Structural Elucidation and Total Synthesis for the Pair of Unprecedented Polypyridines with Anti-AChE and HIV-1 Protease Activities from Alangium chinense.

Unlike reported pyridine hybrids, 2S (1a) and 2R-alanginenmine A (1b) from Alangium chinense featuring an unprecedented piperidine-bridged polypyridine skeleton represented a pair of alkaloid subtypes with a unique multiple pyridine scaffold. Enlightened by the rare structural characteristics and possible biosynthetic pathway, (±)-alanginenmine A (1) have been achieved in ideal yield by gram-class total synthesis with four steps. In addition, both compounds 1a and 1b exhibited anti-acetylcholinesterase (AChE) and HIV-1 protease activities in the biological activity evaluation. Further, molecular docking was investigated for the mechanism of action between the isolated compounds and HIV-1 protease. The stronger Coulomb interactions and van der Waals interaction, as well as the hydrogen bond interactions of 1a, might be the main cause for its better anti-HIV-1 protease activity than 1b. This work provided a comprehensive research including natural product discovery, bioactivity evaluation, and total synthesis for the new type of leading anti-HIV-1 protease.

New Monoterpenoid Indoles with Osteoclast Activities from Gelsemium elegans.

The well-known toxic medicine Gelsemium elegans is widely and historically used to treat bone fracture and skin ulcers by the folk people of China. Two new monoterpenoid indole alkaloids, gelselegandines D and E, together with the known analogue gelegamine A were isolated from G. elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. All isolated compounds were tested for the effects on RANKL-induced osteoclast formation. Interestingly, gelselegandine E and gelegamine A, respectively, showed significant promoting and inhibitory activities on osteoclastogenesis, while gelselegandine D had no activity under the same concentration. This work suggested the different configurations for the carbons near the C-19/20 oxygen rings of the isolated compounds may be the key active groups on osteoclast formation and provided the evidence for the rationality as the traditional treatment for bone-related diseases of G. elegans.

Wip1 phosphatase deficiency impairs spatial learning and memory.

Spatial learning and memory are typically assessed to evaluate hippocampus-dependent cognitive and memory functions in vivo. Protein phosphorylation and dephosphorylation by kinases and phosphatases play critical roles in spatial learning and memory. Here we report that the Wip1 phosphatase is essential for spatial learning, with knockout mice lacking Wip1 phosphatase exhibiting dysfunctional spatial cognition. Aberrant phosphorylation of the Wip1 substrates p38, ATM, and p53 were observed in the hippocampi of Wip1-/- mice, but only p38 inhibition reversed impairments in long-term potentiation in Wip1-knockout mice. p38 inhibition consistently ameliorated the spatial learning dysfunction caused by Wip1 deficiency. Our results demonstrate that deletion of Wip1 phosphatase impairs hippocampus-dependent spatial learning and memory, with aberrant downstream p38 phosphorylation involved in this process and providing a potential therapeutic target.

Unprecedented sugar bridged bisindoles selective inhibiting glioma stem cells.

Unlike reported bisindoles linked by single bond directly, alstoniasidines A (1) and B (2), from Alstonia scholaris featuring unprecedented skeleton with two indole moieties bridged by a sugar, represented a novel bisindole type having strictosamide-glucopyranose-picraline scaffold. Both compounds exhibited selective cytotoxicity against human glioma stem cells (GSCs) and induced caspase-3 dependent extrinsic apoptosis by increasing the expression of interleukin 1 (IL-1), tumor necrosis factor (TNF-α), and the cleaved caspase-3, while damaged the unlimited proliferation and self-renewal capacity of GSCs. This finding might provide new type of leads for the selective killing of human glioma stem cells.

Monoterpene indole N-oxide alkaloids from Tabernaemontana corymbosa and their antimicrobial activity.

Tabernaemontana corymbosa is a traditional folk medicine. In our research, six monoterpene indole N-oxide alkaloids and their parent alkaloids were obtained from the stem bark of T. corymbosa, including seven new alkaloids (1-7) and five known alkaloids (8-12). Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, and DP4+ probability analyses. The antimicrobial activity of the obtained compounds was evaluated, among which alkaloids 4, 8, 12 showed significant antimicrobial activity against Staphylococcus aureus with an MIC value of 6.25 µg/mL, while alkaloids 11, 12 showed moderate antimicrobial activity against Bacillus subtilis with an MIC value of 25 µg/mL.

New oxindole alkaloids with selective osteoclast inhibitory activity from Gelsemium elegans.

