Effects of Aconitum Alkaloid Kobusine and Pseudokobusine Derivatives on Cutaneous Blood Flow in Mice; II.

Abstract

Aconitum alkaloids of the C20-diterpenoid type, kobusine (1) and pseudokobusine (2), their anisoyl, veratroyl, p-nitrobenzoyl, nicotinoyl or pivaloyl derivatives, and dehydrokobusine and N,6-seco-6-dehydropseudokobusine derivatives were examined for their peripheral vaso-activities by laser-flowmetrical measurement of the cutaneous blood flow in the hind foot of mice after intravenous administration. Kobusine 15-anisoate (4), 11-veratroate (5), 15-veratroate (6), 11-pivaloate (9) and 15-pivaloate (10) were significantly effective at a low dose of 0.5 or 0.05 mg/kg. Pseudokobusine derivatives were all active at 1, 0.5 or 0.05 mg/kg, and the effects of pseudokobusine 15-anisoate (13), 15-veratroate (16) and 15-p-nitrobenzoate (19) at 0.1 mg/kg were remarkable. Yesoline (26) and alkaloid (28) were significantly effective at a low dose of 1 mg/kg, whereas yesonine (25) and N-acetyl-N,6-seco-6-dehydropseudokobusine (27) were inactive. Dehydrokobusine derivatives (29, 30) were significantly effective at a low dose of 0.5 or 0.1 mg/kg. It is thought that the hydroxyl groups of alkaloids, especially a free OH group of 2 at C-6, are important for action on the peripheral vasculature leading to dilatation, and the results indicated that esterification of the hydroxyl group at C-15 with either anisoate, veratroate orp-nitrobenzoate may contribute to enhancement of the activity of the parent alkaloids.

Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

“…macroyesoense , followed by purification and identification by methods described previously [22, 23]. Thirty acyl derivatives, N -benzyl- N ,6-seco-6-dehydropseudokobusine ( 3 ) [19], N ,15-dibenzyl- N ,6-seco-6-dehydropseudokobusine ( 4 ) [19], 6-benzoylpseudokobusine ( 5 ) [23], 6,11-dibenzoylpseudokobusine ( 6 ) [23], 15-benzoyl-6,11-di- p -nitrobenzoylpseudokobusine ( 7 ) [19], 6-veratroylpseudokobusine ( 8 ) [7], 11-veratroylpseudokobusine ( 9 ) [7], 6-anisoylpseudokobusine ( 11 ) [7], 11-anisoylpseudokobusine ( 12 ) [7], 15-anisoylpseudokobusine ( 13 ) [7], 6,11-dianisoylpseudokobusine ( 14 ) [7], 6,15-dianisoylpseudokobusine ( 15 ) [7], 11,15-dianisoylpseudokobusine ( 16 ) [7], 6- p -nitrobenzoylpseudokobusine ( 17 ) [23], 11- p -nitrobenzoylpseudokobusine ( 18 ) [7], 15- p -nitrobenzoylpseudokobusine ( 19 ) [24], 6,11-di- p -nitrobenzoylpseudokobusine ( 20 ) [24], 6,15-di- p -nitrobenzoylpseudokobusine ( 21 ) [24], 11,15-di- p -nitrobenzoylpseudokobusine ( 22 ) [7], 6,11,15-tri- p -nitrobenzoylpseudokobusine ( 23 ) [24], 6-cinnamoylpseudokobusine ( 24 ) [6], 11-cinnamoylpseudokobusine ( 25 ) [6], 6-( m -trifluoromethylbenzoyl)pseudokobusine ( 26 ) [19], 11-( m -trifluoromethylbenzoyl)pseudokobusine ( 27 ) [19], 11-benzoylkobusine ( 30 ) [6], 11-anisoylkobusine ( 31 ) [7], 11-veratroylkobusine ( 32 ) [7], dihydrokobusine ( 33 ) [7], 11-cinnamoylkobusine ( 34 ) [6] and 11-( m -trifluoromethylbenzoyl)kobusine ( 36 ) [19], were prepared by methods described previously. Six semi-synthetic derivatives, 6-( p -trifluoromethylbenzoyl)pseudokobusine ( 28 ), 11-( p -trifluoromethylbenzoyl)pseudokobusine ( 29 ), 11-( p -trifluoromethylbenzoyl)kobusine ( 35 ), 11- p -nitrobenzoylkobusine ( 37 ), 15- p -nitrobenzoylkobusine ( 38 ) and 11,15-di- p -nitrobenzoylkobusine ( 39 ), were prepared from kobusine ( 1 ) and pseudokobusine ( 2 ).…”

“…Kobusine ( 1 ) and pseudokobusine ( 2 ), the major alkaloid constituents of Aconitum yesoense var. macroyesoense , and certain semi-synthetic derivatives of diterpenoid alkaloids have been shown by using a Doppler-type laser blood flow meter to significantly increase cutaneous blood flow in the hind feet of anaesthetized mice [5–7]. …”

Asymmetric Synthetic Access to the Hetisine Alkaloids: Total Synthesis of (+)‐Nominine

“…The C 20 -diterpenoid alkaloids have long been recognized as active constituents within many traditional Eastern herbal medicines. Pharmacological investigations have revealed that the hetisine alkaloids exhibit a diverse range of biological activities, [1,[10][11][12] exemplified by local anesthetic, anti-inflammatory, anti-arrhythmic activities of nominine (7), potent vasodilatory activities of kobusine (8) and pseudokobusine (9), and hypotensive activity of hetisine (10).…”

Suppressive effects of novel derivatives prepared from Aconitum alkaloids on tumor growth

“…Furthermore, there is little information about the pharmacological properties of C 20 -diterpenoid alkaloids which show low toxicities. In previous reports, we have reported that Aconitum C 20 -diterpenoid alkaloids and their novel derivatives showed an increased cutaneous blood flow [15][16][17]. Very recently, we found that some novel derivatives derived from C 20 -diterpenoid alkaloids suppress the growth of human tumor cell lines (unpublished data).…”