ABSTRACT
Background: Chemotherapy resistance is a barrier to effective cancer prognoses. Cisplatin (CDDP) resistance is a major challenge for esophageal cancer (EC) therapy. A deeper understanding of the fundamental mechanisms of cisplatin resistance and improved targeting strategies are required in clinical settings. This study was performed to identify and characterize a marker of cisplatin resistance in EC cells. Method: KYSE140 and Eca-109 cells were subjected to escalating concentrations of cisplatin, resulting in the development of cisplatin-resistant KYSE140/CDDP and Eca-109/CDDP cell lines, respectively. RNA Sequencing (RNA-seq) was utilized to screen for the genes exhibiting differential expression between cisplatin-resistant and parental cells. Reverse transcription quantitative PCR was conducted to assess gene expression, and western blotting was employed to analyze protein levels. A sphere-formation assay was performed to validate tumor cell stemness. Cell counting kit-8 (CCK-8) experiments were conducted to confirm the sensitivity of cells to cisplatin. We examined the relationship between target genes and the clinicopathological features of patients with EC. Furthermore, the expression of target genes in EC tissues was evaluated via western blotting and fluorescence probe in situ hybridization (FISH). Results: KYNU was upregulated in cisplatin-resistant EC cells (KYSE140/CDDP and Eca-109/CDDP cells) and in EC tissues compared to that in the respective parental cell lines (KYSE140 and Eca-109 cells) and non-carcinoma tissues. Downregulation of KYNU increased cell sensitivity to cisplatin and suppressed tumor stemness, whereas abnormal KYNU expression had the opposite effect. KYNU expression was correlated with the expression of tumor stemness-associated factors (SOX2, Nanog, and OCT4) and the tumor size. Conclusions: KYNU may promote drug resistance in EC by regulating cancer stemness, and could serve as a biomarker and therapeutic target for EC.
ABSTRACT
Seven new phenolic bisabolane sesquiterpenoids (1-7), along with 10 biogenetically related analogues (8-17), were obtained from the deep-sea-derived fungus Aspergillus versicolor YPH93. The structures were elucidated based on extensive analyses of the spectroscopic data. Compounds 1-3 are the first examples of phenolic bisabolanes that contain two hydroxy groups attached to the pyran ring. The structures of sydowic acid derivatives (1-6 and 8-10) were carefully studied, leading to the structure revisions of six known analogues, including a revision of the absolute configuration for sydowic acid (10). All metabolites were evaluated for their effects on ferroptosis. Compound 7 exerted inhibition on erastin/RSL3-induced ferroptosis with EC50 values ranging from 2 to 4 µM, while it exhibited no effects on TNFα-induced necroptosis or H2O2-induced cell necrosis.
Subject(s)
Ferroptosis , Sesquiterpenes , Aspergillus/chemistry , Hydrogen Peroxide , Molecular Structure , Monocyclic Sesquiterpenes , Phenols/pharmacology , Sesquiterpenes/chemistryABSTRACT
The fungal strain YPGA3 was isolated from the sediments of the Yap Trench and identified as Penicillium thomii. Eight new chromone derivatives, named penithochromones M-T (1-8), along with two known analogues, 9 and 10, were isolated from the strain. The structures were established by detailed analyses of the spectroscopic data. The absolute configuration of the only chiral center in compound 1 was tentatively determined by comparing the experimental and the calculated specific rotations. Compounds 7 and 8 represent the first examples of chromone derivatives featuring a 5,7-dioxygenated chromone moiety with a 9-carbon side chain. Bioassay study revealed that compounds 6-10 exhibited remarkable inhibition against α-glucosidase with IC50 values ranging from 268 to 1017 µM, which are more active than the positive control acarbose (1.3 mmol).
Subject(s)
Chromones/metabolism , Glycoside Hydrolase Inhibitors/chemistry , Penicillium/metabolism , alpha-Glucosidases/metabolism , Chromones/chemistry , Enzyme Activation/drug effects , Glycoside Hydrolase Inhibitors/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
The fungus strain DZ-3 was isolated from twigs of the well-known medicinal plant Eucommia ulmoides Oliver and identified as Aspergillus flavipes. Two new alkaloids, named asperflaloids A and B (1 and 2), together with 10 known compounds (3-12) were obtained from the EtOAc extract of the strain. Interestingly, the alkaloids 1-4 with different frameworks are characterized by the presence of the same anthranilic acid residue. The structures were established by detailed analyses of the spectroscopic data. The absolute configuration of asperflaloids A and B was resolved by quantum chemistry calculation. All compounds were screened for their inhibitions against α-glucosidase and the antioxidant capacities. The results were that compound 3 had an IC50 value of 750.8 µM toward α-glucosidase, and the phenol compounds 7 and 8 exhibited potent antioxidant capacities with IC50 values 14.4 and 27.1 µM respectively.
