Protein tyrosine phosphatase 1B inhibitory effects of depsidone and pseudodepsidone metabolites from the Antarctic lichen Stereocaulon alpinum

Seven phenolic lichen metabolites (1–7) have been isolated from a methanol extract of the Antarctic lichen Stereocaulon alpinum by various chromatographic methods. The structures of these compounds were determined mainly by analysis of NMR spectroscopic data. A depsidone-type compound, lobaric acid (1) and two pseudodepsidone-type compounds, 2 and 3, exhibited potent inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC₅₀ values of 0.87 μM, 6.86 μM, and 2.48 μM, respectively. Kinetic analyses of PTP1B inhibition by compounds 1 and 2 suggested that these compounds inhibited PTP1B activity in a non-competitive manner.     

A novel sesquiterpene quinone from Hainan sponge Dysidea villosa

A new sesquiterpene quinone, 21-dehydroxybolinaquinone (5), together with two known related analogues, bolinaquinone (6) and dysidine (7), had been isolated from the Hainan sponge Dysidea villosa. The structure of the new compound 5 was elucidated on the basis of detailed analysis of spectroscopic data and by comparison with related model compounds. Compounds 5–7 were evaluated for the inhibitory activity against hPTP1B, a potential drug target for treatment of type-II diabetes and obesity, and cytotoxic activity against Hela cell line. The results showed that dysidine (7) had the strongest hPTP1B inhibitory activity with an IC₅₀ value of 6.70 μM and 6 had significant cytotoxic activity against Hela cell line with an IC₅₀ value of 5.45 μM. New compound 5 showed moderate PTP1B inhibitory activity and cytotoxicity with IC₅₀ values of 39.50 and 19.45 μM, respectively.     

New prenylated isoflavonoids as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Erythrina addisoniae

Bioassay-guided fractionation of the EtOAc extract of the root of Erythrina addisoniae (Leguminosae) resulted in the isolation of four new (1–4), along with 2 known prenylated isoflavonoids (5–6). The structures of the isolates were assigned on the basis of spectroscopic data analysis, focusing on interpretation of 1D and 2D NMR, and MS data. All the isolates were evaluated for their inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), as well as their growth inhibition on MCF7, adriamycin-resistant MCF7 (MCF7/ADR), and MDA-MB-231 breast cancer cell lines. Compounds which exhibited PTP1B inhibitory activity (IC₅₀ values ranging from 4.6 ± 0.3 to 24.2 ± 2.1 μM) showed potential cytotoxic activity (IC₅₀ values ranging from 3.97 ± 0.17 to 11.4 ± 1.9 μM). Taken together, our data suggest that prenylated isoflavonoids, especially the isoflavone-type skeleton could be considered as new lead compounds against breast cancer via PTP1B inhibition.     

Ellagitannin and flavonoid constituents from Agrimonia pilosa Ledeb. with their protein tyrosine phosphatase and acetylcholinesterase inhibitory activities

A new ellagitannin, agritannin (1), a new flavone glycoside, agriflavone (2), and another flavone glycoside with spectroscopic data reported for the first time, kaempferol-3-O-[(S)-3-hydroxy-3-methylglutaryl (1→6)]-β-d-glucoside (3), along with 16 known compounds were isolated from the aerial parts of Agrimonia pilosa Ledeb. These compounds were evaluated for PTP1B inhibitory activity. Among them, compounds 9 and 18 displayed potential inhibitory activity against PTP1B with IC₅₀ values of 7.14 ± 1.75 and 7.73 ± 0.24 μM, respectively. In addition, compound 1 showed significant inhibitory effect with an IC₅₀ value of 17.03 ± 0.09 μM. Furthermore, these compounds were tested in AChE inhibitory assays. Most of them were found to have moderate inhibitory effects, with IC₅₀ values ranging from 60.20 ± 1.09 to 92.85 ± 1.12 μM. Except compounds 3, 8, and 18 were inactive.     

