Biomimetic conversion of aconitine-type C19-diterpenoid alkaloids to lactone-type alkaloids

The first biomimetic conversion from the aconitine-type C(19)-diterpenoid alkaloids to the corresponding alkaloids of lactone-type C(19)-diterpenoid alkaloid has been achieved. Chasmanine was used as starting material with Baeyer-Villiger oxidation as a key reaction. It was also observed that the oxygenated group at C-16 did not change the relative migration tendencies of C-13 and C-9 during the oxidation. Meantime, a novel D-ring fragmented compound was obtained during the course of the present investigation. The plausible mechanism of the formation of this compound was also proposed.     

An O-to-N intramolecular acyl migration in C19-diterpenoid alkaloids

The O-acyl group at C-1 of two C₁₉-diterpenoid alkaloids 2 and 5 was transferred to the secondary amine nitrogen to form amides 3 and 6 in the basic condition. This kind of O-to-N intramolecular acyl migration could be caused by the near distance between the nucleophilic nitrogen atom and the carbonyl group of the ester at C-1 in the C₁₉-diterpenoid alkaloids, which is consistent with the conformation of rings A and E in the C₁₉-diterpenoid alkaloids.     

Three new diterpenoid alkaloids from the roots of Aconitum duclouxii

Three new C₁₉-diterpenoid alkaloids, ducloudines C (1), D (2), and E (3), were isolated from the roots of Aconitum duclouxii. Their structures were established on the basis of extensive spectroscopic analyses. Ducloudine C (1) is the first aconitine-type C₁₉-diterpenoid alkaloid with a C = O group at C-3 and a C = C bond between C-1 and C-2. All compounds were tested for their biological activities against one pathogenic fungi and two pathogenic bacteria.     

紫乌头生物碱的化学研究

从紫乌头根中分出四种新二萜生物碱,分别命名为紫乌生、紫乌生宁、紫乌亭和紫乌定。根据红外光谱、紫外光谱、质谱、氢谱和碳谱以及制备衍生物,证明了前三个生物碱的结构(3,4,5),对紫乌定的结构曾初步推定为(8)⁽¹⁾;后来,经单晶X射线衍射结构分析修正为(9)。此外,作者认为,根据化学结构特点应从C₁₉二萜生物碱中划分出C-4失甲基的一类生物碱,称C₁₈二萜生物碱。     

Regioselective O-demethylation of two C19-diterpenoid alkaloids

The regioselective demethylations of two C₁₉-diterpenoid alkaloids, 2 and 3, have been achieved with HBr–HOAc, trimethylsilyl iodide, or BBr₃. It was observed that HBr–HOAc is an optimal demethylating agent for these two C₁₉-diterpenoid alkaloids because it could provide different O-demethylation products by using different reaction temperature and reaction time. Especially, 1-O-methyl group in 2 and 3, one of the most difficult ones to be demethylated, could be removed by the treatment with HBr–HOAc at an elevated temperature and a prolonged reaction time.     

Alkaloids with antioxidant activities from Aconitum handelianum

A new C₂₀-diterpenoid alkaloid handelidine (1) and twenty-seven known alkaloids (2–28) were isolated from the roots of Aconitum handelianum. Their structures were established on the basis of extensive spectroscopic analyses. The study indicated that denudatine-type C₂₀-diterpenoid alkaloids with vicinal-triol system and benzyltetrahydroisoquinoline alkaloids exhibited significant antioxidant activities measured by three antioxidant test systems. The aconitine-type C₁₉-diterpenoid alkaloids could serve as potential secondary antioxidants for their strong binding effects to metal ions.     

Two new C19-diterpenoid alkaloids from Aconitum tsaii

Two new C₁₉-diterpenoid alkaloids, 14-benzoylliljestrandisine (1) and 14-anisoylliljestrandisine (2), were isolated from the roots of Aconitum tsaii. Their structures were elucidated by different spectroscopic (IR, UV, 1D and 2D NMR) and mass-spectrometric techniques.     

Two new C19-diterpenoid alkaloids from Aconitum straminiflorum

Two new C₁₉-diterpenoid alkaloids, straconitines A (1) and B (2), were isolated from the roots of Aconitum straminiflorum. Their structures were elucidated as 14-benzoylducloudine D (1) and 6-hydroxy-14-benzoylducloudine D (2) based on spectroscopic analysis, including IR, ESI-MS, HR-ESI-MS, 1D, and 2D NMR.     

An effective O-demethylation of some C19-diterpenoid alkaloids with HBr–glacial acetic acid

The aconitine-type alkaloids talatisamine (1), 8,14-diacetyltalatisamine (11), and compound 3, the lycoctonine-type alkaloid deltaline (5), and the 7,17-seco C₁₉-diterpenoid alkaloids 7 and 9 were treated with HBr–glacial acetic acid to give useful O-demethylated derivatives 2, 2, 4, 6, 8, and 10 respectively in good to high yields (49–90%).     

