Actinophyllic Acid, a Potent Indole Alkaloid Inhibitor of the Coupled Enzyme Assay Carboxypeptidase U/Hippuricase from the Leaves of Alstonia actinophylla (Apocynaceae)

Abstract

Bioassay-guided fractionation of the aqueous extract of the leaves of Alstonia actinophylla with use of a coupled enzyme assay, CPU/hippuricase, to detect carboxypeptidase U inhibitors led to the isolation of a novel indole alkaloid, actinophyllic acid (1). The structure of 1 was determined from detailed 2D NMR studies. Actinophyllic acid was found to be a potent inhibitor of the coupled enzyme assay with an IC(50) of 0.84 microM. Actinophyllic acid possesses a unique 2,3,6,7,9,13c-hexahydro-1H-1,7,8-(methanetriyloxymethano)pyrrolo[1',2':1,2]azocino[4,3-b]indole-8(5H)-carboxylic acid skeleton.

The value of natural products to future pharmaceutical discovery

“…95 The structure of actinophyllic acid represents a unique monoterpene indole alkaloid with a complex ring chromophore. Actinophyllic acid displayed potent inhibitory activity in the coupled enzyme assay of carboxypeptidase U/hippuricase.…”

Unusual indole alkaloid–pyrrole, –pyrone, and –carbamic acid adducts from Alstonia angustifolia

“…4,15e20 Recently, a novel indole alkaloid, actinophyllic acid from an Australian Alstonia (Alstonia actinophylla), was reported to be an effective inhibitor of carboxypeptidase U (CPU), and hence a potential facilitator of fibrinolysis. 21 We previously reported the structure of the novel Alstonia alkaloid, bipleiophylline, a cytotoxic bisindole constituted from the bridging of two indole moieties by an aromatic spacer unit. 15 In continuation of our studies of biologically active alkaloids from Malaysian Alstonia 5e10, 15 we wish to report the structure of three unusual alkaloids, viz., an alkaloidepyrrole, an alkaloidepyrone, and an alkaloidecarbamic acid adduct from the stem-bark extract of the Malayan A. angustifolia Wall.…”

Lumutinines A–D, Linearly Fused Macroline–Macroline and Macroline–Sarpagine Bisindoles from Alstonia macrophylla

“…The ESIMS of 2 showed a pseudomolecular ion [M + H] + at m/z 673, which analyzed for C 42 H 48 N 4 O 4 + H, indicating that 1 and 2 are isomers. Examination of the 1 H and 13 C NMR data (Tables 2 and 1) showed the presence of similar functionalities to those in 1, such as an unsubstituted indole moiety (δ 7.09−7.49), another indole moiety substituted at C-11′ and C-12′ from the presence of a pair of AB doublets at δ 6.66 and 7.16, a vinylic singlet at δ 7.55 associated with a trisubstituted double bond, an α,β-unsaturated carbonyl moiety (δ C 195.9, 121.3, and 157.9; δ H 2.12), and six methyl singlets, corresponding to two N1-Me, two N4-Me, one acetyl methyl, and a methyl attached to a quaternary carbon (18-Me). Thus, except for the aromatic AB doublets in place of the two aromatic singlets and, overall, small differences in the chemical shifts of the other signals, the NMR data bear a close resemblance to those of 1, indicating the presence of the same two constituent units.…”