Chun-Lin Fan

Psiguadials A and B, two novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava.

Psiguadials A (1) and B (2), two novel sesquiterpenoid-diphenylmethane meroterpenoids with unusual skeletons, along with a pair of known epimers, psidial A (3) and guajadial (4), were isolated from the leaves of Psidium guajava. Their structures with absolute configurations were elucidated by means of NMR, X-ray diffraction, and quantum chemical CD calculation. Compounds 1, 2, and 4 exhibited potent inhibitory effects on the growth of human hepatoma cells.

Discovery of Bufadienolides as a Novel Class of ClC-3 Chloride Channel Activators with Antitumor Activities

ClC-3 chloride (Cl(-)) channel has been shown to be involved in cell proliferation, cell cycle, and cell migration processes. Herein, we found that a series of bufadienolides isolated from toad venom were a novel class of ClC-3 Cl(-) channel activators with antitumor activities. Bufalin, which has the most potent antitumor activity, and 15β-acetyloxybufalin, which has no antitumor activity, were chosen as representative compounds to investigate the role of the ClC-3 Cl(-) channel. It was found that bufalin rapidly elicited activation of the ClC-3 Cl(-) channel and subsequently induced apoptosis through inhibition of the PI3K/Akt/mTOR pathway. The PI3K/Akt/mTOR pathway was attenuated by pretreatment with Cl(-) channel blockers [tamoxifen and 5-nitro-2-(3-phenylpropylamino)benzoic acid, NPPB] or ClC-3 small interfereing RNA. In summary, we discovered that activation of the ClC-3 Cl(-) channel, which subsequently induced inhibition of the PI3K/Akt/mTOR signaling pathway, was involved in the antitumor activities of bufadienolides.

Ilelic acids A and B, two unusual triterpenes with a seven-membered ring from Ilex latifolia.

Two unusual triterpenes, ilelic acids A (1) and B (2), together with their biosynthetic related compounds ilelic acids C (3) and D (4) were isolated from the leaves of Ilex latifolia. Their structures with absolute configurations were elucidated by spectroscopic analysis and modified Moshers method. The plausible biogenetic pathway of 1 and 2 is proposed. These triterpenes exhibited a potent inhibitory effect on MCF-7 and MDA-MB-231 cells.

New triterpenoid glycosides from the roots of Ilex asprella.

Eight new triterpenoid glycosides, named ilexasosides A-H, were isolated from the roots of Ilex asprella. Their structures were elucidated by spectroscopic and chemical analyses. Ilexasosides B and D are rare sulfated derivatives of ursane-type triterpenoid glycosides.

Two new iridoid glucosides from Hedyotis diffusa

Two new iridoid glucosides, named diffusosides A and B, were isolated from the aerial part of Hedyotis diffusa Willd. Their structures were elucidated by 1D-, 2D-NMR spectroscopic analysis and HRESIMS. These two compounds showed no cytotoxic activity against SMMC-7721, SW480, SW620, Bel7402, and HepG2 cells.

Triterpenoid saponins from the rhizomes of Anemone flaccida and their inhibitory activities on LPS-induced NO production in macrophage RAW264.7 cells

A new ursane-type triterpenoid saponin, flaccidoside IV (1), and three new oleanane-type triterpenoid saponins, flaccidosides V–VII (2–4), along with 17 known saponins (5–21), were isolated from the rhizomes of Anemone flaccida. The structures of the new triterpenoid saponins were determined based on spectroscopic analyses and chemical methods. All the isolated saponins were tested for their inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages, and several bisdesmosidic oleanane-type triterpenoid saponins (2, 7, and 10) showed significant inhibitory activities, which indicated they had potential anti-inflammatory activities under their noncytotoxic concentrations in vitro.

Three new glycosides from Hylocereus undatus

Three new glycosides, undatusides A–C (1–3), and 11 known compounds (4–14) were isolated from the flowers of Hylocereus undatus. Their structures were elucidated on the basis of spectroscopic data and chemical method.

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.

Chemical Constituents from the Roots and Stems of Erycibe obtusifolia and Their In Vitro Antiviral Activity

Three new quinic acid derivatives, 4-O-caffeoyl-3-O-sinapoylquinic acid methyl ester (1), 5-O-caffeoyl-4-O-syringoylquinic acid methyl ester (2), and 4-O-caffeoyl-3-O-syringoylquinic acid methyl ester (3), as well as four new coumarin glycosides, 7-O-(3-O-sinapoyl-β-D-glucopyranosyl)-6-methoxycoumarin (12), 7-O-(6-O-sinapoyl-β-D-glucopyranosyl)-6-methoxycoumarin (13), 7-O-(2-O-sinapoyl-β-D-glucopyranosyl)-6-methoxycoumarin (14), and 7-O-(6-O-syringoyl-β-D-glucopyranosyl)-6-methoxycoumarin (15), together with eight known compounds (4-11) were isolated from the roots and stems of Erycibe obtusifolia. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. All the compounds were screened for their in vitro antiviral activity against respiratory syncytial virus with a cytopathic effect reduction assay. Among them, the di-O-caffeoyl quinates 8-11 displayed a potent in vitro anti-respiratory syncytial virus effect.

Anemoside A3-induced Relaxation in Rat Renal Arteries: Role of Endothelium and Ca2+ Channel Inhibition

Anemoside A(3), a lupane-type triterpenoid saponin, exists in the roots of Pulsatilla chinensis, but its pharmacological properties are largely unknown. The present study aimed to investigate the mechanisms underlying anemoside A(3)-induced relaxation in rat renal arteries. Changes of isometric force were determined on arteries with a myograph. Anemoside A(3) caused concentration-dependent relaxation in precontracted aortas, mesenteric, left coronary, and renal arteries. Removal of endothelium or treatment with charybdotoxin plus apamin slightly but significantly attenuated the relaxation in renal arteries. TEA(+) inhibited the relaxation caused by anemoside A(3) in renal arteries with and without endothelium while glibenclamide, BaCl(2), or capsaicin had no effect on it. Anemoside A(3) produced less relaxation in rings contracted by 60 mM KCl compared with rings contracted by receptor-dependent constrictors. It further inhibited contractions induced by Ca(2+) influx through nifedipine-sensitive voltage-gated Ca(2+) channels, nifedipine-insensitive receptor-operated Ca(2+) channels, and by intracellular Ca(2+) release. Pretreatment with nifedipine attenuated anemoside A(3)-induced relaxation. Taken together, the present results indicate that anemoside A(3) produces relaxation in rat renal arteries through multiple mechanisms. The release of CTX/apamin-sensitive endothelium-derived hyperpolarizing factor, stimulation of TEA(+)-sensitive K(+) channel, and inhibition of Ca(2+) influx jointly contribute to the relaxation.