Four new C19-diterpenoid alkaloids from the roots of Aconitum ouvrardianum

Four new C₁₉-diterpenoid alkaloids, 3-dehydroxyl-lipoindaconitine (1), 8-dehydroxyl-bikhaconine (2), 19R-acetonyl-talatisamine (3), and 16-hydroxyl-vilmorisine (4), were isolated from the roots of Aconitum ouvrardianum. Their structures were elucidated by spectral analyses, including ESI-MS, HR-ESI-MS, IR, UV, 1D and 2D NMR.     

Conversional studies towards taxoids from C19-diterpenoid alkaloids by the BAC sequence

The conversional synthesis of taxoids by the BAC sequence from the C₁₉-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.     

Diterpenoid alkaloids from Aconitum kirinense

A new C₁₈-diterpenoid alkaloid, kirinenine A (1), was isolated from the root of Aconitum kirinense, along with eight known diterpenoid alkaloids. The structures of all compounds were characterized on the basis of extensive NMR and MS analyses and by comparison with literature values, and the new one was further confirmed by X-ray crystallographic diffraction. All the compounds were isolated from the title plant for the first time.     

Four new C20-diterpenoid alkaloids from Aconitum rotundifolium

Four new C₂₀-diterpenoid alkaloids, rotundifosines D-G (1–4), along with eight known ones (5–12) were isolated from the whole plant of Aconitum rotundifolium Kar. & Kir. The structures of the compounds were elucidated on the basis of spectroscopic analyses, including HR-ESI-MS and 1D, 2D NMR. Rotundifosine F (3) is a rare C₂₀-diterpenoid alkaloid with quaternary ammonium salt. Alkaloids 1–4, 5, 6, 9, and 12 were evaluated for cytotoxicity against MCF-7, HCT-116 and HepG2 human cancer cell lines.     

C18-Diterpenoid alkaloids from Delphinium anthriscifolium var. majus

Five new C₁₈-diterpenoid alkaloids, anthriscifoltines C-G (1–5), along with four known diterpenoid alkaloids anthriscifolcines C-F (6–9), were isolated from the extract of Delphinium anthriscifolium var. majus. Their structures were elucidated by extensive spectroscopic analyses (including 1D-, 2D-NMR, and HR-ESI-MS). Compounds 1–5 were also evaluated for their cytotoxic activity against MCF-7, HepG2, and H460 human cancer cell lines.     

Structure-activity relationships between the <Emphasis Type="Italic">Aconitum</Emphasis> C<Subscript>20</Subscript>-diterpenoid alkaloid derivatives and the growth suppressive activities of Non-Hodgkin’s lymphoma Raji cells and human hematopoietic stem/progenitor cells

The anti-tumor properties of novel derivatives prepared from Aconitum C₂₀-diterpenoid alkaloid, which show the least toxicity among the Aconitum alkaloids, were investigated in the Non-Hodgkin’s lymphoma cell line Raji cells. Two novel Aconitum C₂₀-diterpenoid alkaloid derivatives, 11-m-Trifluorometylbenzoyl (Mb)-pseudokobuisne and 11-Anisoyl (As)-pseudokobusine, showed significant suppressive effects and their 50% inhibitory concentrations were 2.2 μg/ml and 2.4 μg/ml against Raji cells, respectively. Both compounds have the same structure except for a functional group in the C-11 position. One of the active compounds, 11-Mb-pseudokobusine, clearly inhibited the phosphorylation of extracellular signal-regulated kinase, induced enhanced phosphoinositide 3 kinase phosphorylation and led to the subsequent accumulation of G1 and/or sub G1 phase in Raji cells. In addition, no significant suppressive effects on the growth of human CD34⁺ hematopoietic stem/progenitor cells (HSPC) were observed by 11-Mb-pseudokobusine which showed a strong suppressive activity on the growth of Raji cells, whereas 11-As-pseudokobusine also a showed significantly suppressive effect on the growth of HSPC. Therefore, the atisine type structure characteristic of C₂₀-diterpenoid alkaloids plays a very important role in the pharmacological properties. In particular, the C-11 residues are an important component for the anti-tumor properties and for the lower toxicity to hematopoiesis.     

