Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase B␣ (PKB␣), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidaseactivating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in IntroductionThe serine/threonine kinase c-Akt-1, or protein kinase B␣ (PKB), is the cellular homolog of a transforming oncogene initially isolated from a lymphoma. Akt is a downstream target of phosphatidylinositol-3-kinase (PI3K), a family of at least 4 different enzymes, with the prototypical PI3K heterodimer consisting of a p85 (regulatory) and a p110 (catalytic) subunit. The PI3K/Akt pathway is involved in the regulation of diverse cellular functions including proliferation, cytoskeletal organization, survival, and malignant transformation. [1][2][3][4] Upon binding of PI3K products to its pleckstrin homology domain, Akt is translocated to the plasma membrane where it is activated by upstream phosphorylated kinases, including PI3K-dependent kinases 1 and 2 (PDK1 and PDK2) and mammalian target of rapamycin complex 2 (mTORC2). The PI3K/Akt pathway is stimulated by numerous receptor tyrosine kinases and oncogenes, including receptors for insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), ras, Her2/neu, and polyoma middle T oncogenes. [5][6][7][8][9][10] Because Akt plays a central role in regulating apoptosis, angiogenesis, and metabolism of cells, Akt is an attractive pharmacologic target for the treatment of cancer and inflammation. 11,12 Small-molecular-weight inhibitors of PI3K include LY 294002 and the fungal metabolite wortmannin, 13 as well as ether phospholipids, including perifosine, which has entered clinical trials. 14,15 Using the SVR angiogenesis assay, [16][17][18] we found that solenopsin A, 19,20 the primary alkaloid from the fire ant Solenopsis invicta, has antiangiogenic activity. We also discovered that solenopsin disrupted angiogenesis in vivo in embryonic zebrafish. In order to determine the mode of action, we examined the ability of solenopsin to inhibit a battery of cellular kinases and found that solenopsin A inhibited Akt relatively selectively in an ATP-competitive manner without affecting its u...

The boronic acid functional group has been incorporated into various biologically important compounds. In order to study this class of compounds better with molecular mechanics, five alkyl-and arylboronic acids were calculated using ab initio methods (Spartan) at the RHF/6-31G * level. MM3 force field parameters were developed based on the theoretically calculated geometries, vibrational spectra, and torsional profiles.

The physical properties of a diverse group of 12 oxocarbenium ions have been studied with ab initio calculations at the MP2/6‐31+G* level of theory. Based on theoretically derived properties such as molecular equilibrium geometry, dipole moment, and vibrational frequencies, a molecular mechanics (MM3) force field has been developed with the assistance of the programs TORSMART and MPMSR, components of our artificial parameter development and refinement method. The MM3 force field is now able to reproduce bond lengths, bond angles, moments of inertia, dipole moments, torsional energy profiles, and vibrational frequencies of oxocarbenium ions, which will allow further studies of glycoside hydrolysis and their rates of reaction. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 329–339, 2000

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Fetal alcohol syndrome (FAS) refers to a pattern of birth defects occurring in a subpopulation of children born to women who consume alcohol during pregnancy. The significant medical, social, and economic impact of FAS is increasing. Particularly hard-hit are African-American and native-American women and children. Over the past two decades, basic and clinical research produced voluminous data on ethanol effects on developing organisms. In 1991, Duester and Pullarkat proposed that competition of ethanol with retinol at the alcohol dehydrogenase (ADH) binding site formed the basis of the FAS mechanism. This competition adversely affects the developing fetus caused by deregulation of retinoic acid (RA) homeostasis essential for proper fetal tissue development. Stated concisely, the FAS hypothesis is: 1. Class I ADH catalyzes the rate-limiting step in oxidation of retinol (ROH) to RA, and ethanol (ETOH) to acetic acid, thus establishing competition for ADH between ROH and ETOH. 2. RA is required as a signal molecule for cell differentiation critical for normal fetal morphogenesis. 3. ADH binds ingested ETOH, thus deregulating RA homeostasis leading to improper RA signal transduction. Preliminary results from molecular modeling studies of ROH-ADH and ETOH-ADH structures, and physiologic pharmacokinetic modeling confirm the hypothesis with remarkable fidelity.