 1 – 3 , 6 – 8 , 14 , 16 – 18 showed cytotoxic activity with IC 50 values of 0.24–8.71 μ M. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two enantiomeric pairs of acylphloroglucinols were isolated from Syzygium szemaoense. • They possess a macrocyclic system with an unprecedented carbon skeleton. • A new biogenetically related long-chain acylphloroglucinol was also obtained. • Some of the isolates showed inhibitory effects on ACLY and DRAK2. Two enantiomeric pairs of macrocyclic acylphloroglucinols (1a / 1b and 2a / 2b) with an unprecedented carbon skeleton featuring a bicyclo[12.3.1]octadecane core, together with an undescribed biogenetically related long-chain acylphloroglucinol (3), were isolated from Syzygium szemaoense. Their structures were fully established by spectroscopic method, X-ray crystallographic analysis, and ECD calculation. Compounds 1b and 2a / 2b exhibited inhibition against death-associated protein kinase-related apoptosis inducing protein kinase 2 (DRAK2) and ATP citrate lyase (ACLY), respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • Four types of novel heterocyclic derivatives (a total of 31 compounds) as glycogen phosphorylase (GP) inhibitors were designed, synthesized and evaluated. • The structure–activity relationship (SAR) of synthesized compounds was demonstrated. • Compound IIIh showed strong inhibitory activity against both RMGP (IC 50 = 0.21 ± 0.03 µM) and HBGP (IC 50 = 0.09 ± 0.002 µM). • Compound IIIh as a potential glycogen phosphorylase inhibitor has beneficial effect on cardioprotective. The purpose of this study was to evaluate the effect of GP inhibitor as a potential pharmaceutical target on MI/R injury. Four different structural types of novel compounds (I, II, III, and IV) were designed and synthesized, obtaining 31 novel GP inhibitors. SAR studies revealed that the conjugates of 5-chloroindole with benzo six-membered heterocyclic were found to elevate the activity. In particular, compound IIIh (IC 50 = 0.21 ± 0.03 µM) emerged as a potent derivative against RMGPa, being approximately 2-fold less potent than that of PSN-357. In order to screen out a compound for in vivo activity test, we further conducted an experiment of inhibition against three different subtypes of GPa (HLGPa, HMGPa and HBGPa) and the corresponding affinity experiment. As a result, compound IIIh showed strong inhibitory activity against the above three subtypes of GP, especially on HBGPa (IC 50 = 0.09 ± 0.002 µM), which was relatively close to that of positive control ingliforib (IC 50 = 0.16 ± 0.02 µM). The affinity of compound IIIh to HBGPa was 4.3 times higher than that of HLGPa, and 1.1 times higher than that of HMGPa. This fact further proved that compound IIIh has a higher inhibitory effect on HMGPa than the other two subtypes. Besides, in vivo activity evaluation demonstrated that compound IIIh exhibited obviously cardioprotective effect on MI/R injury mice. The discovery of compound IIIh provides a new strategy for developing novel GP inhibitors with myocardial ischemia protection. [ABSTRACT FROM AUTHOR]

[Display omitted] • Four undescribed seco -polyprenylated acylphloroglucinols from H. elodeoides. • A possible biosynthetic pathway of 1 – 4 from normal PAPs was proposed. • Compound 1 induced MCF-7 cell apoptosis. • Compound 1 arrested cell cycle at S phase via inducing oxidative DNA damage. Four undescribed seco -polyprenylated acylphloroglucinols (seco -PAPs), elodeoidesones A-D (1 – 4), were characterized from Hypericum elodeoides. Compound 1 represents the 1,6- seco -PAPs with fascinating 5/5 fused ring, while 2 – 4 possess a 1,2- seco -PAPs skeleton with a five-membered lactone core. Their structures including absolute configurations were established by spectroscopic analyses and quantum chemical computations. A possible biosynthetic pathway of 1 – 4 from normal PAPs was proposed. All the isolates were investigated for their cytotoxicity against tumor cells. Notably, 1 inhibited the proliferation of MCF-7 cells with the IC 50 value of 7.34 μM. Mechanism investigation indicated that 1 induced MCF-7 cells apoptosis by blocking cell cycle at S phase via inducing oxidative DNA damage. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ten new polypropionate derivatives, decempyrones A–J (1 – 10) were isolated from Fusarium graminearum. • Absolute configurations were fixed by JBCA, chemical degradation, geminal proton rule, and modified Mosher's method. • Decempyrones C and J exhibited potent anti-inflammatory activity. • Decempyrones C and J also displayed MptpA kinase inhibitory activity. Under guidance of 1H NMR, ten new polypropionate derivatives, decempyrones A–J (1 – 10) along with two known analogues (11 and 12), were isolated from the marine-derived fungus Fusarium decemcellulare SYSU-MS6716. The planar structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, and HR-ESIMS). The absolute configuration of the chiral centers in the side chain is a major obstacle for the structure identification of natural polypropionate derivatives. Herein, the J -based configurational analysis (JBCA), chemical degradation, geminal proton rule, and the modified Mosher's method were adopted to fix their absolute configurations in the side chain. Compounds 3 and 10 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide with IC 50 values 22.4 ± 1.8 and 21.7 ± 1.1 μM. In addition, compounds 3 and 10 displayed MptpA inhibitory activity with an IC 50 value of 19.2 ± 0.9 and 33.1 ± 2.9 µM. Structure-activity relationships of the polypropionate derivatives were discussed. [ABSTRACT FROM AUTHOR]

