Search

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 7β-oxygen-substituted group.

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.

Three new C(19)-diterpenoid alkaloids, anthriscifoldines A-C (1-3), and two new C(18)-diterpenoid alkaloids, anthriscifolcines F and G (5, 6), were obtained from the whole herbs of Delphinium anthriscifolium var. savatieri during our further investigation on a larger scale of recollected plants. Their structures were elucidated based on the interpretation of NMR and high-resolution ESI-MS data, and chemical transformation. In addition, five known C(19)-diterpenoid alkaloids were also isolated and identified as nudicaulamine (4), delbruninol (7), blacknine (8), winkleriline (9), and deltaline (10).

For evaluation of C(18)- and C(19)-diterpenoid alkaloids as analgesics, three C(19)-diterpenoid alkaloids were isolated from the roots of Aconitum hemsleyanum var. circinatum and A. transsecutum; and twenty-five semisynthetic C(18)- or C(19)-diterpenoid alkaloids were prepared from lappaconitine, crassicauline A or yunaconitine. In a mice acetic acid-induced abdominal constriction assay, four crassicauline A analogs and three yunaconitine analogs exhibited good analgesic activities with 77.8-94.1% inhibition range in 0.1-10 mg/kg subcutaneous (s.c.) dose range at the point of 20 min after drug administration. Among them, 8-O-deacetyl-8-O-ethylcrassicauline A (ED(50)=0.0972 mg/kg) and 8-O-ethylyunaconitine (ED(50)=0.0591 mg/kg) were the most potent analgesics relative to the reference drugs lappaconitine (ED(50)=3.50 mg/kg) and crassicauline A (ED(50)=0.0480 mg/kg). Analgesic activity data of these C(18)- and C(19)-diterpenoid alkaloids indicate that a tertiary amine in ring A, an acetoxyl or an ethoxyl group at C-8, an aromatic ester at C-14, and the saturation state of the ring D are important structural features necessary to the analgesic activity of the C(19)-diterpenoid alkaloids.

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).

Three new norditerpenoid alkaloids, trifoliolasines A (1), B (3), and C (5), were isolated from the whole plant of Delphinium trifoliolatum FINET et GAGNEP, and their structures were established based on the spectral data.

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.

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.

Bioassay-guided fractionation of an n-BuOH extract of the lateral roots of Aconitum carmichaeli. led to the isolation of 5 cardioactive C(19)-diterpenoid alkaloids: N-deethylaconine (1), beiwutinine (2), hypaconine (3), mesaconine (4), and 15α-hydroxyneoline (5). N-Deethylaconine and beiwutinine are new aconitine-type C(19)-diterpenoid alkaloids. Hypaconine was isolated from this species for the first time. Among them, mesaconine, hypaconine, and beiwutinine showed the strongest cardiac actions on the isolated perfused bullfrog heart. Furthermore, mesaconine has protective effects, including improved inotropic effect and left ventricular diastolic function, on myocardial ischemia-reperfusion injury in rat at a dose of 10(-9) mol/L. However, mesaconine has almost no effect on heart rate.

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.

Two new, rare heteratisine-hetidine-type bisditerpenoid alkaloids designated as trichocarpines A 1 and B 2, together with twelve known compounds have been isolated from the whole plants of Aconitum tanguticum var. trichocarpum. Their structures were elucidated by spectroscopic data interpretation and chemical transformation.

A new and efficient approach toward the conversion of C(19)-diterpenoid alkaloids into diterpenes with [6+8+5+6] ring system is reported. Treatment of imines 5, 14, and 24 derived from the C(19)-diterpenoid alkaloids with NaNO(2)-NaOAc-HOAc afforded a series of novel rearrangement diterpenes 6-8, 15-19, and 25-27, respectively. The lactone 11 was obtained in 41% yield by treating 5 with NaNO(2)-HBr-Br(2). The formation of diazonium intermediate is postulated, which was subsequently subjected to skeletal rearrangement, leading to the enlargement of B ring. All the new compounds were isolated and fully characterized.

From the roots of Delphinium potaninii var. jiufengshanense, two new lycoctonine-type C(19)-diterpenoid alkaloids called jiufengdine (1) and jiufengtine (4) have been isolated. The structures of the new alkaloids (1, 4) were established by 1D and 2D NMR spectra.

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.