Preparation of novel antiproliferative emodin derivatives and studies on their cell cycle arrest, caspase dependent apoptosis and DNA binding interaction.

Emodin (1) is the major bioactive compound of several herb species, which belongs to anthraquinone class of compound. As a part of our drug discovery program, large quantities of emodin (1) was isolated from the roots of Rheum emodi and a library of novel emodin derivatives 2-15 were prepared to evaluate their antiproliferative activities against HepG2, MDA-MB-231 and NIH/3T3 cells lines. The derivatives 3 and 12 strongly inhibited the proliferation of HepG2 and MDA-MB-231 cancer cell line with an IC50 of 5.6, 13.03 and 10.44, 5.027, respectively, which is comparable to marketed drug epirubicin (III). The compounds 3 and 12 were also capable of inducing cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines and exhibit DNA intercalating activity. These emodin derivatives hold promise for developing safer alternatives to the marketed epirubicin.

Glucose uptake stimulatory effect of 4-hydroxypipecolic acid by increased GLUT 4 translocation in skeletal muscle cells.

Peganum harmala Linn, commonly known as 'harmal' belonging to the family Zygophyllaceae, is one of the most important medicinal plants of India. In continuation of our drug development program on Indian medicinal plants we discovered antihyperglycemic activity in 4-hydroxypipecolic acid (4-HPA), isolated from the seed of P. harmala. Effect of 4-HPA on glucose uptake and glucose transporter-4 (GLUT-4) translocation was investigated in L6 skeletal muscle cell lines. Treatment with 4-HPA stimulated both glucose uptake and GLUT4 translocation from intracellular to cell surface in skeletal muscle cells in a concentration-dependent manner, which might be leading to antihyperglycemic effect.

4-Hydroxyisoleucine stimulates glucose uptake by increasing surface GLUT4 level in skeletal muscle cells via phosphatidylinositol-3-kinase-dependent pathway.

PURPOSE: To determine the effect of 4-Hydroxyisoleucine (4-HIL), an unusual amino acid isolated from the seeds of Trigonella foenum-graecum, on glucose uptake and the translocation of glucose transporter 4 (GLUT4) to plasma membrane in skeletal muscle cells and to investigate the underlying mechanisms of action. METHODS: Rat skeletal muscle cells (L6-GLUT4myc) were treated with 4-HIL, and the effect on glucose uptake was determined by measuring the incorporation of radio-labeled 2-deoxy-[(3)H]-D-glucose (2-DG) into the cell. Translocation of GLUT4myc to plasma membrane was measured by an antibody-coupled colorimetric assay. RESULTS: The prolonged exposure (16 h) of L6-GLUT4myc myotubes to 4-HIL caused a substantial increase in the 2-DG uptake and GLUT4 translocation to the cell surface, without changing the total amount of GLUT4 and GLUT1. Cycloheximide treatment reversed the effect of 4-HIL on GLUT4 translocation to the basal level suggesting the requirement of new protein synthesis. The 4-HIL-induced increase in GLUT4 translocation was completely abolished by wortmannin, and 4-HIL significantly increased the basal phosphorylation of AKT (Ser-473), but did not change the mRNA expression of AKT, IRS-1, GLUT4, and GSK3ß. CONCLUSION: Results suggest that 4-HIL stimulates glucose uptake in L6-GLUT4myc myotubes by enhancing translocation of GLUT4 to the cell surface in a PI-3-kinase/AKT-dependent mechanism.