A new alkaloid 14-hydroxygelseziridine (1), along with four known oxindoles (2-5), was isolated and characterized from the well-known toxic medicine Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemistry calculations. Structurally, new compound 1 has a three membered oxygen ring at N-4/C-20. All compounds were tested for osteoclast (MOC-1) inhibitory activity in vitro. Compound 2 exhibited the selective osteoclast inhibitory activity. Flow cytometry revealed that the apoptosis of osteoclasts induced by 2. Furthermore, the PCR bioassay suggested that compound 2 may activate the apoptotic pathway of osteoclasts by reducing the expression of IL-6 and c-Jun, and increasing caspase 9. This work provided the evidence for the rationality as the traditional treatment for bone related diseases of G. elegans, and shed a new light on its further research.

Tabernaecorymine A, an 18-normonoterpenoid indole alkaloid with antibacterial activity from Tabernaemontana corymbosa.

Tabernaecorymine A, an 18-normonoterpenoid indole alkaloid with conjugated (E)-3-aminoacrylaldehyde fragment was obtained from the stem bark of Tabernaemontana corymbosa. Its structure was elucidated by extensive spectroscopic data analyses, and further verified by ACD/structure elucidator, electronic circular dichroism (ECD) analyses and density functional theory (DFT) chemical shift predictions. The compound exhibited significant antibacterial bioactivity against Streptococcus dysgalactiae with an MIC value of 3.12 µg/mL, which is better than the plant drug berberine.

Synthesis of pterodontic acid derivatives and the study of their anti-influenza A virus (H1N1) activity.

Laggera pterodonta (DC.) Benth, a folk herb widely distributes in southwest China, especially in Yunnan Province, demonstrates anti-pathogenic microorganisms, anti-inflammatory, inhibition of Helicobacter pylori activities in vitro et al. Interestingly, previous studies have shown that pterodontic acid (1), a eudesmane-type sesquiterpene isolated from L. pterodonta (DC.), displays excellent selective antiviral activity to H1N1 subtype of influenza A virus. At the same time, our group also discovered that the antiviral activity of 1 was relatively close to that activity of post-marketed ribavirin. Therefore, we consider that the synthesis of pterodontic acid (1) derivatives and evaluation of their anti-influenza A virus (H1N1) activities is of potential clinical significance. In this manuscript, a series of pterodontic acid derivatives were prepared and demonstrated significantly improved anti-influenza A virus (H1N1) activities, providing more opportunities for the treatment of respiratory viral diseases.

Alstoscholarisine K, an Antimicrobial Indole from Gall-Induced Leaves of Alstonia scholaris.

Alstoscholarisine K, an indole alkaloid with eight chiral carbons and featuring a novel 6/5/6/6/6/6/6/5 octacyclic architecture, was found to be specific to the gall-infected leaves of Alstonia scholaris. Its structure was elucidated by spectroscopy, computational analysis, and single-crystal X-ray diffraction. The unusual highly fused cage-like pyrrolo[1,2-a]pyrimidine structure with an additional -C4N unit is possibly derived from a combination of monoterpenoid indole and polyamine pathways. The fascinating compound exhibited significant antibacterial bioactivities by targeting cell membranes.

Partial Synthesis of Crassicauline A from Yunaconitine.

Both Aconitum hemsleyanum and Aconitum geniculatun have abundant contents of yunaconitine (1). Yunaconitine (1) has similar skeleton to crassicauline A (3); the only difference between them is that 1 contains a α-hydroxyl group at C-3. Our team attempts to convert 1 into 3 because 3 owns pharmacological activity. There are two steps to achieve the transformation above: firstly, use dehydration reaction to transform yunaconitine (1) into dehydroyunaconitine (2); secondly, use hydrogen reduction to acquire crassicauline A (3). Compared with other methods, this one below is more suitable for production application and more concise; moreover, the cost is lower with higher yield.

Resina Draconis Reduces Acute Liver Injury and Promotes Liver Regeneration after 2/3 Partial Hepatectomy in Mice.

AIM: To investigate the protective effects and possible mechanisms of action of resina draconis (RD) on acute liver injury and liver regeneration after 2/3 partial hepatectomy (PH) in mice. METHODS: 2/3 PH was used to induce acute liver injury. Mice were divided into three groups: sham, vehicle + 2/3 PH, and RD + 2/3 PH. Resina draconis was administered intragastrically after 2/3 PH into the RD + 2/3 PH group, and the same volume of vehicle (1% sodium carboxymethyl cellulose) was injected into the vehicle + 2/3 PH group and sham group mice. The index of liver to body weight (ILBW) and proliferating cell nuclear antigen (PCNA) were assayed to evaluate liver regeneration. Blood and liver tissues were collected for serological and western blotting analysis. RESULTS: Resina draconis protected against 2/3 PH-induced acute severe liver injury and promoted liver regeneration as shown by significantly increased ILBW compared with that of controls. 2/3 PH increased serum AST and ALT levels, which were significantly decreased by RD treatment, while 2/3 PH decreased serum TP and ALB, which were increased by RD treatment. In the RD + 2/3 PH group, PCNA expression was significantly increased compared with the 2/3 PH group. Further, hepatocyte growth factor (HGF), TNFα, and EGFR levels were increased in the RD group at postoperative days 2 and 4 compared with the those in the 2/3 PH group. CONCLUSION: Our results suggest that RD ameliorates acute hepatic injury and promotes liver cell proliferation, liver weight restoration, and liver function after 2/3 PH, probably via HGF, TNFα, and EGFR signaling.

Anti-inflammatory and analgesic activities of Neolamarckia cadamba and its bioactive monoterpenoid indole alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Neolamarckia cadamba has been used traditionally to treat inflammation, fever, and pruritus in the Dai ethnopharmacy in Yunnan province, P.R. China. However, according to literature survey, the action basis of anti-inflammatory and analgesic activities of this plant were rarely reported, which accounts for the original intentions of this investigation. AIM OF THE STUDY: The study aimed to investigate the anti-inflammatory and analgesic action of methanolic extract (ME), ethyl acetate (EA), and aqueous (AQS) fractions of N. cadamba and further explore the accurate compounds responsible for the activities of EA fraction. MATERIALS AND METHODS: The in vivo anti-inflammatory and analgesic activities of ME, EA, and AQS fractions at the doses of 200 and 400 mg/kg and two major constituents (compounds 5 and 7) at 50 and 100 mg/kg via intragastrically administrated, respectively, were evaluated by carrageenan-induced paw edema and acetic acid-stimulated writhing animal models. Aspirin (ASP) was used as the positive control at the dose of 200 mg/kg. The monoterpenoid indole alkaloids (MIAs) in EA fraction were phytochemically studied utilizing chromatographic techniques, and their structures and absolute configurations were established on the basis of multiple spectroscopic analyses and quantum computational chemistry method. Moreover, the in vitro anti-inflammatory activities of all the isolates were assessed by suppressing releases of LPS-activated inflammatory mediators (TNF-α, IL-1ß, and COX-2) in RAW 264.7 macrophage cells at a concentration of 10 µg/mL. Dexamethasone (DXM) was used as the positive control. RESULTS: Three fractions (ME, EA, and AQS) significantly ameliorated the paw edema caused by carrageenan and reduced the number of writhing induced by acetic acid in comparison to the control group at the doses of 200 and/or 400 mg/kg (in vivo). Subsequent phytochemical investigation of EA fraction led to the structural characterization of four new monoterpenoid indole alkaloids, neocadambines A-D (1-4), as well as eight known analogues (5-12). Neocadambine A possesses a novel 14-nor-MIA skeleton that could be derived from the corynantheine-type MIAs via oxidative cleavage of C3-C14 bond and subsequently degradation of C14. Moreover, the structure of a bioactive known MIA, cadambine acid (6), was reassigned by analysis of its NMR spectroscopic data. Further biological assays revealed that the major constituent 3ß-dihydrocadambine (7) significantly relieved the paw edema and decreased the number of writhing at 100 mg/kg in vivo. In addition, most of the isolates displayed remarkable in vitro anti-inflammatory effects by inhibiting the secretion of aforementioned inflammatory mediators (COX-2, IL-1ß, and TNF-α) at a concentration of 10 µg/mL, and compounds 4, 7, and 9 showed better anti-inflammatory effects than that of positive control, dexamethasone. CONCLUSIONS: This study further validated the anti-inflammatory and analgesic activities of N. cadamba, and revealed that monoterpenoid indole alkaloids could partly contribute to the efficacy of this ethnodrug. The major constituent 3ß-dihydrocadambine (7) showed significant anti-inflammatory activities both in vitro and in vivo, which suggested that it could be a promising anti-inflammatory lead compound. Our findings provided scientific justification to support the traditional application of N. cadamba for treating inflammatory and nociceptive disorders.

New aporphine alkaloids with selective cytotoxicity against glioma stem cells from Thalictrum foetidum.

Seven new isoquinoline alkaloids, 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy dehydroaporphine (1), 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy oxoaporphine (2), 3-methoxy-2'-formyl oxohernandalin (3), (-)-9-(2'-methoxycarbonyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (4), (-)-2'-methoxycarbonyl thaliadin (5), (-)-9-(2'-methoxyethyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (6), (-)-3-methoxy hydroxyhernandalinol (7), together with six known isoquinoline alkaloids (8-13) were isolated from the roots of Thalictrum foetidum. Their structures were elucidated by extensive spectroscopic measurements. Compounds 1 and 2 showed significant selective cytotoxicity against glioma stem cells (GSC-3# and GSC-18#) with IC50 values ranging from 2.36 to 5.37 µg·mL-1.

Immune-inhibitive phenyl-C1 substituent aporphine alkaloids from Thalictrum cirrhosum.

