Diversity-oriented synthesis of diterpenoid alkaloids yields a potent anti-inflammatory agent.

BACKGROUND: The diterpenoid alkaloids belong to a highly esteemed group of natural compounds, which display significant biological activities. It is a productive strategy to expand the chemical space of these intriguing natural compounds for drug discovery. METHODS: We prepared a series of new derivatives bearing diverse skeletons and functionalities from the diterpenoid alkaloids deltaline and talatisamine based on a diversity-oriented synthesis strategy. The anti-inflammatory activity of these derivatives was initially screened and evaluated by the release of nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-activated RAW264.7 cells. Futhermore, the anti-inflammatory activity of the representative derivative 31a was validated in various inflammatory animal models, including phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice ear edema, LPS-stimulated acute kidney injury, and collagen-induced arthritis (CIA). RESULTS: It was found that several derivatives were able to suppress the secretion of NO, TNF-α, and IL-6 in LPS-activated RAW264.7 cells. Compound 31a, one of the representative derivatives named as deltanaline, demonstrated the strongest anti-inflammatory effects in LPS-activated macrophages and three different animal models of inflammatory diseases by inhibiting nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinase (MAPK) signaling and inducing autophagy. CONCLUSION: Deltanaline is a new structural compound derived from natural diterpenoid alkaloids, which may serve as a new lead compound for the treatment of inflammatory diseases.

On the Famous Traditional Chinese Medicine "Fu Zi": Discovery, Research, and Development of Cardioactive Constituent Mesaconine.

This review summarizes the process of the discovery, research, and development of a cardioactive component, mesaconine, from the lateral roots of Aconitum carmichaelii ("Fu Zi"). To date, pre-clinical showed that mesaconine is a novel type of cardiotonic lead drug with relatively high potency, low toxicity, and a new mechanism.

Two New C19-Diterpenoid Alkaloids from Aconitum nagarum var. lasiandrum.

Continuous investigations of the roots of Aconitum nagarum var. lasiandrum led to the isolation of two new C19-diterpenoid alkaloids, lasiandrine (1) and lasiandroline (2). Their structures were elucidated on the basis of extensive interpretation of spectroscopic and mass spectrometric data.

Three New C20-Diterpenoid Alkaloids from Aconitum tanguticum var. trichocarpum.

Continuous investigations on the whole herbs of Aconitum tanguticum var. trichocarpum led to the isolation of three new C20-diterpenoid alkaloids trichocarpisines A-C (1-3). Their structures were elucidated on the basis of extensive interpretation of the spectroscopic data.

Recent Advances in the Synthesis of Stemona Alkaloids.

Stemona alkaloids, featuring polycyclic structures and interesting bioactivities, constitute a distinct class from the Stemonaceae family. In this review, recent advances in the synthesis of these unique alkaloids are briefly discussed, highlighting the application of novel synthetic strategies to access the core structures, as well as creative solutions to the installation of multiple stereogenic centers. The literature reviewed in this article covers the publications from 2010 to November 2014, a period that witnessed the prosperity of the synthesis of Stemona alkaloids.

Epoxide Opening of a 7,17-Seco-7,8-Epoxy-C19-Diterpenoid Alkaloid.

A new and effective approach toward epoxide opening of a 7,17-seco-7,8-epoxy-C19-diterpenoid alkaloid is herein described. The starting epoxide was prepared from naturally occurring yunnaconitine via a nine-step transformation. Treatment of this epoxide with trifluoroacetic anhydride in dioxane at 110 degrees C followed by reduction with sodium boron hydride generated two epoxide opening compounds 7 and 8. Each of their structures is characteristic of a Δ8,15 bridgehead double bond and a 7ß-oxygen-substituted group.

Further Studies on Structure-Cardiac Activity Relationships of Diterpenoid Alkaloids.

The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1α-OMe or 1α-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3α-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6α-OMe, 13-OH, 15α-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom.

Ring A conformation of aconine and pseudaconine in CDCl3.