Subject(s)
Alkaloids/chemistry , Antioxidants/pharmacology , Aspergillus/chemistry , Eucommiaceae/microbiology , alpha-Glucosidases/chemistry , Alkaloids/pharmacology , Antioxidants/chemistry , alpha-Glucosidases/metabolismABSTRACT
Chemical investigation of a gorgonian coral Ellisella sp. resulted in the isolation of 12 briarane-type diterpenoids, including eight new congeners namely ellisellolides A-H (1-8). Their structures were determined by extensive spectroscopic analysis, aided the calculated ECD data to support the configurational assignment. All compounds were evaluated for the in vitro anti-HBV activities in HepAD38 cell line, while preliminary analyses of the structure-activity relationship demonstrated that junceellolide C featured an 3E,5(16)-diene and a chlorine-substitution at C-6 is the most active congener. Junceellolide C exhibited efficient reduction against the HBV DNA, HBV RNA and HBeAg production with a dose-dependent manner. It also significantly reduced the HBV cccDNA replenishment and promoted the existed HBV cccDNA degradation. These findings suggest junceellolide C to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.
Subject(s)
Antiviral Agents/pharmacology , Diterpenes/pharmacology , Hepatitis B virus/drug effects , Animals , Anthozoa , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Cell Line, Tumor , Diterpenes/chemistry , Diterpenes/isolation & purification , Dose-Response Relationship, Drug , Hepatitis B virus/genetics , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Twelve new polyketides, including a naphthoquinone derivative, penithoketone (1), and 11 chromone derivatives, penithochromones A-L (2-12), together with three known compounds (13-15) were isolated from the deep-sea-derived fungus Penicillium thomii YPGA3. The structures of the metabolites were elucidated based on extensive analyses of the spectroscopic data, and the configuration of 1 was resolved by quantum chemical calculations of NMR shifts and ECD spectra and comparisons to experimental data. Compound 1, containing a naphthoquinone-derived moiety substituted with a butenolide unit, represents a new modified naphthoquinone skeleton. Interestingly, the 5,7-dioxygenated chromone derivatives 2-13 possessed different alkyl acid or alkyl ester side chain lengths, and those with side chain lengths of seven carbon atoms were discovered from nature for the first time. The metabolites were evaluated for their cytotoxicity against four cancer cell lines; compounds 1 and 15 were found to be active, with IC50 values ranging from 4.9 to 9.1 µM.
Subject(s)
Penicillium/chemistry , Polyketides/chemistry , Circular Dichroism , Magnetic Resonance Spectroscopy , Molecular Structure , Oceans and Seas , Water MicrobiologyABSTRACT
Chemical examination of the fermented material of the deep-sea-derived fungus Penicillium thomii YPGA3 led to the identification of a rare 19-nor labdane-type diterpenoid, named penitholabene (1). The structure was elucidated based on extensive analyses of the spectroscopic data and quantum chemical calculations of the 13C NMR and ECD data. A synthetic compound from commercial sources with the same planar structure is recorded in SciFinder (CAS number: 1217878-75-5), but there is no related reference and the configurations of chiral centers and double bond are not depicted. Penitholabene was reported as a new compound in the current study. To our knowledge, Penitholabene represents the first 19-nor labdane-type diterpenoid found in nature. It showed inhibitory effect against α-glucosidase with an IC50 value of 282 µM, being more active than the positive control acarbose (1.33 mM).
Subject(s)
Diterpenes/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Penicillium/chemistry , Seawater/microbiology , Diterpenes/isolation & purification , Glycoside Hydrolase Inhibitors/isolation & purification , Molecular Structure , Pacific OceanABSTRACT
A chemical study of the ethyl acetate (EtOAc) extract from the deep-sea-derived fungus Penicillium thomii YPGA3 led to the isolation of a new austalide meroterpenoid (1) and seven known analogues (28), two new labdane-type diterpenoids (9 and 10) and a known derivative (11). The structures of new compounds 1, 9, and 10 were determined by comprehensive analyses via nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data. The absolute configurations of 1, 9, and 10 were determined by comparisons of experimental electronic circular dichroism (ECD) with the calculated ECD spectra. Compound 1 represented the third example of austalides bearing a hydroxyl group at C-5 instead of the conserved methoxy in other known analogues. To our knowledge, diterpenoids belonging to the labdane-type were discovered from species of Penicillium for the first time. Compound 1 showed cytotoxicity toward MDA-MB-468 cells with an IC50 value of 38.9 M. Compounds 2 and 11 exhibited inhibition against α-glucosidase with IC50 values of 910 and 525 M, respectively, being more active than the positive control acarbose (1.33 mM).
Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Penicillium , Terpenes/pharmacology , Animals , Antineoplastic Agents/chemistry , Antioxidants/chemistry , Cell Line, Tumor/drug effects , Circular Dichroism , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Oceans and Seas , Terpenes/chemistry , alpha-Glucosidases/chemistryABSTRACT
Cyclopianes, featuring a highly rigid 6/5/5/5-fused tetracyclic framework, are structurally unique and biologically significant and belong to a rarely reported diterpenoid family. Chemical investigation of an EtOAc extract of a deep-sea-derived Penicillium sp. led to the isolation of three new cyclopiane diterpenes, namely, conidiogenols C-D (1-2) and conidiogenone L (3). The structures were determined by extensive analyses of the spectroscopic data in association with ECD calculations and chemical conversion for configurational assignments. Compound 1 represents the second example of cyclopianes bearing a hydroxyl group at C-13. Compound 2, the third example of conidiogenols, possesses a distinct α-oriented 1-hydroxy group relative to other analogues. The bioassay study demonstrated that compounds 2 and 4-6 exhibited moderate inhibitory effects against five esophageal cancer cell lines with IC50 values ranging from 25 to 55⯵M. The cytotoxicities of all compounds toward esophageal cancer cell lines were evaluated for the first time.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma/drug therapy , Diterpenes/pharmacology , Esophageal Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , Diterpenes/chemistry , Diterpenes/isolation & purification , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Penicillium/chemistry , Structure-Activity RelationshipABSTRACT
Three new butenolide derivatives, namely aspernolides N-P (1-3), together with six known analogues (4-9), were isolated from the ethyl acetate (EtOAc) extract of the deep sea-derived fungus Aspergillus terreus YPGA10. The structures of compounds 1-3 were determined on the basis of comprehensive analyses of the nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data, and the absolute configurations of 1 and 2 were determined by comparisons of experimental electronic circular dichroism (ECD) with calculated ECD spectra. Compound 1 represents the rare example of Aspergillus-derived butenolide derivatives featured by a monosubstituted benzene ring. Compounds 6-9 exhibited remarkable inhibitory effects against α-glucosidase with IC50 values of 3.87, 1.37, 6.98, and 8.06 µM, respectively, being much more active than the positive control acarbose (190.2 µM).
Subject(s)
4-Butyrolactone/analogs & derivatives , Aquatic Organisms/chemistry , Aspergillus/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , 4-Butyrolactone/chemistry , 4-Butyrolactone/isolation & purification , 4-Butyrolactone/pharmacology , Acetates/chemistry , Circular Dichroism , Enzyme Activation/drug effects , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/isolation & purification , Magnetic Resonance Spectroscopy , Mass SpectrometryABSTRACT
Twelve terpenoids, including two new 3,5-dimethylorsellinic acid-based meroterpenoids (1 and 2) and two new monoterpenoids (11 and 12), were obtained from the deep-sea fungus Penicillium sp. YPGA11. Their structures were determined by extensive analyses of spectroscopic data, and the absolute configurations of 1 and 2 were determined by comparisons of experimental and calculated ECD spectra. Compounds 1 and 2, bearing a 23-aldehyde or 23-carboxylic acid group, were rarely found in compounds with similar carbon skeleton. All compounds but 11 were evaluated for inhibitory effects towards nitric oxide production induced by lipopolysaccharide in RAW 264.7 macrophage cells. Compound 9 exhibited significant inhibitory effects with an IC50 value of 7.58⯵M, being comparable to the positive control, quercetin (10.97⯵M).
