Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities.

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 µM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 µM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.

Synthesis and Biological Evaluation of Celastrol Derivatives as Potential Immunosuppressive Agents.

Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a-1t, 2a-2l, and 3a-3j) were synthesized and evaluated for their immunosuppressive activities. Compounds 2a-2e showed immunosuppressive effects, with IC50 values ranging from 25 to 83 nM, and weak cytotoxicity (CC50 > 1 µM). Compound 2a, with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that 2a exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.

Anti-inflammatory Meroterpenoids from Baeckea frutescens.

Frutescones H-R (1-11), new sesqui- or monoterpene-based meroterpenoids, were isolated from the aerial parts of Baeckea frutescens. Their structures and absolute configurations were established by means of spectroscopic analyses (HRESIMS, 1D and 2D NMR, and ECD), as well as single-crystal X-ray crystallography of 1, (-)-7, and 9. The anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophages, and the structure-activity relationships of 1-11 are also discussed. Compound 8 exhibited anti-inflammatory activity with an IC50 value of 0.36 µM, which might be related to the regulation of the NF-κB signaling pathway via the suppression of p65 nuclear translocation and the consequent decrease of IL-6 and TNF-α.

Overexpression of Arabidopsis CBF1 gene in transgenic tobacco alleviates photoinhibition of PSII and PSI during chilling stress under low irradiance.

A known arabidopsis cDNA clone, the CRT/DRE binding factor 1 (CBF1), was isolated and introduced into tobacco plants. It has been reported that CBF1 is one member of CBF gene family related to low temperature and enhancing low temperature tolerance of plants. In the present work, the transcripts could be detected in the transgenic lines. The photochemical efficiency of PSII (F(v)/F(m)) and the photo-oxidizable P700 in the transgenic lines overexpressing CBF1 were higher than that in the wild type plants during the chilling stress under low irradiance. Similarly, the higher NPQ, higher qf, lower Phi(NF), higher activity of SOD, and lower content of MDA were also detected in the transgenic tobacco lines. Additionally, higher expression levels of Nicotiana tabacum copper/zinc superoxide dismutase (Cu/Zn SOD) were also detected in the transgenic lines. These results suggest that CBF1 protein plays an important role in protection of PSII and PSI during the chilling stress under low irradiance.