On the basis of intensive interpretation of the 1H NMR spectroscopic data, the ring A conformation of aconine (1) was speculated as twist boat in CDCl3, and as chair or twist boat in acetone-d6 and pyridine-d5. The ring A of pseudaconine (2) adopts the chair conformation in CDCl3, acetone-d6, and pyridine-ds. Accordingly, the boat conformation of ring A in these two diterpenoid alkaloids in CDCl3 reported in the literature [1] should be revised. The difference in 13C NMR data for the same compound (1 or 2) in two different solvents (CDCl3, pyridine-d5) can be attributed to solvent effects.

New C20-diterpenoid alkaloids from Delphinium laxicymosum var pilostachyum.

From the whole herb of Delphinium laxicymosum var pilostachyum, three new C20-diterpenoid alkaloids, laxipilostine, laxipilosdine, and laxipilosline (1-3), were isolated, together with fourteen known diterpenoid alkaloids. Their structures were determined by extensively interpretation of their spectroscopic data (1D- and 2D-NMR, MS, and IR).

Full assignments of the 1H, 13C and 15N magnetic resonance spectra of two porphyrin compounds.

Two chlorin derivatives, rhodochlorin dimethyl ester (7) and chlorin-e6 trimethyl ester (8), were prepared from methyl pheophobide a (6) through base-degradation of the E ring and methylation of the carboxylic acids. Full assignments of the 1H, 13C and 15N magnetic resonance spectra of compounds 7 and 8 were made by 2D NMR techniques (1H-1H COSY, 1H-13C HMQC, 1H-13C HMBC, 1H-15N HMBC).

[Identification of aminoalcohol-diterpenoid alkaloids in Aconiti Lateralis Radix Praeparata and study of their cardiac effects].

In order to affirm the cardioactive components in Fuzi, we identified a group of aminoalcohol- diterpenoid alkaloids in Fuzi using ultra high-performance liquid chromatography coupled with electrospray ionization mass spectrometer (UPLC-ESI-MS) method. Among a total of forty-one isolated ingredients, thirteen major aminoalcohol-diterpenoid alkaloids were identified by comparing their retention times and MS spectra with those of the reference substances. Moreover, Fuzi samples from different places of origin and with different processing methods were examined and their components displayed a pattern of high similarity, though the relative abundance varies probably due to their different processing methods. Furthermore, the cardiac effect of each identified alkaloid was individually evaluated using the isolated bullfrog heart perfusion experiment. Among the thirteen aminoalcohol diterpenoid alkaloids tested, six of them significantly enhanced the amplitude rates. Taken together, we affirm that the cardioactive components in Fuzi are aminoalcohol-diterpenoid alkaloids, shedding light on future studies of the mechanisms and development of these cardioactive compounds.

Stemona alkaloids: biosynthesis, classification, and biogenetic relationships.

Stemona alkaloids form a unique class, which can be attributed to hemiterpenoid pyrrolidine- and monoterpenoid pyrrolidine-class alkaloids originated from L-ornithine and glutamic acid. By the end of 2013, approximately 183 Stemona alkaloids had been isolated from nature. The literature on Stemona alkaloids in the realms of chemical structure, synthesis, and bioactivities has been elegantly summarized and reviewed. We thus summarize in this review the biosynthesis, structural classification, and the intrinsic, biogenetic relationships of Stemona alkaloids. Based on the comprehensive consideration of biogenetic pathways and chemical features, the 183 Stemona alkaloids are classified into two classes (hemiterpenoid pyrrolidine- and monoterpenoid pyrrolidine) and fourteen types.

New access to 7,17-seco C19-diterpenoid alkaloids via vacuum pyrolysis of N-Deethyl-8-acetyl derivatives.

A novel access to 7,17-seco Cl9-diterpenoid alkaloids via vacuum pyrolysis of N-deethyl-8-acetyl derivatives is described.

Synthesis of taxane ABC tricyclic skeleton from lycoctonine.

