The first total synthesis of ingenol

Ingenol is a tetracyclic diterpene polyol which was originally isolated from plants of the Euphorbiaceae family. The synthetic appeal of this densely functionalized natural product can be attributed to both the unique molecular architecture and the diverse biological activity.* This dissertation depicts the first total synthesis of ingenol which comprises nearly two decades of research. The most notable feature of this synthesis is construction of the “In-Out” tricycle through implementation of the novel [2+2] dioxenone photocycloaddition/retroaldol fragmentation methodology. Also, the high degree of oxygenation located along the lower hemisphere of the molecule was installed in a highly efficient manner. The total synthesis was completed in 38 steps, with an average yield per step of 82% and an overall yield of 0.06%. *Please see dissertation for diagram

The first total synthesis of ingenol

Ingenol is a tetracyclic diterpene polyol which was originally isolated from plants of the Euphorbiaceae family. The synthetic appeal of this densely functionalized natural product can be attributed to both the unique molecular architecture and the diverse biological activity.* This dissertation depicts the first total synthesis of ingenol which comprises nearly two decades of research. The most notable feature of this synthesis is construction of the “In-Out” tricycle through implementation of the novel [2+2] dioxenone photocycloaddition/retroaldol fragmentation methodology. Also, the high degree of oxygenation located along the lower hemisphere of the molecule was installed in a highly efficient manner. The total synthesis was completed in 38 steps, with an average yield per step of 82% and an overall yield of 0.06%. *Please see dissertation for diagram

Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor

<div><p>Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via <i>PI3K/PTEN</i> mutation or loss) while cell lines with activating mutations in the MAPK pathway (<i>KRAS/BRAF</i>) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.</p></div

Effect of GSK2141795 on AKT signaling and growth inhibition in human cancer cell lines.

<p><i>A</i>, BT474 (left) and LNCaP (right) cell lines were treated with DMSO or GSK2141795 for 1 h. Western analysis was performed to assay levels of phosphorylated and total GSK-3, PRAS40, AKT and ERK, phosphorylated FOXO, Caspase 9, and MEK. Tubulin was used as a loading control. <i>B</i>, Scatter plot of EC₅₀'s for anti-proliferative effect of GSK2141795 against various haematological cancer cell lines. Cell lines are grouped according to their disease classification and sub-divided into cellular origin of B cell (black diamond), pre-B cell (red diamond), T cell (blue diamond) or other (grey diamond). <i>C</i>, Scatter plot of EC₅₀'s for various solid cancer cell lines treated with GSK2141795. Cells were treated as described above. Cell lines are grouped by tissue of origin then further divided by genetic status. <i>KRAS/BRAF^V600E</i> mutation status is represented by color with mutant (red), wild type (black) or other (blue); whereas <i>PIK3CA</i> or <i>PTEN</i> status represented with shape, mutant (diamond) and wild type (circle).</p

Anti-tumor activity of GSK2141795 in vivo.

<p>Mice bearing either BT474 (<i>A</i>) or SKOV3 (<i>B</i>) tumors were treated with vehicle (black line) or GSK2141795 at 10 (red line), 20 (blue line) or 30 (gold line) mg/kg, once daily for 21 d (QDx21). Duration of treatment is shown by the horizontal grey line. Tumor volume was measured twice per week. Data represents mean ± SEM. #p<0.05, *p<0.01.</p