Design and semisynthesis of oleanolic acid derivatives as VEGF inhibitors: Inhibition of VEGF-induced proliferation, angiogenesis, and VEGFR2 activation in HUVECs.

Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases, such as cancer, rheumatoid arthritis, and age-related macular degeneration. Recent studies have revealed that oleanolic acid (OA), a natural pentacyclic triterpenoid, inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs, which may represent an attractive VEGF inhibitor. In this paper, rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential. As a result, a series of novel OA derivatives, possessing α,ß-unsaturated ketone system in ring A and amide functional group at C-28, were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs. The results showed that two promising derivatives, OA-1 and OA-16, exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs, compared with OA. The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VEGFR2 activation. Furthermore, small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2. Thus, the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors, which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.

Japonisine A, a fawcettimine-type Lycopodium alkaloid with an unusual skeleton from Lycopodium japonicum Thunb.

Japonisine A, a novel fawcettimine-type Lycopodium alkaloid with an unusual skeleton and two new fawcettimine-type ones, along with 20 known Lycopodium alkaloids, were isolated from the whole plants of Lycopodium japonicum Thunb. Their structures were determined by extensive spectroscopic analysis, including 1D and 2D NMR, and HR-ESIMS, as well as by comparison with the literature data. Notably, japonisine A (1) was the first example of fawcettimine-related Lycopodium alkaloid with a 2-oxopropyl attached at C-6. All the isolates were evaluated for their inhibitory effects on acetylcholinesterase (AChE) and α-glucosidase. Unfortunately, the results indicated that all the compounds were inactive against the acetylcholinesterase (AChE) and α-glucosidase.

Four new cembranoids from the Chinese soft coral Sinularia sp. and their anti-Aß aggregation activities.

Four new cembranoids (1-4) were isolated from the extracts of a soft coral collected from the sea area near Xisha Island, South China Sea. The structures of these compounds were determined mainly by spectroscopic analyses, with the absolute configuration of 1 being established by X-ray diffraction analysis. In bioassay, compounds 1 and 3 displayed moderate inhibitory activity against Aß42 aggregation (20.6% and 37.2% inhibition at 10 µM). The binding mode of 1 with Aß42 monomer was predicted by molecular docking. In addition, compounds 1 and 3 did not show cytotoxicity against human tumor cell lines (SH-SY5Y, MDA-MB-426, A549, Hep3B, and HT-29) at 100 µM. Taken together, these cembranoids as new anti-Aß aggregation agents derived from Sinularia sp. provided a new chemical scaffold for anti-Alzhemer's disease drug discovery.

A new lindenane-type sesquiterpenoid lactone from Chloranthus japonicus.

Chromatographic fractionation of the EtOH extracts of the Traditional Chinese Medicine (TCM) Chloranthus japonicus, has led to the isolation of a new lindenane-type sesquiterpenoid lactone derivative (1). Rosmarylchloranthalactone E (1), which consists of lindenane sesquiterpenoid lactone and rosmarinic acid moieties linked via an ester bridge, was structurally elucidated by 1D and 2D NMR and HRMS data. Compound 1 was a potent phosphodiesterase-4 (PDE4) inhibitor with an IC50 value of 0.96 ± 0.04 µM.

New Octadecanoid Enantiomers from the Whole Plants of Plantago depressa.

In this study, 19 octadecanoid derivatives-four pairs of enantiomers (1⁻8), two racemic/scalemic mixtures (9⁻10), and nine biosynthetically related analogues-were obtained from the ethanolic extract of a Chinese medicinal plant, Plantago depressa Willd. Their structures were elucidated on the basis of detailed spectroscopic analyses, with the absolute configurations of the new compounds assigned by time-dependent density functional theory (TD-DFT)-based electronic circular dichroism (ECD) calculations. Six of them (1, 3⁻6, and 9) were reported for the first time, while 2, 7, and 8 have been previously described as derivatives and are currently obtained as natural products. Our bioassays have established that selective compounds show in vitro anti-inflammatory activity by inhibiting lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells.

Antibacterial sorbicillin and diketopiperazines from the endogenous fungus Penicillium sp. GD6 associated Chinese mangrove Bruguiera gymnorrhiza.

One new sorbicillin derivative, 2-deoxy-sohirnone C (1), one new diketopiperazine alkaloid, 5S-hydroxynorvaline-S-Ile (2), and two naturally occurring diketopiperazines, 3S-hydroxylcyclo(S-Pro-S-Phe) (3) and cyclo(S-Phe-S-Gln) (4), together with three known compounds were isolated from the Chinese mangrove endophytic fungus Penicillium sp. GD6. Their structures were determined on the basis of extensive spectroscopic analyses and by comparison with literature data. The absolute configuration of 3-hydroxyl moiety in 3 was determined by Mosher's method, while the absolute stereochemistry of 2 and 4 was established by comparison with the CD spectra of natural and synthesized diketopiperazines. Compound 1 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with a MIC value of 80 µg·mL-1.

Phenolic bisabolane sesquiterpenoids from a Thai mangrove endophytic fungus, Aspergillus sp. xy02.

Seven new phenolic bisabolane sesquiterpenoids, (7R,10S)-7,10-epoxysydonic acid (1), (7S,10S)-7,10-epoxysydonic acid (2), (7R,11S)-7,12-epoxysydonic acid (3), (7S,11S)-7,12-epoxysydonic acid (4), 7-deoxy-7,14-didehydro-12-hydroxysydonic acid (5), (Z)-7-deoxy-7,8-didehydro-12-hydroxysydonic acid (6), and (E)-7-deoxy-7,8-didehydro-12-hydroxysydonic acid (7), along with five known analogues (8-12), were obtained from the culture of an endophytic fungus Aspergillus sp. xy02 isolated from the leaves of a Thai mangrove Xylocarpus moluccensis. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configurations of 1-4, being two pairs of epimers, were established by TDDFT-ECD calculations. Compound 12 showed mild antioxidative activity to scavenge DPPH radical with an IC50 of 72.1 µM, whereas 2, 3, 5, 7, 9, 11, and 12 displayed moderate inhibitory activities against Staphylococcus aureus ATCC 25923 with IC50 values ranging from 31.5 to 41.9 µM.

Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional neuroprotective agents.

Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4-oxadiazole ring system and show various bioactivities. However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-ß25-35 (Aß25-35)-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4-oxadiazole derivatives for the treatment of Alzheimer's disease.

Further casbane-type diterpenes from the soft coral Sinularia depressa.

AIM: To study the minor diterpenes from the soft coral Sinularia depressa METHOD: The chemical constituents were isolated and purified by various chromatographic techniques, and the chemical structures, including absolute configuration, were established on the basis of detailed analysis of spectroscopic data and by literature comparison with the data of related known compounds. RESULTS: A new casbane-type diterpene, 2-epi-10-hydroxydepressin (1), was isolated and identified. CONCLUSION: Compound 1 is a new casbane-type diterpene.

Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades.

This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented.