Clerodane diterpenes: sources, structures, and biological activities

Daphniphyllum is an evergreen species known since 1826. After initial systematic investigations, more than 320 members of this family have been isolated, which comprise complex and fascinating structures. Unique azapolycyclic architectures containing one or more quaternary stereocenters render these alkaloids synthetically challenging. This review covers efforts toward the synthesis of Daphniphyllum alkaloids spanning the period from 2005 to the beginning of 2016, including reported biological activities as well as the isolation of new members of this genus.

Recent Progress in the Chemistry of Daphniphyllum Alkaloids

Four new carbazole alkaloids, claurailas A−D (1−4), as well as 12known carbazoles and three known coumarins were isolated from the roots of Clausena harmandiana. Heptaphylline (6) and 7-methoxyheptaphylline (7) showed strong cytotoxicity against NCI-H187 and KB cell lines with IC50 values ranging from 1.3 to 2.7 μM. Compound 7 showed no cytotoxicity against Vero cells.

Claurailas A-D, cytotoxic carbazole alkaloids from the roots of Clausena harmandiana.

The Wnt/β-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/β-catenin signaling pathway is closely related to tumorigenesis. In order to identify potent small molecules to treat the over-activated Wnt signaling-mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15-oxospiramilactone (NC043) that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin D1 and Survivin , as well as decreases in the protein levels of Cdc25c and Cdc2. NC043 did not affect the cytosol-nuclear distribution and protein level of soluble β-catenin, but decreased β-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of β-catenin stability and may be a potential compound for treating colorectal cancer.

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A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/β-catenin signaling and colon cancer cell tumorigenesis.

In vitro activity of C20-diterpenoid alkaloid derivatives in promastigotes and intracellular amastigotes of Leishmania infantum.

Antiplatelet aggregation activity of diterpene alkaloids from Spiraea japonica

Eight new limonoids, khayseneganins A-H (1-8), and 31 known limonoids were isolated from the leaves and twigs of Khaya senegalensis. The structures of the new compounds were elucidated by 2D-NMR spectroscopy and mass spectrometry, and the absolute configuration of 1 was determined by the CD exciton chirality method. Compounds 9, 10, 12, and 15 showed antimicrobial activities against Pseudomonas aeruginosa, MRSA 92(#), and MRSA 98(#), all with a MIC value of 12.5 mu g/mL.

Khayseneganins A-H, Limonoids from Khaya senegalensis

Two new degraded diterpenoids, trigohowilols A (1) and B (2), four new heterodimers, trigohowilols C-F (3-6), one new homodimer, trigohowilol G (7), and three known degraded diterpenoids (8-10) were isolated from the methanol extract of the stems of Trigonostemon howii. Compounds 1-7 were evaluated for their cytotoxic activity against five human tumor cell lines by an MTT assay, and trigohowilols E (5) and F (6) exhibited inhibitory activity with IC50 values ranging from 2.33 to 12.57 mu M Moreover, compounds 1-6 showed weak antimicrobial activities (MIC values: 6.25-25 mu g/mL) against Staphylococcus aureus, Pseudomonas aeruginosa, MRSA 92(#), and MRSA 98(#) using a 2-fold dilution method.

Trigohowilols A-G, degraded diterpenoids from the stems of Trigonostemon howii.

The new dinorditerpene 14,15-dinorclerod-3-ene-2,13-dione (2), the eight new clerodane diterpenes 4. 5. 7-10, 13, and 14, and the new furoquinoline alkaloid 15, besides thirty known compounds, were isolated from the aerial part of Clausena dunniana collected in Xishuangbanna, the south of China. The structures were elucidated by spectroscopic analysis including 1D- and 2D-NMR.

Guo-Ying Zuo

Papers

Antiplatelet aggregation activity of diterpene alkaloids from Spiraea japonica

Khayseneganins A-H, Limonoids from Khaya senegalensis

Trigohowilols A-G, degraded diterpenoids from the stems of Trigonostemon howii.

Dinorditerpene, diterpenes, alkaloids, and coumarins from Clausena dunniana

Myrifabine, the first dimeric Myrioneuron alkaloid from Myrioneuron faberi.