Chemical constituents of Ligularia alticola Worosch. leaves and their biological activities

Seven eremophilane-type sesquiterpenes (1–7), six cycloartane derivatives (8–13) and α-amyrin acetate (14) were isolated from the leaves of the far-eastern plant Ligularia alticola Worosch. (Family Asteraceae). (4S,5R,8S,10R)-8-Ethoxyeremophil-7(11)-en-12(8)-olide (1), 8α,11-epidioxy-8β-methoxyeremophil-6-ene (2) and 29-norcycloartan-3α-ol (8) have not been previously reported. Fukinone α-epoxide (3) was isolated for the first time from a natural source. The structures of all the compounds were established by the extensive analysis of their 1D and 2D NMR spectra and HR ESI mass spectrometry. The absolute stereochemistry of 1 was determined by comparison of theoretical and experimental ECD spectra with the application of B3LYP-TDDFT and B3LYP-GIAO calculations as well as by NMR spectroscopy. Compound 1 showed cytotoxic action against human cancer HL-60, Raji, and THP-1 cell lines (IC₅₀ 12.6, 6.0 and 6.9 μM, respectively). Compounds 2 and 4 demonstrated significant cytotoxic activities against HL-60 (IC₅₀ 2.8 and 5.8 μM, respectively) and Raji cells (IC₅₀ 2.9 and 4.2 μM, respectively). Compound 6 was cytotoxic against Raji cells (IC₅₀ 4.6 μM). None of tested compounds were cytotoxic against RAW 264.7 cells. Compounds 1 and 4–7 significantly decreased intracellular ROS levels, induced by endotoxic LPS from Escherichia coli in RAW 264.7 murine macrophages.     

Inhibitory effect of chalcones and their derivatives from Glycyrrhiza inflata on protein tyrosine phosphatase 1B

Compounds (1–6) isolated from the CH₂Cl₂ extract of Glycyrrhiza inflata and semisynthetic licochalcone A derivatives (7–14) were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activities. Licochalcones A (4) and E (6), each with an allyl group at position 5 in the B ring exhibited significant inhibitory effects. Licochalcone A derivative 7, the most potent among the series, had an IC₅₀ value of 11.7 ± 2.0 μM, ca. twofold better than that of licochalcone A (4).     

Derivatives (halogen,nitro and amino) of 8-hydroxyquinoline with highly potent antimicrobial and antioxidant activities

8-Hydroxyquinoline (8HQ) compounds have been reported to possess diverse bioactivities. In recent years, drug repositioning has gained considerable attention in drug discovery and development. Herein, 8HQ (1) and its derivatives (2–9) bearing various substituents (amino, nitro, cyano and halogen) were investigated for their antimicrobial against 27 microorganisms (agar dilution method) and antioxidant (DPPH method) activities. The parent 8HQ (1) exerted a highly potent antimicrobial activity against Gram-positive bacteria including diploid fungi and yeast with MIC values in the range of 3.44–13.78 μM. Moreover, the halogenated 8HQ, especially 7-bromo-8HQ (4) and clioquinol (6), displayed a high antigrowth activity against Gram-negative bacteria compared with the parent compound (1). Apparently, the derivatives with a relatively high safely index, e.g., nitroxoline (2), exhibited strong antibacterial activity against Aeromonas hydrophila (MIC=5.26 μM) and selectively inhibited the growth of P. aeruginosa with the MIC value of 84.14 μM; cloxyquin (3) showed a strong activity against Listseria monocytogenes and Plesiomonas shigelloides with MIC values of 5.57 and 11.14 μM, respectively. Most compounds displayed an antioxidant activity. Specifically, 5-amino-8HQ (8) was shown to be the most potent antioxidant (IC₅₀=8.70 μM) compared with the positive control (α-tocopherol) with IC₅₀ of 13.47 μM. The findings reveal that 8HQ derivatives are potential candidates to be further developed as antimicrobial and antioxidant agents.     

