No abstract

No abstract

Abbreviations: SA-J schweinfurthin A-J; TGN trans-Golgi-network; PTEN phosphatase and tensin homolog; DLBCL diffuse large B cell lymphoma; mTOR mammalian target of rapamycin; PDK1 phosphoinositide-dependent kinase 1; PIP3 phosphatidylinositol (3,4,5)-triphosphate; WGA wheat germ agglutinin; ConA concanavalin; MAA Maackia amurensis agglutinin; PNA peanut agglutinin; ORPs oxysterol-binding protein related family proteins Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golginetwork trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTENdeficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/ AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.

The first total synthesis of ipomoeassin F was carried out using a convergent approach that relied upon the use of Schmidt glycosidation technology for the coupling of two suitably protected monosaccharide fragments. After two steps, ring-closing metathesis was used to form the macrocyclic ring, and seven more steps then furnished ipomoeassin F. In vitro inhibitory activity against a four-panel cell line showed low nanomolar inhibitory activity.