Mei-Chin Lu

Cytotoxic Triterpenoids from the Stems of Microtropis japonica

Bioassay-guided fractionation of a methanol extract obtained from stems of Microtropis japonica led to the isolation of six new ursane-type triterpenoids (1-6) and a new 2,3-seco-oleanane-type triterpenoid (7), together with seven known compounds. The structures of the new compounds were elucidated using spectroscopic data analysis. Among the known compounds isolated, the main component, 8 (ursolic acid), was active for HL60 cells, and its effects on histone hyperacetylation and the inhibition of histone deacetylase (HDAC) activity were investigated.

Towards the small and the beautiful: a small dibromotyrosine derivative from Pseudoceratina sp. sponge exhibits potent apoptotic effect through targeting IKK/NFκB signaling pathway.

A dibromotyrosine derivative, (1′R,5′S,6′S)-2-(3′,5′-dibromo-1′,6′-dihydroxy-4′-oxocyclohex-2′-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl-cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFκB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFκB pathway.

Lupane-Type Triterpenoids from Microtropis fokienensis and Perrottetia arisanensis and the Apoptotic Effect of 28-Hydroxy-3-oxo-lup-20(29)-en-30-al

Seven new lupane triterpenoids were isolated from bioactive methanol extracts of Microtropis fokienensis (1- 4) and Perrottetia arisanensis (4-7), along with 18 known compounds. The structures of the new compounds were elucidated on the basis of spectroscopic data analysis. All triterpenoids were evaluated for their in vitro cytotoxicity toward seven human cancer cell lines. Compound 8 (28-hydroxy-3-oxo-lup-20(29)-en-30-al) was among the most cytotoxic substances obtained and was found to induce apoptosis of human leukemia HL60 cells and mediate cleavage of PARP and up-regulation of Bax proteins.

Lobocrassins A–E: New Cembrane-Type Diterpenoids from the Soft Coral Lobophytum crassum

Five new cembrane-type diterpenoids, lobocrassins A–E (1–5), were isolated from the soft coral Lobophytum crassum. The structures of cembranes 1–5 were established by spectroscopic and chemical methods and by comparison of the spectral data with those of known cembrane analogues. Lobocrassin A (1) is the first cembranoid possessing an α-chloromethyl-α-hydroxy-γ-lactone functionality and is the first chlorinated cembranoid from soft corals belonging to the genus Lobophytum. Lobocrassins B (2) and C (3) were found to be the stereoisomers of the known cembranes, 14-deoxycrassin (6) and pseudoplexaurol (7), respectively. Lobocrassin B (2) exhibited modest cytotoxicity toward K562, CCRF-CEM, Molt4, and HepG2 tumor cells and displayed significant inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils.

5-Episinuleptolide Acetate, a Norcembranoidal Diterpene from the Formosan Soft Coral Sinularia sp., Induces Leukemia Cell Apoptosis through Hsp90 Inhibition

5-Episinuleptolide acetate (5EPA), a cytotoxic norcembranoidal diterpene recently identified from the Formosan soft coral Sinularia sp., exhibited potent activity against the K562, Molt 4 and HL 60 cancer cell lines. The antiproliferative assay, as well as the annexin V-FITC/propidium iodide (PI) apoptotic assay, indicated that the HL 60 cell line is the most sensitive one towards 5EPA. This diterpenoid led to caspases -3, -8, and -9 activation as well as PARP cleavage. It also induced ROS generation, calcium accumulation and disruption of mitochondrial membrane potential. Additionally, the expression levels of Hsp90 protein and several client proteins were downregulated in response to 5EPA treatment. These results suggest that 5EPA’s cytotoxic effect on HL 60 cells may be attributed to the inhibition of Hsp90 as well as the induction of mitochondrial stress which finally results in apoptotic cell death.

Cytotoxic C21 and C22 terpenoid-derived metabolites from the sponge Ircinia sp.

One novel C21 terpenoidal natural product, ircinolin A (2), two new C22 furanoterpene metabolites, 15-acetylirciformonin B (3) and 10-acetylirciformonin B (4), and two known compounds, irciformonin B (1) and irciformonin F (5), were isolated from the sponge Ircinia sp. The structures of these compounds were elucidated on the basis of their spectroscopic data. Moreover, the absolute configuration of 1 was determined by Moshers method. Among these metabolites, 2 is the first C21 terpenoid-derived metabolite to be reported from this genus. Compounds 1 and 3-5 exhibited significant cytotoxic activity against K562, DLD-1, HepG2, and Hep3B cancer cell lines.

Cytotoxic Sesterterpenoids from a Sponge Hippospongia sp.

One new pentacyclic sesterterpene, hippospongide A (1), and one new scalarane sesterterpenoid, hippospongide B (2), along with six previously reported known scalarane–type sesterterpenes (3–8), were isolated from a sponge Hippospongia sp. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. These metabolites are the first pentacyclic sesterterpene and scalarane-type sesterterpenes to be reported from this genus. Compounds 3–5 exhibited significant cytotoxicity against DLD-1, HCT-116, T-47D and K562 cancer cell lines.

Echinohalimane A, a Bioactive Halimane-Type Diterpenoid from a Formosan Gorgonian Echinomuricea sp. (Plexauridae)

A new halimane-type diterpenoid, echinohalimane A (1), was isolated from a gorgonian, identified as Echinomuricea sp. The structure of 1 was determined by spectroscopic methods and this compound was found to exhibit cytotoxicity toward various tumor cells and display an inhibitory effect on the release of elastase by human neutrophils. Echinohalimane A (1) is the first halimane analogue from the marine organisms belonging to phylum Cnidaria.

Excavatoids O and P, New 12-Hydroxybriaranes from the Octocoral Briareum excavatum

Two new 12-hydroxybriarane diterpenoids, designated as excavatoids O (1) and P (2), were isolated from the octocoral Briareum excavatum. The structures of briaranes 1 and 2 were established on the basis of extensive spectral data analysis. Excavatoid P (2) is the first metabolite which possesses a 6β -chlorine atom in briarane analogues.

Flexibilins A–C, New Cembrane-Type Diterpenoids from the Formosan Soft Coral, Sinularia flexibilis

Three new cembrane-type diterpenoids, flexibilins A–C (1–3), along with a known cembrane, (−)-sandensolide (4), were isolated from the soft coral, Sinularia flexibilis. The structures of cembranes 1–4 were elucidated by spectroscopic methods. The structure of 4, including its absolute stereochemistry, was further confirmed by single-crystal X-ray diffraction analysis. Cembrane 2 displayed a moderate inhibitory effect on the release of elastase by human neutrophils.