Structure–cytotoxic activity relationship of sesquilignan,morinol A

The cytotoxic activities of sesquilignans, (7S,8S,7′R,8′R)- and (7R,8R,7′S,8′S)-morinol A and (7S,8S,7′S,8′S)- and (7R,8R,7′R,8′R)-morinol B were compared, showing no significant difference between stereoisomers (IC₅₀ = 24–35 μM). As a next stage, the effect of substituents at 7, 7′, and 7″-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18 (IC₅₀ = 6–7 μM). In the research on the structure–activity relationship of 7″-position of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18, the most potent compounds were 7,7′,7″-phenyl derivative 18 (IC₅₀ = 6 μM) against HeLa cells. Against HL-60 cells, 7″-(4-nitrophenyl)-7,7′-phenyl derivative 33 and 7″-hexyl-7,7′-phenyl derivative 37 (IC₅₀ = 5 μM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7′R,8′R)-morinol A. It was also confirmed that the 7′-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity.     

Design and synthesis of 2-substituted benzoxazoles as novel PTP1B inhibitors

A series of benzoxazole compounds containing oxamic acid were synthesized and screened for the PTP1B inhibition. Compound 31d showed best biochemical potency (K_i) of 6.7 μM. Structure–activity relationship were explained with the help of molecular modeling approach.     

Acylated iridoid glycosides and acylated rhamnopyranoses from Gmelina arborea flowers

Nine acylated iridoid glycosides (1–9), five acylated rhamnopyranoses (10–14) and verbascoside (15) were isolated from Gmelina arborea flowers, including 5 new compounds (1, 2, and 10–12). The cytoprotective activity of 11 selected compounds (1–8, 10, 11, and 15) against CCl₄-induced cytotoxicity on liver was determined. Compounds 1, 2, 4, 7, 8 and 15 displayed hepatoprotective activity. 6-O-α-l-(2″, 3″-di-O-trans-p-hydroxycinnamoyl)rhamnopyranosylcatalpol (2) exhibited the most potent cytoprotective effect with an EC₅₀ value of 42.5 μM (SI = 19.3) compared with biphenyldimethylesterate (DDB, EC₅₀ = 277.3 μM, SI = 9.8) and bicylo-ethanol (EC₅₀ = 279.2 μM, SI = 12.2). Among the acylated iridoid glycosides, the compounds (2 and 8) containing phenolic hydroxy groups were more active than were those lacking them.     

PTP1B inhibitors from Selaginella tamariscina (Beauv.) Spring and their kinetic properties and molecular docking simulation

Diabetes is one of the most popular worldwide diseases, regulated by the defects in insulin secretion, insulin action, or both. The overexpression of protein tyrosine phosphatase 1B (PTP1B) was found to down-regulate the insulin-receptor activation. PTP1B has been known as a strategy for the treatment of diabetes via the regulation of insulin signal transduction pathway. Herein, we investigated the PTP1B inhibitors isolated from natural sources. The chemical investigation of Selaginella tamariscina (Beauv.) Spring revealed seven unsaturated alkynyl phenols 1–7, four new selaginellins T–W 1–4 together with three known compounds 5–7 isolated from the aerial parts. The structures of the isolates were determined by spectroscopic techniques (1D/2D-NMR, MS, and CD). The inhibitory effects of these isolates on the PTP1B enzyme activity were investigated. Among them, compounds 2–7 significantly exhibited the inhibitory effects with the IC₅₀ values ranging from 4.8 to 15.9 μM. Compound 1 moderately displayed the inhibitory activity with an IC₅₀ of 57.9 μM. Furthermore, active compounds were discovered from their kinetic and molecular docking analysis. The results revealed that compounds 2 and 4–7 were mixed-competitive inhibitors, whereas compound 3 was a non-competitive inhibitor. This data confirm that these compounds exhibited potential inhibitory effect on the PTP1B enzyme activity.     

