Synthesis and in vitro evaluation of new wortmannin esters: Potent inhibitors of phosphatidylinositol 3-kinase

Journal of Medicinal Chemistry

Volumn 39, Issue 25, 1996, Pages 5021-5024

  Creemer, Lawrence C ^a   Kirst, Herbert A ^a   Vlahos, Chris J ^a   Schultz, Richard M ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

11 O DESACETYLWORTMANNIN; ANTINEOPLASTIC AGENT; ENZYME INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; UNCLASSIFIED DRUG; WORTMANNIN; WORTMANNIN DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CONTROLLED STUDY; DEACETYLATION; DRUG CYTOTOXICITY; DRUG SCREENING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; LEUKEMIA CELL LINE; LIPOPHILICITY; REDUCTION; SIGNAL TRANSDUCTION;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANDROSTADIENES; ENZYME INHIBITORS; ESTERS; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; PHOSPHOTRANSFERASES (ALCOHOL GROUP ACCEPTOR); TUMOR CELLS, CULTURED;

EID: 0029774179     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960283z     Document Type: Article

References (18)

1. Boyd, M. R. The future of new drug development. In Current Therapy in Oncology; Neiderhuber, J. E., Ed.; B. C. Decker, Inc; Philadelphia, PA, 1992; pp 11-22.
2. Stephens, L. R.; Jackson, T. R.; Hawkins, P. T. Agonist-stimulated synthesis of phosphatidylinositol (3,4,5)-triphosphate: a new intracellular signaling system? Biochim. Biophys. Acta 1993, 1179, 27-75.
3. Yano, H.; Nakanishi, S.; Kimura, K.; Hanai, N.; Saitoh, Y.; Fukui, Y.; Nonomura, Y.; Matsuda, Y. Inhibition of Histamine Secretion by Wortmannin through the Blockade of Phosphatidylinsoitol 3-Kinase in RBL-2H3 Cells. J. Biol. Chem. 1993, 268 (34), 25846-25856.
4. Arcaro, A.; Wymann, M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. J. Biochem. (London) 1993, 296, 297-301.
5. Powis, G.; Bonjouklian, R.; Berggren, M. M.; Gallegos, A.; Abraham, R.; Ashendel, C.; Zalkow, L.; Matter, W. F.; Dodge, J.; Grindey, G.; Vlahos, C. J. Wortmannin, a Potent and Selective Inhibitor of Phosphatidylinositol 3-Kinase. Cancer Res. 1994, 54, 2419-2423.
6. Abbas, H. K.; Mirocha, C. J. Isolation and Purification of a Hemorrhagic Factor (Wortmannin) for Fusarium oxysporum (N17B). Appl. Environ. Microbiol. 1988, 54 (5), 1268-1274.
7. Schultz, R. M.; Merriman, R. L.; Andis, S. L.; Bonjouklian, R.; Grindey, G. B.; Rutherford, P. G.; Gallegos, K. M.; Powis, G. In Vitro and in Vivo Antitumor Activity of the Phosphatidylinositol-3-kinase Inhibitor, Wortmannin. Anticancer Res. 1995, 15, 1135-1140.
8. Haefliger, W.; Kis, Z.; Hauser, D. Selektive Funktionalisierung von Wortmannin mit Hilfe einer Furanring-Maskierung. (Selective Functionalization of Wortmannin with the Help of a Masked Furan Ring.) Helv. Chim. Acta 1975, 58, 1620-1628.
9. Escobido, J. A.; Kaplan, D. R.; Kavanaugh, W. M.; Turck, C. W.; Williams, L. T. A Phosphatidylinositol 3-Kinase Binds to Platelet-Derived Growth Factor Receptors Through a Specific Receptor Sequence Containing Phosphotyrosine. Mol. Cell. Biol. 1991, 11, 1125-1132.
10. Varticovski, L.; Drucker, B.; Morrison, D.; Cantley, L.; Roberts, T. The Colony Stimulating Factor-1 Receptor Associates with and Activates Phosphatidylinositol 3-Kinase. Nature 1989, 342, 699-702.
11. Backer, J. M.; Myers, M. G., Jr.; Shoelson, S. E.; Chin, D. J.; Sun, X. J.; Miralpeix, M.; Hu, P.; Margolis, B.; Skolnick, E. Y.; Schlessinger, J.; White, M. F. The Phosphatidylinositol 3-kinase Is Activated by Association with IRS-1 during Insulin Stimulation. EMBO J. 1992, 11, 3469-3479.
12. Fukui, Y.; Saltiel, A. R.; Hanafusa, H. Phosphatidylinositol-3 Kinase Is Activated in v-src, v-yes, and v-fps Transformed Chicken Embryo Fibroblasts. Oncogene 1991, 6, 407-411.
13. Whitman, M.; Kaplan, D. R.; Schaffhausen, B. S.; Cantley, L. C.; Roberts, T. M. Association of Phosphatidylinositol Kinase Activity with Polyoma Middle-T Competent for Transformation. Nature 1985, 315, 239-242.
14. Serunian, L. A.; Haber, M. T.; Fukui, T.; Kim, J. W.; Rhee, S. G.; Lowenstein, J. M.; Cantley, L. C. Polyphosphoinositides Produced by Phosphatidylinositol 3-Kinase Are Poor Substrates for Phospholipases C from Rat Liver and Bovine Brain. J. Biol. Chem. 1989, 264, 17809-17815.
15. R. T. Abraham, personal communication.
16. Nakanishi, S.; Kakita, S.; Takahashi, I.; Kawahara, K.; Tsukuda, E.; Sano, T.; Yamada, K.; Yoshida, M.; Kase, H.; Matsuda, Y.; Hashimoto, Y.; Nonomura, Y. Wortmannin, a Microbial Product Inhibitor of Myosin Light Chain Kinase. J. Biol. Chem. 1992, 267, 2157-2163.
17. Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. A Specific Inhibitor of Phosphatidylinositol 3-Kinase: 2-(4-Morpholinyl)-8-Phenyl-4H-Benzopyran-4-one(LY294002). J. Biol. Chem. 1994, 269, 5241-5248.
18. Vlahos, C. J.; Matter, W. F. Signal Transduction in Neutrophil Activation: Phosphatidylinositol 3-Kinase is Stimulated without Tyrosine Phosphorylation. FEBS Lett. 1992, 309, 242-248.