Subject(s)
Monoterpenes/pharmacology , Nitric Oxide/biosynthesis , Penicillium/chemistry , Terpenes/pharmacology , Animals , Aquatic Organisms/chemistry , Macrophages/drug effects , Mice , Molecular Structure , Monoterpenes/isolation & purification , RAW 264.7 Cells , Terpenes/isolation & purificationABSTRACT
One new indole diterpenoid, drechmerin I (1), was isolated from the fermentation broth of Drechmeria sp. isolated from the root of Panax notoginseng. Its structure was elucidated based on 1 D and 2 D nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectrum (HRESIMS), and electronic circular dichroism (ECD) spectroscopic analyses as well as TD DFT calculations of ECD spectra. Drechmerin I (1) was assayed for its antimicrobial activity against Candida albicans, Staphylococcus aureus, Bacillus cereus, B. subtillis, Pseudomonas aeruginosa, and Klebsiella pneumonia, respectively. Drechmerin I (1) showed antimicrobial activities against B. subtillis with an MIC value of 200 µg/mL. The interaction of S. aureus peptide deformylase with drechmerin I (1) was investigated by molecular docking.
Subject(s)
Anti-Infective Agents/pharmacology , Diterpene Alkaloids/pharmacology , Hypocreales/chemistry , Indole Alkaloids/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/isolation & purification , Bacillus cereus/drug effects , Candida albicans/drug effects , Circular Dichroism , Diterpene Alkaloids/chemistry , Diterpene Alkaloids/isolation & purification , Indole Alkaloids/chemistry , Indole Alkaloids/isolation & purification , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Pseudomonas aeruginosa/drug effects , Spectrometry, Mass, Electrospray Ionization , Staphylococcus aureus/drug effectsABSTRACT
A new indole diterpene, named penicindopene A (1), together with seven known compounds (2 - 8), was isolated from the deep-sea fungus Penicillium sp. YPCMAC1. The structure of penicindopene A was elucidated by extensive spectroscopic analyses (1 D and 2 D NMR, and HRESIMS data), in addition to the ECD calculations for the assignments of its absolute configuration. Penicindopene A represented the first example of indole diterpenes possessing a 3-hydroxyl-2-indolone moiety, and it exhibited moderate cytotoxicities against A549 and HeLa cell lines with IC50 values of 15.2 and 20.5 µM, respectively.
Subject(s)
Diterpenes/isolation & purification , Indoles/isolation & purification , Molecular Conformation , Penicillium/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Diterpenes/chemistry , Drug Screening Assays, Antitumor , Fungi , HeLa Cells , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy/methods , Molecular StructureABSTRACT
[This corrects the article DOI: 10.1039/C6RA26956G.].
ABSTRACT
Chemical examination of the EtOAc extract of the deep sea-derived fungus Penicillium sp. YPGA11 resulted in the isolation of four new farnesylcyclohexenones, peniginsengins Bâ»E (1â»4), and a known analog peniginsengin A (5). The structures of compounds 1â»4 were determined on the basis of comprehensive analyses of the nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data, and the absolute configurations of 1, 2, and 4 were determined by comparisons of experimental electronic circular dichroism (ECD) with calculated ECD spectra. Compounds 1â»5, characterized by a highly oxygenated 1-methylcyclohexene unit and a (4E,8E)-4,8-dimethyldeca-4,8-dienoic acid side chain, are rarely found in nature. Compounds 2â»4 exhibited antibacterial activity against Staphylococcus aureus.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cyclohexanones/chemistry , Diterpenes/chemistry , Fungi/chemistry , Indole Alkaloids/chemistry , Penicillium/chemistry , Circular Dichroism/methods , Cyclohexanones/pharmacology , Diterpenes/pharmacology , Indole Alkaloids/pharmacology , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Microbial Sensitivity Tests , Staphylococcus aureus/drug effectsABSTRACT
A novel 1(2), 2(18)-diseco indole diterpenoid, drechmerin H (1), was isolated from the fermentation broth of Drechmeria sp. together with a new indole diterpenoid, 2'-epi terpendole A (3), and a known analogue, terpendole A (2). Their structures were determined by HRESIMS, 1D and 2D NMR, ECD, and X-ray single crystal diffraction analyses as well as quantum chemical calculation. The abosulte configuration of terpendole A (2) was determined for the first time. Compound 1 displayed the significant agonistic effect on pregnane X receptor (PXR) with EC50 value of 134.91⯱â¯2.01â¯nM, and its interaction with PXR was investigated by molecular docking. Meantime, a plausible biosynthetic pathway for compounds 1-3 is also discussed in the present work.
