Acylated dolabellane-type diterpenes from Nigella sativa seeds with triglyceride metabolism-promoting activity in high glucose-pretreated HepG2 cells

Two new acylated dolabellane-type diterpenes, nigellamines B₃ (9) and D (10), were isolated from Nigella sativa (Ranunculaceae) seeds using column chromatography and preparative HPLC. Their structures were determined based on chemical and physicochemical evidence, and confirmed using previously isolated related compounds as reference. Of the seed constituents, nigellamines A₂ (2), A₃ (3), A₅ (5), B₁ (6), and B₂ (7) had in vitro triglyceride metabolism-promoting activities in the high glucose-pretreated human liver carcinoma cell line, HepG2.     

Chemical constituents from the roots of Euphorbia nematocypha Hand.-Mazz.

A new myrsinol-type diterpene (1), three myrsinol-type diterpenes (2–4), three ent-abietane-type diterpenes (5–7), one tigliane-type diterpene (8), two cycloartane-type triterpenes (9–10), and two tirucallane-type triterpenes (11–12) were isolated from the roots of Euphorbia nematocypha Hand.-Mazz. Their structures were identified by spectroscopic analyses and by comparison of their spectral data with those reported in the literature. Compound 12 was isolated and reported from plants for the first time. All compounds were isolated from E. nematocypha for the first time.     

Two new glycosides from the whole plant of Anemone rivularis var. flore-minore

Phytochemical investigation on the whole plant of Anemone rivularis var. flore-minore led to the isolation of a new labdane-type diterpene glycoside (1) and a new trihydroxyfuranoid lignanoid glycoside (2), together with three known triterpene and triterpenoid glycosides (3–5). The structures of the two new compounds were elucidated as β-d-glucopyranosyl (13S)-13-hydroxy-7-oxo-labda-8,14-diene-18-oate (1) and (7S,7′R,8R,8′S)-7′-butoxy-7,9′-epoxy-4,4′,9-trihydroxy-3,3′-dimethoxylignane 9-O-β-d-glucopyranoside (2), on the basis of extensive spectral analysis and chemical evidence. Compound 1 is characterized by a glucose (Glc) esterified C-18 carboxyl group, which is a rarely encountered labdane-type diterpene glycoside in nature. The two new compounds (1 and 2) reported here are the first examples of diterpene glycoside and lignanoid glycoside found in the genus Anemone, and the known triterpene and triterpenoid glycosides (3–5) are identified for the first time from the title plant.     

Two new compounds from Trigonostemon heterophyllus

Phytochemical investigation on the stems of Trigonostemon heterophyllus led to the isolation of a new diterpene, trigonoheterene (1), and a new naphthoquinone, trigonoheterone (2), together with two known compounds, 3,4-seco-sonderianol, (3) and trigonochinene E, (4). Their structures were determined by spectroscopic techniques (UV, IR, MS, 1D and 2D NMR). All compounds were evaluated for cytotoxic activities and antibacterial activities.     

Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes

α₁-Adrenoceptor (α₁-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2–17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH₃, 2-CH₃ or 2, 5-CH₃, respectively, exhibited potent α₁-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (?)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α_1A), spleen (α_1B) and thoracic aorta (α_1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α_1D/1A subtype selectivity, especially improved α_1A subtype selectivity, and the ratios pA₂ (α_1D)/pA₂ (α_1B) and pA₂ (α_1A)/pA₂ (α_1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.     

Melanogenesis inhibitory daphnane diterpenoids from the flower buds of Daphne genkwa

Two new daphnane-type diterpene esters, daphneresiniferins A (1) and B (2), along with seven known diterpenes, yuanhuacine (3), yuanhuadine (4), yuanhuahine (5), genkwadaphnin (6), genkwanine A (7), genkwanine F (8), and genkwanine H (9), were isolated from the methanol extract of the flower buds of Daphne genkwa. Their structures were elucidated on the basis of spectroscopic methods, especially 2D NMR spectra such as HMQC, HMBC, and NOESY. All the isolates were evaluated for their inhibitory effects of the melanogenesis against α-melanocyte stimulating hormone (α-MSH)-activated B16 melanoma cells.     

Aureolic acids from a marine-derived Streptomyces sp. WBF16

A marine-derived actinomycete (Streptomyces sp. WBF16) exhibiting antitumor activities was investigated. The strain was identified using morphological, biochemical and genetic techniques. 16S rDNA sequence of the isolate indicated that it was most closely related to Streptomyces coelicolor A3 (2). Furthermore, a new aureolic acid (Chromomycin B, 1), along with Chromomycin A₂ (2) and Chromomycin A₃ (3) were isolated from its secondary metabolites. Their structures were determined by chemical and spectroscopic methods including 1D, 2D NMR and HRMS. Compounds 1–3 showed strong cytotoxicity against SGC7901, HepG2, A549, HCT116 and COC1 and HUVEC.     