A fragmentation study on four C19-diterpenoid alkaloids by electrospray ionization ion-trap time-of-flight tandem mass spectrometry

High-resolution electrospray ionization ion-trap time-of-flight tandem mass spectrometry (HR-ESI-IT-TOF-MSⁿ) in positive-ion mode was used to determine the accurate masses and fragmentation pathways of four C₁₉-diterpenoid alkaloids, aconitine (1), yunnaconitine (2), crassicauline A (3), and benzoylmesaconine (4). The [M+H]⁺ ions of compounds 1–4 were readily observed in conventional single-stage mass spectrometry. Based on the MS^1–6 analyses, detailed fragmentation rules of the four compounds were proposed. The neutral losses of AcOH, MeOH, H₂O, CO, C₂H₄, PhCOOH and p-OMePhCOOH segments were the characteristic eliminations from the precursor ions due to the presence of acetyl, methoxyl, hydroxyl, N-ethyl, benzoyl and p-methoxyl-benzoyl units in the structures. Benefited from the high resolution of the mass analyzer, the loss of 28 Da corresponding to CO or CH₄ segment in product ions was unambiguously distinguished. The losing sequence of the main substituent groups was summarized as: C(8)-acetyl>C(16)-methotyl>C(15)-hydroxyl>C(6)-methoxyl>C(1)-methoxyl/C(3)-hydroxyl>C(18)-methoxyl>>C(13)-hydroxyl. The sequential loss of (16)-methoxyl moiety and CO (generating from enol–ketone tautomerism) groups could be recognized as the characteristic eliminations for the compounds with C(16)-methoxyl and C(15)-hydroxyl groups simultaneously. The application of HR-ESI-IT-TOF-MSⁿ technique to investigate the fragmentation of C₁₉-diterpenoid alkaloids provided useful information to understand their fragmentation behaviors.     

Structure,property, biogenesis,and activity of diterpenoid alkaloids containing a sulfonic acid group from Aconitum carmichaelii

Three new C₂₀-diterpenoid alkaloids with a sulfonic acid unit, named aconicarmisulfonines B and C (1 and 2) and chuanfusulfonine A (3), respectively, were isolated from the Aconitum carmichaelii lateral roots (“fu zi” in Chinese). Structures of 1–3 were determined by spectroscopic data analysis. Intriguing chemical properties and reactions were observed for the C₂₀-diterpenoid alkaloids: (a) specific selective nucleophilic addition of the carbonyl (C-12) in 1 with CD₃OD; (b) interconversion between 1 and 2 in D₂O; (c) stereo- and/or regioselective deuterations of H-11α in 1–3 and both H-11α and H-11β in aconicarmisulfonine A (4); (d) TMSP-2,2,3,3-d₄ promoted cleavage of the C-12−C-13 bond of 4 in D₂O; (e) dehydrogenation of 4 in pyridine-d₅, and (f) Na₂SO₃-assisted dehydrogenation and N-deethylation of songorine (5, a putative precursor of 1–4). Biogenetically, 1 and 2 are correlated with 4, for which the same novel carbon skeleton is proposed to be derived from semipinacol rearrangements via migrations of C-13−C-16 and C-15−C-16 bonds of the napelline-type skeleton, respectively. Meanwhile, 3 is a highly possible precursor or a concurrent product in the biosynthetic pathways of 1, 2, and 4. In the acetic acid-induced mice writhing assay, at 1.0 mg/kg (i.p.), compounds 1, 2, 5, 5a, and 5b exhibited analgesic effects against mice writhing.     

New C19-diterpenoid alkaloids from Aconitum hemsleyanum var leueanthus and Delphinium potaninii

A new franchetine-type (leueandine 1) and two new lycoctonine-type [potanisines F (3) and G (5)] C¹⁹-diterpenoid alkaloids have been isolated from the roots of Aconitum hemsleyanum var. leueanthus and Delphinium potaninii, respectively, and their structures were established on the basis of spectral data.     

宣威乌头中生物碱成分的研究

目的 研究宣威乌头Aconitum nagarumvar lasiandrum中的生物碱成分.方法 采用酸提碱沉法提取总碱、硅胶层析法分离,用波谱法鉴定结构.结果和结论 从宣威乌头中分得10个单体化合物,应用光谱法鉴定了其结构为:光翠雀碱(denudatine)、宋果灵(songorine)、delnuttaline等3个C20-二萜生物碱和尼奥灵(neoline)、3-去氧乌头碱(3-deoxyaconitine)、8-methoxy-14-benzoylaconine、伏乌碱(flavaconitine)、异塔拉萨敏(isotalatizidine)、乌头碱(aconitine)和nevadensine等7个C19-二萜生物碱.     

Two new bis-C20-diterpenoid alkaloids with anti-inflammation activity from Aconitum bulleyanum

Two new bis-C₂₀-diterpenoid alkaloids, bulleyanines A and B (1 and 2), were isolated from Aconitum bulleyanum. Their structures were elucidated by comprehensive spectroscopic analyses including UV, IR, MS, 1D and 2D NMR. Biological activity tests indicated that compound 1 exhibited significant inhibitory activity against nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages with the inhibition rate of 74.60% (40 μmol/L), while positive control dexamethasone gave 78.70% inhibition at 100 μg/ml.