Subject(s)
Biological Products/pharmacology , Diterpenes/pharmacology , Hypocreales/chemistry , Indoles/pharmacology , Pregnane X Receptor/agonists , Biological Products/chemistry , Biological Products/isolation & purification , Diterpenes/chemistry , Diterpenes/isolation & purification , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Indoles/chemistry , Indoles/isolation & purification , Molecular Structure , Structure-Activity RelationshipABSTRACT
Further chemical examination of a coral-associated fungus Aspergillus versicolor LZD-14-1 by the PHLC-DAD detection resulted in the isolation of six new polycyclic alkaloids, namely versiquinazolines L-Q (1-6). Their structures were determined by extensive analyses of spectroscopic data, including quantum ECD calculation and X-ray single crystal diffraction for the assignment of absolute configurations. Versiquinazoline L bearing a d-Ala residue and versiquinazoline M containing an l-serine residue are rarely found in the fumiquinazoline-type alkaloids, while versiquinazoline P displayed an unusual scaffold with a spiro-γ-lactone. Versiquinazolines P and Q exhibited significant inhibition against thioredoxin reductase (TrxR) with IC50 values of 13.6 ± 0.6 and 12.2 ± 0.7 µM, which showed higher activity than the positive control curcumin (IC50 = 25 µM). The weak cytotoxicity and potent inhibition toward TrxR suggested that versiquinazolines P and Q are potential for microenvironmental regulation of tumor progression and metastasis.
ABSTRACT
Two heterodimeric diterpenoids (1 and 2) comprising abietane lactone and nor-rosane constituent units were isolated from Euphorbia ebracteolata roots. Compound 1 exhibited a moderate inhibitory effect on α-glucosidase (IC50 = 7.94 µM), with a Ki value of 10.8 µM. In silico molecular docking has been performed to investigate the inhibition mechanism. Compound 2 inhibited the acetyl transfer activity of Mycobacterium tuberculosis GlmU (IC50 = 41.85 µM), which is a novel tuberculosis treatment target.
Subject(s)
Diterpenes/chemistry , Diterpenes/pharmacology , Euphorbia/chemistry , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Plant Roots/chemistry , alpha-Glucosidases/metabolism , Lactones/chemistry , Lactones/pharmacology , Molecular Docking Simulation/methods , Mycobacterium tuberculosis/drug effects , Structure-Activity RelationshipABSTRACT
Bioassay-guided fractionation of the ethanolic extract of the leaves of Psidium guajava led to the isolation of 11 new Psidium meroterpenoids, psiguajadials A-K (1-11), along with 17 known ones (12-28). Their structures and absolute configurations were elucidated by spectroscopic methods and comparison of experimental and calculated ECD. Compounds 1 and 2 represent two unprecedented skeletons of 3,5-diformyl-benzyl phloroglucinol-coupled sesquiterpenoid, while 3 is the first example of Psidium meroterpenoids coupling via an oxepane ring. Putative biosynthetic pathways towards 1 and 2 are proposed. Compounds 1-13 and 16-26 exhibited moderate inhibitory activities against phosphodiesterase-4 (PDE4), a drug target for asthma and chronic obstructive pulmonary disease, with IC50 values in the range of 1.34-7.26 µM.
Subject(s)
Phosphodiesterase 4 Inhibitors/pharmacology , Plant Leaves/chemistry , Psidium/chemistry , Terpenes/pharmacology , Biosynthetic Pathways , Chemical Fractionation , Inhibitory Concentration 50 , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/isolation & purification , Spectrum Analysis , Terpenes/chemistry , Terpenes/isolation & purificationABSTRACT
Aristoyunnolin H is a novel aristophyllene sesquiterpenoid isolated from the traditional Chinese medicine Aristolochia yunnanensis Franch. The present research was designed to explore the anti-fibrotic effects of aristoyunnolin H in adult rat cardiac fibroblasts (CFs) stimulated with angiotensin II (Ang II). Western blot analysis data showed that aristoyunnolin H reduced the upregulation of fibronectin (FN), connective tissue growth factor and collagen I(Col I) production induced by Ang II in CFs. By studying the dynamic intracellular changes of Ca2+, we further found that while aristoyunnolin H relieved the calcium influx, it has no effect on intracellular calcium store release. Meanwhile, aristoyunnolin H also inhibited the Ang II-stimulated phosphorylation of Ca2+/calmodulin-dependent protein kinase II. In conclusion, aristoyunnolin H may attenuate extracellular matrix secretion in vitro by inhibiting Ang II-induced calcium signaling.