Topoisomerase II inhibitors from the roots of Stellera chamaejasme L.

Three new compounds, including one daphnane diterpene (1), one sesquiterpene (6), and one lignan (7) have been isolated from the Stellera chamaejasme L., together with five other known compounds, including four daphnane diterpenenoids (2–5) and one lignan (8). The structures of the new compounds were elucidated by spectroscopic analysis. The cytotoxicities of compounds 1–8 towards human lung adenocarcinoma cells (A549 cells) were evaluated using a sulforhodamine B assay. All of the compounds displayed significant cytotoxicity, with IC₅₀ values in the ranging of 0.2 nM to 2.0 μM. Mechanistic studies revealed that the antitumor activities of compounds 1–3 and 7 were derived from their inhibition of topoisomerase II (Topo II). Furthermore, as a Topo II inhibitor, compound 1 was found to effectively induced G2-M phase cell cycle arrest and apoptosis in cancer cells.     

Anti-inflammatory diterpenes from the seeds of Vitex negundo

Phytochemical investigation of a dichloromethane-soluble extract of Vitex negundo seeds led to the isolation of five labdane diterpenes, negundoins A–E (1–5), a 9,10-seco-abietane diterpene, negundoin F (6), a sandaracopimara-7,15-diene diterpene, negundoin G (7), and two known diterpene derivatives (8, 9). Their chemical structures were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. The anti-inflammatory effects of metabolites 1–7 were also evaluated in vitro. Compounds 3 and 5 were among the most potent inhibitors on nitric oxide production by LPS-stimulated RAW 264.7 macrophages, with IC₅₀ values of 0.12 and 0.23 μM, respectively. Further studies revealed that compounds 3 and 5 (5 μM) significantly reduced the levels of the iNOS protein to 0.40 ± 0.13% and 41.02 ± 6.02%, respectively, and COX-2 protein to 2.06 ± 0.53% and 26.40 ± 7.43%, respectively.     

Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET

Radiolabelled piperidine derivatives such as [¹¹C]MDL 100907 and [¹⁸F]altanserin have played an important role in diagnosing malfunction in the serotonergic neurotransmission. A variety of novel piperidine MDL 100907 derivatives, possible to label with ¹⁸F-fluorine, were synthesized to improve molecular imaging properties of [¹¹C]MDL 100907. Their in vitro affinities to a broad spectrum of neuroreceptors and their lipophilicities were determined and compared to the clinically used reference compounds MDL 100907 and altanserin. The novel compounds MA-1 (53) and (R)-MH.MZ (56) show K_i-values in the nanomolar range towards the 5-HT_2A receptor and insignificant binding to other 5-HT receptor subtypes or receptors. Interestingly, compounds MA-1 (53), MH.MZ (55) and (R)-MH.MZ (56) provide a receptor selectivity profile similar to MDL 100907. These compounds could possibly be preferable antagonistic ¹⁸F-tracers for visualization of the 5-HT_2A receptor status. Medium affine compounds (VK-1 (32), (51), (52), (54)) were synthesized and have K_i values between 30 and 120 nM. All promising compounds show log P values between 2 and 3, that is, within the range of those for the established radiotracers altanserin and MDL 100907. The novel compounds MA-1 (53) and (R)-MH.MZ (56) thus appear to be promising high affine and selective tracers of ¹⁸F-labelled analogues for 5-HT_2A imaging with PET.     

Acremonoside,a phenolic glucoside from the sea fan-derived fungus Acremonium polychromum PSU-F125

A new phenolic glucoside, acremonoside (1), along with two known compounds, F-11334 A₂ and 2,2-dimethyl-2H-chromen-6-ol, were isolated from the sea fan-derived fungus Acremonium polychromum PSU-F125. The structure of 1 was elucidated by spectroscopic techniques, acid hydrolysis and X-ray crystallographic analysis. The isolated compounds were tested for antibacterial, antimalarial, antimycobacterial and cytotoxic activities.     

Diterpenes and kawalactone from the rhizomes of Amomum uliginosum J.Koenig

Seven compounds, including three labdane diterpenes (1, 4, 6), one bisnorlabdane diterpene (2), one steroid (3), one sesquiterpene (5) and one kawalactone (7) were isolated from the rhizomes of Amomum uliginosum J.Koenig. Compounds 1–4, 6 and 7 were firstly isolated from the genus Amomum. This work represented the first phytochemical study on this plant. The chemotaxonomic significance of these compounds was summarized.     

Effect of outer sphere anions on the structure and color of nitrosylpentaamminechromium complex

Three kinds of crystalline compounds containing the nitrosylpentaamminechromium complexes [Cr(NO)(NH₃)₅]²⁺(A) were obtained: chloride ACl₂ (red-orange), chloride perchlorate ACl(ClO₄) (brown), and perchlorate A(ClO₄)₂ (green). The cause of the color change of the complex A with the change of outer sphere anions was sought using X-ray structural data of ACl₂, ACl(ClO₄), and A(ClO₄)₂. Crystal data: ACl₂, orthorhombic, space group Cmcm, a=10.0236 (9) Å, b=9.098 (3) Å, c=10.357(1) Å, V=944.5 (5) ų, Z=4; ACl(ClO₄), tetragonal, space group P4/nmm, a=7.6986 (8) Å, c=9.9566(8) Å, V=590.1 (1) Å^3,Z=2; A(ClO₄)₂, orthorhombic, space group Pnma, a=15.760 (2) Å, b=11.480(2) Å, c=7.920 (2) Å, V=1432.9 (4) ų, Z=4. The complex cation in ACl₂ has a distorted octahedral structure with a linear CrNO moiety. The short CrN (nitrosyl) distance of 1.692 (7) Å indicates the presence of multiple bonding between the chromium atom and the nitrogen atom in the nitrosyl group. The interatomic distances and angles within the complex cations hardly change with the change of the counter anions, while the distances between the complex cations in each crystal increase in the order ACl₂<ACl(ClO₄)<A(ClO₄)₂. The bulky perchlorate anions seems to separate the complex cations, while smaller chloride anions are not large enough to separate them. The distance (3.213(5) Å) between O(NO) and N(NH₃ in the adjacent complex cation) is rather short in the crystal of ACl₂, and there are six hydrogen bonds, where the NO group is surrounded by four NH₃ ligands. The distance (4.002(5) Å) between O(NO) and N(NH₃) is much longer in the crystal of A(ClO₄)₂, indicating the presence of no hydrogen bonding. In the crystal of ACl(ClO₄) the distance (3.452(4) Å) between O(NO) and N(NH₃) is in between those of ACl₂ and A(ClO₄)₂. The presence of hydrogen bonding between O(NO) and N(NH₃ in the adjacent complex cation) seems to cause the color change with the change of outer sphere anions.     

Three new diterpenes and two new sesquiterpenoids from the endophytic fungus Trichoderma koningiopsis A729

Three new diterpenes koninginols A-C (1–3) and two new sesquiterpenoids 11-hydroxy-15-drimeneoic acid (4), koninginol D (5), together with twelve known compounds (6–17) were isolated from the endophytic fungus Trichoderma koningiopsis A729 derived from Morinda officinalis. Their structures were fully assigned with the aid of extensive spectroscopic analysis and reported data from the previous literatures. Koninginols A and B were disclosed as intriguing diterpene alkaloids, whereas the koninginol C was disclosed as one of the two examples of harziandione diterpene. All the isolates were evaluated for their antitumor activity, and compounds 1–2, 4–6, 11–13, 16–17 were evaluated for their antibacterial activity, wherein the new compounds 1 and 2 exhibited significant antibacterial activity against Bacillus subtilis with MIC values of 10 and 2 μg/mL, respectively.     

Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors

Four bis-N-n-propyl analogues (3–6) in the uracil ring of two hybrid molecules (1 and 2) of caffeine and eudistomin D, a β-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A₁, A_2A, and A₃ were examined. All the compounds (3–6) showed better potency as adenosine receptor ligands than caffeine. Bis-N-n-propylation (3 and 4, respectively) of the uracil ring in 1 and 2 resulted in higher affinity for A₁ and A_2A adenosine receptors. Furthermore, it was found that a compound (5) possessing a n-propyloxy group at C-7 in compound 3 with a nitrogen at the β-position of the pyridine ring (β-N type) enhanced remarkably affinity for adenosine receptor A₃ subtype, while n-propyloxy substitution (compound 6) at C-5 in compound 4 with a nitrogen at the δ-position of the pyridine ring (δ-N type) reduced affinity for all the adenosine receptor, A₁, A_2A, and A₃. Among all the compounds (1–6) examined, compound 5 showed the most potent affinity for adenosine receptor A₃ subtype (K_i value, 0.00382 μM).     