As a continuation to our previous research, we preliminarily identified VEGFR-2 as potential intracellular targets of active candidates with the potency of inducing vascular normalization. • Discovery and functional assessment of novel photoaffinity probes were performed. • VEGFR-2 was identified as a potential intracellular target for active candidates. • These probes could be used for subcellular localization of target proteins. We previously developed two candidates with potency of inducing vascular normalization, BD7 and B14. However, the definite intracellular molecular target(s) responsible for their activity remains unknown. Herein, we report the discovery and functional assessment of several multifunctional photoaffinity probes for determining the potential biological targets of active compounds. The probes bear a photoaffinity moiety and a bioorthogonal unit attached to B7 or B14 and maintained the bioactivity of the parent active molecules. Using in vitro biological assays, we preliminarily identified VEGFR-2 as a potential intracellular target for the active candidates. Our results demonstrate the utility of these multifunctional photoaffinity probes for analyzing the biological activity and subcellular localization of the intracellular target proteins of active candidates. [ABSTRACT FROM AUTHOR]

• Eight new and five known prenylflavonol glycosides were isolated from the leaves of Cyclocarya paliurus. • Prenylflavonol glycosides were discovered in Cyclocarya paliurus for the first time. • The compounds were evaluated for the inhibitory effects on xanthine oxidase activity. • Compounds 2 and 7 exhibited significant inhibition on xanthine oxidase activity. Eight new prenylflavonol glycosides (1 – 8), along with five known analogues (9 – 13) were isolated from the n -butanol extract of the dried leaves of Cyclocarya paliurus (family Juglandaceae) for the first time. The structures of these compounds were characterized by comprehensive analysis of 1D, 2D NMR, HRESIMS, UV data and acid hydrolysis. In bioassay, all these thirteen prenylflavonol glycosides exhibited inhibitory effects on xanthine oxidase (XOD) activity. Especially compounds 2 and 7 , showed outstanding IC 50 values of 31.81 ± 2.20 and 29.71 ± 3.69 μM, respectively. [ABSTRACT FROM AUTHOR]

• Scutellarin methyl ester-4′-dipeptide conjugates were synthesized and evaluated as potential protective agents against HIE. • 5k exhibit the highest P app A to B , lowest ER value in Caco-2 cells, and the highest uptake value in hPepT1-MDCK cells. • 5k exhibit more potent protective activity against oxidative damage by improving the relevant detection indicators. • 5k has significantly therapeutic effect on HIE rat pups by reducing infarct area and APP/ BACE-1 expression. • Favorable pharmacokinetic profiles of 5k were also confirmed in our studies. A series of novel scutellarin methyl ester-4′-dipeptide conjugates exhibiting active transport characteristics and protection against pathological damage caused by hypoxic-ischemic encephalopathy (HIE) were successfully designed and synthesized. The physiochemical properties of the obtained compounds, as well as the Caco-2 cell-based permeability and uptake into hPepT1-MDCK cells were evaluated using various analytical methods. Scutellarin methyl ester-4′-Val-homo-Leu dipeptide (5k) was determined as the optimal candidate with a high apparent permeability coefficient (P app A to B) of 1.95 ± 0.24 × 10−6 cm/s, low ER (P app BL to AP /P app AP to BL) of 0.52 in Caco-2 cells, and high uptake of 25.47 μmol/mg/min in hPepT1-MDCK cells. Comprehensive mechanistic studies demonstrated that pre-treatment of PC12 cells with 5k resulted in more potent anti-oxidative activity, which was manifested by a significant decrease in the malondialdehyde (MDA) and reactive oxygen species (ROS) levels, attenuation of the H 2 O 2 -induced apoptotic cell accumulation in the sub-G1 peak, and improvement in the expression of the relevant apoptotic proteins (Bcl-2, Bax, and cleave-caspase-3). Moreover, evaluation of in vivo neuroprotective characteristics in hypoxic-ischemic rat pups revealed that 5k significantly reduced infarction and alleviated the related pathomorphological damage. The compound was also shown to ameliorate the neurological deficit at 48 h as well as to decrease the brain tissue loss at 4 weeks. Conjugate 5k was demonstrated to reduce the amyloid precursor protein (APP) and β-site APP-converting enzyme-1 (BACE-1) expression. Pharmacokinetic characterization of 5k indicated favorable druggability and pharmacokinetic properties. The conducted docking studies revealed optimal binding of 5k to PepT1. Hydrogen bonding as well as cation-π interactions with the corresponding amino acid residues in the target active site were clearly observed. The obtained results suggest 5k as a potential candidate for anti-HIE therapy, which merits further investigation. [ABSTRACT FROM AUTHOR]

