triptohypol-C and celastrol

Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a K

Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Drug Design; Hep G2 Cells; Humans; Molecular Docking Simulation; Molecular Structure; Nuclear Receptor Subfamily 4, Group A, Member 1; Pentacyclic Triterpenes; Protein Binding; Sequestosome-1 Protein; Structure-Activity Relationship; TNF Receptor-Associated Factor 2; Triterpenes; Zebrafish

Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight lowering effects in adult obese mice.

Topics: Allosteric Site; Animals; Anti-Obesity Agents; Catalytic Domain; Diet, High-Fat; Hypothalamus; Magnetic Resonance Spectroscopy; Male; Mice, Transgenic; Obesity; Pentacyclic Triterpenes; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 2; Structure-Activity Relationship; Triterpenes; Weight Loss

Celastrol and its derivatives have been reported for their potent anticancer activity. Among other celastrol analogues, novel carbamate derivatives were designed and synthesised, and their biological activity on the viability of human cancer cell lines was evaluated. Additionally, a preliminary structure-activity relationship study was conducted. Derivative 18 showed the highest activity on cancer cell viability, combined with the best selectivity between malignant cells and non-malignant fibroblasts. Preliminary mechanistic studies of its anti-tumour action indicated that compound 18 has an antiproliferative effect on SKOV-3 human ovarian cancer cells (IC

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Cytotoxins; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pentacyclic Triterpenes; Structure-Activity Relationship; Triterpenes; Tumor Cells, Cultured

Celastrol is one of the most active antitumour compounds among the natural triterpenoids. It has been reported to be highly active against a wide variety of tumours and to affect multiple cellular pathways. A series of new celastrol derivatives, including compounds bearing a urea group, have been synthesised and analysed for their biological activity against human cancer cell lines. Several compounds presented a stronger growth inhibition effect than celastrol on the cell lines studied. Among them, compound 24 was the most promising derivative, as it exhibited both a remarkable antiproliferative activity and an improved selectivity in tumour versus non-tumour cells. The anticancer molecular mechanism of compound 24 in the human ovary cancer cell line SKOV-3 was further studied and the results showed that compound 24 induced apoptosis through the activation of the extrinsic death receptor pathway. Interestingly, the results revealed that compound 24 might be able to decrease the levels of dysfunctional p53. The assays also suggested that compound 24 is an Hsp90 inhibitor, and that the Akt/mTOR pathway might be involved in the downstream regulation that leads to its antiproliferative activity. Moreover, a synergistic anticancer effect was evidenced when SKOV-3 cells were simultaneously treated with compound 24 and cisplatin. Taken together, these results suggest that compound 24 may be a promising lead for the development of new cancer therapies.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Conformation; Pentacyclic Triterpenes; Structure-Activity Relationship; Triterpenes