A new conversional synthesis of the ABC ring system of taxoids from the C19-diterpenoid alkaloid lycoctonine was developed in 6 steps with 2% overall yield. The distinctive features of the conversion include pinacol rearrangement, enlargement of ring B, and opening of a four-membered ring.

Structure-cardiac activity relationship of C19-diterpenoid alkaloids.

Thirty three C19-diterpenoid alkaloids, twenty-two prepared from known C19-diterpenoid alkaloids and eleven isolated from Aconitum and Delphinium spp. were evaluated for their cardiac activity in the isolated bullfrog heart assay. Among them, eleven compounds exhibited cardiac activity, with average rate of amplitude increase in the range of 16-118%. Compound 7, mesaconine (17), hypaconine (25), and beiwutinine (26) exhibited strong cardiac activities relative to the reference drug. The structure-activity relationship data acquired indicated that an alpha-hydroxyl group at C-15, a hydroxyl group at C-8, an alpha-methoxyl or hydroxyl group at C-1, and a secondary amine or N-methyl group in ring A are important structure features necessary for the cardiac activities of the aconitine-type C19-diterpenoid alkaloids without any ester groups. In addition, an alpha-hydroxyl group at C-3 is also helpful for the cardiac activity of these alkaloids.

Unusual reactions of a 7,17-seco-type C19-diterpenoid alkaloid derived from deltaline.

Treatment of a 7,17-seco-type C19-diterpenoid alkaloid (3), prepared from deltaline (8), with triethylamine in either DMF or TEG (triethylene glycol) at 120 degrees C provided two interesting compounds 6 and 7. The structures of compounds 3, 6, and 7 were established based on extensive interpretations of their 1D and 2D NMR data. Compound 6, a lycoctonine-type C19-diterpenoid alkaloid, can be transformed from alkaloid 3 via Grob fragmentation, Prins reaction, and intramolecular disproportionation. The mechanism of the formation of compound 6 was confirmed by deuteration experiments. Product 7 was formed through a pinacol-like rearrangement of alkaloid 3.

Conversional synthesis of heteratisine.

The first conversional synthesis of heteratisine has been accomplished in 14 steps and 3.2% overall yield from deltaline, mainly including deoxygenation at C-10, removal of the dioxymethylene moiety, O-demethylation, as well as Baeyer-Villiger oxidation.

Conversional studies towards taxoids from C(19)-diterpenoid alkaloids by the BAC sequence.

The conversional synthesis of taxoids by the BAC sequence from the C(19)-diterpenoid alkaloids, 14-acetyltalatisamine (1), yunaconitine (12), and 14-acetylchasmanine (19), was designed and explored. Two aconane-type diterpenes 17 and 28, the advanced intermediates for our conversional synthesis, were synthesized. The key steps include the rupture of the C(7)-C(17) bond, the formation of imine, and the denitrogenation.

Two new C20-diterpenoid alkaloids from Delphinium anthriscifolium var. savatieri.

Further phytochemical investigation of the whole herb of Delphinium anthriscifolium var. savatieri resulted in the isolation of two new C20-diterpenoid alkaloids, anthriscifolmines I (1) and J (2). The structures of the two new alkaloids were elucidated on the basis of spectral data, including 2D NMR and HRESIMS.

Cytotoxic bisbenzylisoquinoline alkaloids from the roots of Cyclea racemosa.

Six new bisbenzylisoquinoline alkaloids, racemosidines A-C (1-3) and racemosinines A-C (4-6), and four known compounds were isolated from the roots of Cyclea racemosa. Compound 1 is the first bisbenzylisoquinoline alkaloid reported that has diphenyl ether bridges at C-11/C-7' and C-8/C-12' and a benzyl-phenyl ether bridge at C-7/C-11'. Structures and absolute configurations of 1-6 were established by interpretation of spectroscopic data and confirmed by X-ray crystallographic analysis of representative compounds. Compounds 1-3 exhibited significant cytotoxicity against HCT-8 and BEL-7402 tumor cells, and compound 1 was also cytotoxic against A2780 tumor cells.