Xanthine oxidase inhibitory terpenoids of Amentotaxus formosana protect cisplatin-induced cell death by reducing reactive oxygen species (ROS) in normal human urothelial and bladder cancer cells

The diterpenoids (+)-ferruginol (1), ent-kaur-16-en-15-one (2), ent-8(14),15-sandaracopimaradiene-2α,18-diol (3), 8(14),15-sandaracopimaradiene-2α,18,19-triol (4), and (+)-sugiol (5) and the triterpenoids 3β-methoxycycloartan-24(24¹)-ene (6), 3β,23β-dimethoxycycloartan-24(24¹)-ene (7), 3β,23β-dimethoxy-5α-lanosta-24(24¹)-ene (8), and 23(S)-23-methoxy-24-methylenelanosta-8-en-3-one (9), isolated from Amentotaxus formosana, showed inhibitory effects on xanthine oxidase (XO). Of the compounds tested, compound 5 was a potent inhibitor of XO activity, with an IC₅₀ value of 6.8 ± 0.4 μM, while displaying weak ABTS radical cation scavenging activity. Treatment of the bladder cancer cell line, NTUB1, with 3–10 μM of compound 5 and 10 μM cisplatin, and immortalized normal human urothelial cell line, SV-HUC1, with 0.3–1 μM and 10–50 μM of compound 5 and 10 μM cisplatin, respectively, resulted in increased viability of cells compared with cytotoxicity induced by cisplatin. Treatment of NTUB1 with 20 μM cisplatin and 10 or 30 μM of compound 5 resulted in decreased ROS production compared with ROS production induced by cisplatin. These results indicate that 10 or 30 μM of compound 5 in NTUB1 cells may mediate through the suppression of XO activity and reduction of reactive oxygen species (ROS) induced by compound 5 cotreated with 20 μM cisplatin and protection of subsequent cell death.     

Melanogenesis inhibitory activity of a 7-O-9′-linked neolignan from Alpinia galanga fruit

An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC₅₀ = 7.3 μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9′-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2–15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC₅₀ = 2.5 μM), 1′S-1′-acetoxychavicol acetate (2, 5.0 μM), and 1′S-1′-acetoxyeugenol acetate (3, 5.6 μM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1′-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9′-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1′ (IC₅₀ = 1.9 μM) and 2′ (4.5 μM)] and racemic mixtures [(±)-1 (2.2 μM) and (±)-2 (4.4 μM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1–3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity.     

Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

Lactarane sesquiterpenoids from Lactarius subvellereus and their cytotoxicity

Subvellerolactones B (1), D (2), and E (3), structurally unusual lactarane sesquiterpenoids, were isolated from the fruiting bodies of Lactarius subvellereus together with four known lactarane sesquiterpenes (4–7). The chemical structures and stereochemistries of compounds 1–3 were determined on the basis of spectroscopic analyses, including 1D and 2D NMR experiments and a convenient Mosher ester procedure. Subvellerolactone B (1) exhibited cytotoxicity against the A549, SK-MEL-2, and HCT-15 cell lines with IC₅₀ values of 26.5, 18.3, and 14.2 μM, respectively, and subvellerolactones D (2) and E (3) showed cytotoxicity against the A549 and HCT-15 cell lines (IC₅₀ (2): 25.1 and 17.8 μM, and IC₅₀ (3): 19.6 and 28.7 μM, respectively).     

Two new diphenyl ethers from Acanthopanax senticosus (Rupr. & Maxim.) Harms with PTP1B inhibitory activity

Bioassay-guided fractionation of an EtOAc-soluble extract of Acanthopanax senticosus (Rupr. & Maxim.) Harms yielded two new diphenyl ethers, 3-[3′-methoxy-4′-(4″-formyl-2″,6″-dimethoxy-phenoxy)-phenyl]-propenal (1) and 3-[3′,5′-dihydroxy-4′-(4″-hydroxymethyl-3″,5″-dimethoxy-phenoxy)-phenyl]-propenal (2), along with eight other known compounds (3–10). The structures of these new ethers were elucidated with spectroscopic and physico-chemical analyses. All of the isolates were evaluated for their in vitro inhibitory activity against PTP1B, VHR and PP1. The new compounds (1 and 2) inhibited PTP1B with IC₅₀ values ranging from 9.2 ± 1.4 to 12.6 ± 1.2 μM.     