• Eight new serratane triterpenoids were isolated from Lycopodium complanatum. • The absolute configurations of 6 – 8 were determined by DFT GIAO 13C NMR calculations. • The cytotoxic activities were assessed on seven different human cancer cell lines. • All compounds could inhibit the NO release of RAW 264.7 cells induced by LPS. Phytochemical investigation of the ethyl acetate fraction of Lycopodium complanatum led to eight new serratane triterpenoids (lycomplanatums A-H, 1 – 8), along with five known analogues (9 – 13). Their structures were elucidated by extensive spectroscopic methods, including 1D/2D NMR, HRESIMS, and DFT GIAO 13C NMR calculation. Among them, compounds 2 and 13 showed moderate antiproliferative effects against seven human cancer cell lines, especially for MCF-7 with IC 50 values of 13.8–44.7 μM. Additionally, the compounds were screened for anti-inflammatory effects based on their inhibitory activities of nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 2 and 13 diminished NO production more potently than others in a concentration-dependent manner. [ABSTRACT FROM AUTHOR]

• Eight new dammarane triterpenoid glycosides were isolated from the leaves of Cyclocarya paliurus (family Juglandaceae). • The absolute configuration of the epoxy group of 1 was determined by DFT GIAO 13C NMR calculation. • Dammarane triterpenoids showed good hypoglycemic effect in 3T3-L1 adipocytes. Four new rarely occurred seco -dammarane triterpenoid glycosides (1 – 4) and four new dammarane triterpenoid glycosides (5 – 8), along with four known triterpenoids (9 – 12), were isolated from the 70% ethanol extract of the leaves of Cyclocarya paliurus (family Juglandaceae). Their structures were elucidated by extensive spectroscopic methods, including 1D/2D NMR and HRESIMS data, together with chemical analysis and DFT GIAO 13C NMR calculation. In bioassay, compounds 5 – 8 significantly increased glucose consumption in 3T3-L1 adipocytes, which could be the bioactive constituents for the anti-diabetes effect of the traditional usage of C. paliurus. [ABSTRACT FROM AUTHOR]

• Chalcone analogues containing a thieno[2,3- d ]pyrimidin-2-yl group were synthesized and evaluated as anti-tumor agents. • Compound 8d was the most potent analogue, with IC 50 values ranging between 2.65 and 11.44 μM in seven cancer cell lines. • Compound 8d induced an accumulation of HCT-116 cells in the sub-G1 phase. • 8d -induced apoptosis was confirmed by Annexin-V, JC-1, H2DCFDA and MitoSox™ Red staining assays. • The mitochondrial death pathway might be involved in 8d -induced apoptosis in HCT-116 cells. Many natural or synthetic chalcones have potential anti-tumor activity. Here, we synthesized two series of chalcone analogues containing a thieno[2,3- d ]pyrimidin-2-yl group and evaluated for their cytotoxic activity towards cultured human lung cancer A549 and colorectal HCT-116 cells. Among them, compound 8d was the most cytotoxic against HCT-116 cells, with an IC 50 value of 2.65 μM. Analyses of the phenotypic changes induced by this compound found a dose-dependent accumulation of HCT-116 cells in sub-G1 phase, indicating that compound 8d might induce apoptosis. Furthermore, we found that 8d triggered mitochondrial membrane potential depolarization, promoted reactive oxygen species formation in HCT-116 cells, and increased the percentage of early and late apoptotic cells. Finally, immunoblotting indicated that 8d increased PARP-1 and caspases 3, 7 and 9 cleavage. These data suggest that compound 8d induces apoptosis via the mitochondrial death pathway. [ABSTRACT FROM AUTHOR]

• Four new polyketides were isolated from a coral-derived fungus Penicillium sclerotiorin. • Five isolated compounds exhibited significant anti-inflammatory activities by inhibiting NO production. • The possible anti-inflammatory mechanism was downregulating the expression of iNOS and COX-2 at mRNA level. • Binding interactions with iNOS were predicted. Four new polyketides, including an unusual naphthoquinone derivative (1), two azaphilone analogous (2 , 7) and an α -pyrone (12), were isolated from the gorgonian-derived fungus Penicillium sclerotiorum CHNSCLM-0013 together with nine known compounds. Their structures were identified based on the 1D, 2D NMR, HRESIMS, single crystal X-ray diffraction and the absolute configurations were determined by comparing the 1H NMR chemical shift and optical rotations with those reported in literature. In the bioassay, compounds 2 , 6 , 7 , 10 and 12 exhibited significant inhibitory activities against the nitric oxide (NO) production in the LPS-induced macrophage RAW 264.7 with the IC 50 values in the range of 2.5–18.0 μM. Compounds 2 , 6 and 7 exhibited the possible mechanism of downregulating the expression of iNOS and COX-2 in mRNA level. The primary structure-activity relationship was also discussed based on the molecular-modeling. This study will make a contribution to the chemical diversities of polyketides especially the azaphilone derivatives and the discovery of potential anti-inflammatory agent from marine fungi. [ABSTRACT FROM AUTHOR]