Five new phenyl-C1 substituent aporphine alkaloids, 6aR-2'-methoxycarbonyl-thaliadin (1), 6aR-2'-carboxyl-thaliadin (2), 6aR-3-methoxy-hernandalinol (3), 6aS-1,3,10-trimethoxy-natalamine (4), and 3-methoxy-2'-methoxycarbonyl-oxohernandalincin (5), together with sixteen known isoquinoline alkaloids (6-21) were isolated from the whole herb of Thalictrum cirrhosum (Levl.). Their structures were elucidated by extensive spectroscopic measurements, and six isoquinoline alkaloids showed significant inhibitory activity on concanavalin A-stimulated splenocytes proliferation with IC50 values 36-44 µM by the immunosuppressive bioassay.

Nepenthe-Like Indole Alkaloids with Antimicrobial Activity from Ervatamia chinensis.

Two monoterpenoid indole alkaloid erchinines A (1) and B (2), possessing unique 1,4-diazepine fused with oxazolidine architecture and three hemiaminals, were isolated from Ervatamia chinensis. Their structures were elucidated on the basis of intensive spectroscopic analysis, and a plausible biosynthetic pathway from ibogaine was proposed. Both compounds exhibited significant antimicrobial activity against Trichophyton rubrum and Bacillus subtilis, and their activities were comparable to the first line antifungal drug griseofulvin and antibiotic cefotaxime.

Antibacterial Indole Alkaloids with Complex Heterocycles from Voacanga africana.

Voacafricines A and B, two unique monoterpenoid indole alkaloids each bearing five fused heterocycles, were obtained from the fruits of Voacanga africana. Their structures were elucidated by extensive spectroscopic methods and computational studies. A plausible biogenetic pathway was proposed from a common precursor, 19- epi-voacristine. Both compounds exhibited potent activity against Staphylococcus aureus and Salmonella typhi, and their activities were superior to those of the well-known antibacterial drugs berberine and fibrauretine.

The Anticancer Activities Phenolic Amides from the Stem of Lycium barbarum.

Four new phenolic amides, 4-O-methylgrossamide (1), (E)-2-(4,5-dihydroxy-2-{3-[(4-hydroxyphenethyl)amino]-3-oxopropyl}-phenyl)-3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenethyl)acryl-amide (2), (Z)-lyciumamide C (3), (Z)-thoreliamide B (4), together with thirteen known phenolic amides were identified from the stem of Lycium barbarum. The structures of the new compounds were determined by spectroscopic methods. All compounds were evaluated for their anti-cancer activities against human glioma stem cell lines.

Three New Pyridine Alkaloids from Vinca major Cultivated in Pakistan.

Three new pyridine type alkaloids, (-)-vinmajpyridines A-C (1-3), along with two known alkaloids, have been isolated from the aerial parts of Vinca major cultivated in Pakistan. Their structures have been elucidated by means of NMR and HRESIMS spectroscopic data. The new alkaloids were evaluated for their cytotoxicity against glioma initiating cell lines (GITC-3# and GITC-18#), glioblastoma cell lines (U-87MG and T98G), and lung cancer cell line A-549, but none of them was active at 20 µg/mL concentration.

Indole Alkaloids Inhibiting Neural Stem Cell from Uncaria rhynchophylla.

Uncaria rhynchophylla is commonly recognized as a traditional treatment for dizziness, cerebrovascular diseases, and nervous disorders in China. Previously, the neuro-protective activities of the alkaloids from U. rhynchophylla were intensively reported. In current work, three new indole alkaloids (1-3), identified as geissoschizic acid (1), geissoschizic acid N 4-oxide (2), and 3ß-sitsirikine N 4-oxide (3), as well as 26 known analogues were isolated from U. rhynchophylla. However, in the neural stem cells (NSCs) proliferation assay for all isolated compounds, geissoschizic acid (1), geissoschizic acid N 4-oxide (2), isocorynoxeine (6), isorhynchophylline (7), (4S)-akuammigine N-oxide (8), and (4S)-rhynchophylline N-oxide (10) showed unexpected inhibitory activities at 10 µM. Unlike previous neuro-protective reports, as a warning or caution, our finding showcased a clue for possible NSCs toxicity and the neural lesions risk of U. rhynchophylla, while the structure-activity relationships of the isolated compounds were discussed also.

Indole Glycosides from Aqueous Fraction of Strychnos nitida.

Three new indole glycosides 22-deoxystrictosamide (1), 22-deoxystrictosamide N b-oxide (2) and vincosamide 2'-O-ß-D-xylopyranoside-11-O-ß-D-glucopyranoside (3), together with four known analogues were isolated from aqueous fraction of Strychnos nitida. Their structures were elucidated on the basis of extensive analysis of spectroscopic data. All the alkaloids were tested for their cytotoxic activity, but they did not show any exciting result.