Furanoterpenes,new types of protein tyrosine phosphatase 1B inhibitors,from two Indonesian marine sponges,Ircinia and Spongia spp.

Protein tyrosine phosphatase (PTP) 1B negatively regulates the insulin and leptin signaling pathways, and, thus, the clinical application of PTP1B inhibitors to the prevention and treatment of type 2 diabetes and obesity is expected. During our studies on PTP1B inhibitors, two furanosesterterpenes and a C21 furanoterpene were obtained as new types of PTP1B inhibitors from two Indonesian marine sponges. (7E, 12E, 20Z, 18S)-Variabilin (1) and (12E, 20Z, 18S)-8-hydroxyvariabilin (2) from Ircinia sp. and furospongin-1 (3) from Spongia sp. inhibited PTP1B activity with IC₅₀ values of 1.5, 7.1, and 9.9 μM, respectively. The inhibitory activity of compound 1 against T-cell PTP (TCPTP) was approximately 2-fold that against PTP1B, whereas the vaccinia H-1-related phosphatase (VHR) inhibitory effects of 1 were 4-fold weaker than that of its PTP1B inhibitory activity. Compounds 1–3 at 50 μM did not show cytotoxicity against two human cancer cell lines, hepatoma Huh-7 and bladder carcinoma EJ-1. Compound 1 did not enhance the phosphorylation level of Akt, a key downstream effector of the cascade, in Huh-7 cells.     

New diterpene furanoids from the Antarctic lichen Huea sp

In the course of ongoing research on protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from Antarctic lichens, four new diterpene furanoids, hueafuranoids A–D (1–4) have been isolated from the MeOH extract of Antarctic lichen Huea sp. by various chromatographic methods. The structures of these compounds were elucidated by analysis of NMR and MS data, and comparing their spectral data with those in the literature. Compound 1 showed inhibitory activity against therapeutically targeted protein, PTP1B with an IC₅₀ value of 13.9 μM. The kinetic analysis of PTP1B inhibition by hueafuranoid A (1) suggested that the diterpene furanoids encountered in this study inhibited PTP1B activity in a non-competitive manner.     

Novel thiophene derivatives as PTP1B inhibitors with selectivity and cellular activity

A series of novel thiophene derivatives was designed, synthesized and their activities as competitive inhibitors of protein tyrosine phosphatase (PTPs) 1B (PTP1B) inhibitors were evaluated. All the compounds showed inhibitory potencies, and 10 of these exhibited moderate inhibitory activities with IC₅₀ values less than 10 μM. The activity of the most potent compound P28 (IC₅₀ = 2.1 μM) was 15 times higher than that of the hit compound P01. Further, four representative compounds (P19, P22, P28, and P31) demonstrated remarkably high selectivities against other PTPs (e.g., PTPα, LAR, CD45, and TCPTP); P19 exhibited greater than sixfold selectivity over highly homologous TCPTP. More importantly, these compounds are permeable to cell membranes. The treatment of CHO-K1 cells with P28 (10 μM) resulted in increased phosphorylation of AKT, which suggested extensive cellular activity of this compound. The novel chemical entities reported in this study could be used for overcoming the poor selectivity and low cellular activity of PTP1B inhibitors and might represent a starting point for development of therapeutic PTP inhibitors.     

Design,synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues

The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC₅₀ = 20 μM—visual CPE score; EC₅₀ = 18 μM—MTS method; MCC >100 μM, CC₅₀ >100 μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC₅₀ = 9 and 12 μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC₅₀ = 2.9 and 4 μM, respectively) and feline herpes virus in CRFK cells (EC₅₀ = 4 μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC ⩾ 4 μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC₅₀ in the 4–50 μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC₅₀ in the 4–7 μM range).