Novel imidazobenzazepine derivatives as dual H1/5-HT2A antagonists for the treatment of sleep disorders

A novel imidazobenzazepine template (5a) with potent dual H₁/5-HT_2A antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R¹-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H₁/5-HT_2A receptor antagonist activities and good developability profiles.     

Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system

Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT_1A, 5-HT_2A, 5-HT₆, 5-HT₇, D₂ and α₁ receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30?mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5?mg/kg and ED₅₀?=?26.33?mg/kg, respectively), which can be justified by the receptor profile: 5-HT_1A K_i?=?5?nM (antagonist), 5-HT₇ K_i?=?70?nM, α₁ K_i?=?15?nM, D₂ K_i?=?189?nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30?min after administration (at 10?mg/kg, ED₅₀?=?23.50?mg/kg, at 30?mg/kg, respectively), which can be related with 5-HT_1A weak antagonism (K_i?=?146?nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT_1A, 5-HT_2A, 5-HT₇, D₂ and α_1A).     

Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile

A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT_1A, 5-HT_2A and D₂ receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D₂ receptors with compounds 6f (K_i = 0.6 nM), 6c and 6i (K_i = 0.4 nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT_2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT_1AR and were the most selective ligands with K_i = 62.7 nM and K_i = 30.5 nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D₂, 5-HT_1A and 5-HT_2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT_1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT_2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D₂ antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D₂-receptor and 5-HT_2A antagonism and metabolic stability.     

Fatty acid derivatives and dammarane triterpenes from the glandular trichome exudates of Ibicella lutea and Proboscidea louisiana

Ibicella lutea and Proboscidea louisiana, both of the Martyniaceae family, are known for rich glandular trichomes on their leaves and stems. Chemical investigations of the glandular trichome exudates on leaves of the two plants furnished three types of secondary metabolites, glycosylated fatty acids, glycerides (2-O-(3,6-diacetyloxyfattyacyl)glycerols and 2-O-(3-acetyloxyfattyacyl)glycerols) and dammarane triterpenes. The glycosylated fatty acids from I. lutea were determined to be 6(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-octadecanoic acid (1A), -eicosanoic acid (1B) and -docosanoic acid (1C), as well as their respective deacetyl congeners (2A, 2B and 2C), whereas P. louisiana furnished 8(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-eicosanoic acid (3A) and -docosanoic acid (3B) and their respective deacetyl congeners (4A and 4B), together with 2B. Both plants contained 12 identical 2-O-[(3R,6S)-3,6-diacetyloxyfattyacyl]glycerols (5A-L), in which the fatty acyl moieties contained between 17 and 21 carbon atoms. The corresponding mono-acetyloxy compounds, 2-O-[(3R)-3-acetyloxyfattyacyl]glycerols (6A–L) were detected in both plants. Among these glycerides, ten compounds (5A, 5C, 5F, 5H, 5K, 6A, 6C, 6F, 6H and 6K) had iso-fattyacyl structures and four (5E, 5J, 6E and 6J) had anteiso-fattyacyl structures. A previously unknown dammarane triterpene, betulatriterpene C 3-acetate (7), was isolated together with three known dammarane triterpenes, 24-epi-polacandrin 1,3-diacetate (8), betulatriterpene C (9) and 24-epi-polacandrin 3-acetate (10) from I. lutea, whereas 12 dammarane triterpenes, named probosciderols A–L (12–23), and the known compound betulafolienetriol (11) were isolated from P. louisiana. The structures of these compounds were elucidated by spectroscopic analysis including 2D-NMR techniques and chemical transformations. The 6-O-acetylglucosyloxy-fatty acids 1A–C (42%) and the dammarane triterpenes 7–10 (31%) were the two most abundant constituents in the glandular trichome exudate of I. lutea, whereas the dammarane triterpenes 11–23 (47%) and the glucosyloxy-fatty acids (4A, 4B and 2B) (38%) were the most abundant constituents in the glandular trichome exudate of P. louisiana.     

A new diterpene from the fungal mycelia of Hericium erinaceus

One new diterpene (1) and new compound (2), along with four known compounds (3–6) were isolated from the fungal mycelia of Hericium erinaceus by the tracking method of antibacterial activity. The structures of compounds (1–6) were elucidated on the basis of spectral data. Compound (3) showed strong antibacterial activity against Helicobacter pylori (ATCC43504) and compounds (1), (2) and (4) showed moderate antibacterial activity. Compound (1) exhibited good cytotoxicity against three human cancer cell lines (K562, LANCAP, HEP2).