Current status and future prospects of C1 domain ligands as drug candidates

Current Topics in Medicinal Chemistry

Volumn 11, Issue 11, 2011, Pages 1370-1392

  Boije af Gennäs, Gustav ^a   Talman, Virpi ^a   Yli Kauhaluoma, Jari ^a   Tuominen, Raimo K ^a   Ekokoski, Elina ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

Alzheimer's disease; Bryostatins; C1 domain; Cancer; DAGlactones; Drug discovery; Ingenol 3 angelate; Protein kinase C

Indexed keywords

ALPHA SECRETASE; ANTHRACYCLINE DERIVATIVE; BENZOLACTAM DERIVATIVE; BRYOSTATIN 1; C1 DOMAIN; CALPHOSTIN C; CISPLATIN; DIACYLGLYCEROL; FLUDARABINE; G PROTEIN COUPLED RECEPTOR; GEMCITABINE; INDOLACTAM V; INGENOL; INGENOL MEBUTATE; INTERLEUKIN 2; LACTAM DERIVATIVE; LACTONE; PACLITAXEL; PHORBOL ESTER; PROTEIN; PROTEIN KINASE C; PROTEIN KINASE C DELTA; PROTEIN TYROSINE KINASE; UNCLASSIFIED DRUG; VINCRISTINE;

ACTINIC KERATOSIS; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; APOPTOSIS; B LYMPHOCYTE; B LYMPHOCYTE ACTIVATION; BINDING AFFINITY; BINDING SITE; CANCER CELL CULTURE; CELL CYCLE ARREST; CELL CYCLE G1 PHASE; CELL CYCLE G2 PHASE; CELL CYCLE M PHASE; CELL PROLIFERATION; CENTRAL NERVOUS SYSTEM; CHEMICAL STRUCTURE; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CRYSTAL STRUCTURE; CYTOKINE RELEASE; CYTOTOXICITY; DRUG EFFICACY; DRUG PROTEIN BINDING; DRUG SAFETY; ENZYME ACTIVITY; ENZYME BINDING; ENZYME INDUCTION; ERADICATION THERAPY; ESOPHAGUS CANCER; FIBROBLAST; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; HYDROPHILICITY; HYDROPHOBICITY; IMMUNOGENICITY; IMMUNOMODULATION; KIDNEY CANCER; LYMPHOCYTE PROLIFERATION; LYMPHOMA; NONHODGKIN LYMPHOMA; NONHUMAN; PANCREAS CANCER; PHARMACOPHORE; PROTEIN BINDING; PROTEIN DOMAIN; REVIEW; SIGNAL TRANSDUCTION; SKIN TUMOR; STOMACH CANCER; STRUCTURE ACTIVITY RELATION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TUMOR; TUMOR DIFFERENTIATION;

ANIMALS; BIOLOGICAL FACTORS; DRUG DISCOVERY; HUMANS; LIGANDS; PROTEIN KINASE C; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79956372197     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/156802611795589584     Document Type: Review

References (258)

1. Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature, 1984, 308, 693-698.
2. Steinberg, S. F. Structural basis of protein kinase C isoform function. Physiol. Rev., 2008, 88, 1341-1378.
3. Newton, A. C. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem. Rev., 2001, 101, 2353-2364.
4. Hofmann, J. Protein kinase C isozymes as potential targets for anticancer therapy. Curr. Cancer Drug Targets, 2004, 4, 125-146.
5. Griner, E. M.; Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nat. Rev. Cancer, 2007, 7, 281-294.
6. Baier, G.; Wagner, J. PKC inhibitors: potential in T cell-dependent immune diseases. Curr. Opin. Cell Biol., 2009, 21, 262-267.
7. Hayashi, K.; Altman, A. Protein kinase C theta (PKC[): a key player in T cell life and death. Pharmacol. Res., 2007, 55, 537-544.
8. Sabri, A.; Steinberg, S. F. Protein kinase C isoform-selective signals that lead to cardiac hypertrophy and the progression of heart failure. Mol. Cell. Biochem., 2003, 251, 97-101.
9. Churchill, E.; Budas, G.; Vallentin, A.; Koyanagi, T.; Mochly-Rosen, D. PKC isozymes in chronic cardiac disease: possible therapeutic targets? Annu. Rev. Pharmacol. Toxicol., 2008, 48, 569-599.
10. Chou, W. H.; Messing, R. O. Protein kinase C isozymes in stroke. Trends Cardiovasc., Med. 2005, 15, 47-51.
11. Battaini, F. Protein kinase C isoforms as therapeutic targets in nervous system disease states. Pharmacol. Res., 2001, 44, 353-361.
12. Pascale, A.; Amadio, M.; Govoni, S.; Battaini, F. The aging brain, a key target for the future: the protein kinase C involvement. Pharmacol. Res., 2007, 55, 560-569.
13. Olariu, A.; Yamada, K.; Nabeshima, T. Amyloid pathology and protein kinase C (PKC): possible therapeutics effects of PKC activators. J. Pharmacol. Sci., 2005, 97, 1-5.
14. Alkon, D. L.; Sun, M. K.; Nelson, T. J. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends Pharmacol. Sci., 2007, 28, 51-60.
15. Clarke, M.; Dodson, P. M. PKC inhibition and diabetic microvascular complications. Best Pract. Res. Clin. Endocrinol. Metab., 2007, 21, 573-586.
16. Herbst, R. S.; Oh, Y.; Wagle, A.; Lahn, M. Enzastaurin, a protein kinase Cβ-selective inhibitor, and its potential application as an anticancer agent in lung cancer. Clin. Cancer Res., 2007, 13, s4641-4646.
17. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science, 2002, 298, 1912-1934.
18. Wang, Q. J. PKD at the crossroads of DAG and PKC signaling. Trends Pharmacol. Sci., 2006, 27, 317-323.
19. Yang, C.; Kazanietz, M. G. Chimaerins: GAPs that bridge diacylglycerol signalling and the small G-protein Rac. Biochem. J., 2007, 403, 1-12.
20. Sakane, F.; Imai, S.; Kai, M.; Yasuda, S.; Kanoh, H. Diacylglycerol kinases as emerging potential drug targets for a variety of diseases. Curr. Drug Targets, 2008, 9, 626-640.
21. Stone, J. C. Regulation of Ras in lymphocytes: get a GRP. Biochem. Soc. Trans., 2006, 34, 858-861.
22. Betz, A.; Ashery, U.; Rickmann, M.; Augustin, I.; Neher, E.; Sudhof, T. C.; Rettig, J.; Brose, N. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron, 1998, 21, 123-136.
23. Leung, T.; Chen, X. Q.; Tan, I.; Manser, E.; Lim, L. Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization. Mol. Cell. Biol., 1998, 18, 130-140.
24. Toker, A. The biology and biochemistry of diacylglycerol signalling. Meeting on molecular advances in diacylglycerol signalling. EMBO Rep., 2005, 6, 310-314.
25. Warrilow, D.; Gardner, J.; Darnell, G. A.; Suhrbier, A.; Harrich, D. HIV type 1 inhibition by protein kinase C modulatory compounds. AIDS Res. Hum. Retroviruses, 2006 22, 854-64.
26. Blumberg, P. M.; Kedei, N.; Lewin, N. E.; Yang, D.; Czifra, G.; Pu, Y.; Peach, M. L.; Marquez, V. E. Wealth of opportunity-the C1 domain as a target for drug development. Curr. Drug Targets, 2008, 9, 641-652.
27. Zeidman, R.; Löfgren, B.; Påhlman, S.; Larsson, C. PKC[, via its regulatory domain and independently of its catalytic domain, induces neurite-like processes in neuroblastoma cells. J. Cell Biol., 1999, 145, 713-726.
28. Cameron, A. J.; Procyk, K. J.; Leitges, M.; Parker, P. J. PKC alpha protein but not kinase activity is critical for glioma cell proliferation and survival. Int. J. Cancer, 2008, 123, 769-779.
29. Cameron, A. J.; Parker, P. J. Protein kinase C-a family of protein kinases, allosteric effectors or both? Adv. Enzyme Regul., 2010, 50, 169-177.
30. Colon-Gonzalez, F.; Kazanietz, M. G. C1 domains exposed: from diacylglycerol binding to protein-protein interactions. Biochim. Biophys. Acta, 2006, 1761, 827-837.
31. Zhang, G.; Kazanietz, M. G.; Blumberg, P. M.; Hurley, J. H. Crystal structure of the cys2 activator-binding domain of protein kinase CCCCin complex with phorbol ester. Cell, 1995, 81, 917-924.
32. Lomize, A. L.; Pogozheva, I. D.; Lomize, M. A.; Mosberg, H. I. The role of hydrophobic interactions in positioning of peripheral proteins in membranes. BMC Struct. Biol., 2007, 7, 44-74.
33. Sugita, K.; Neville, C. F.; Sodeoka, M.; Sasai, H.; Shibasaki, M. Stereocontrolled syntheses of phorbol analogs and evaluation of their binding affinity to PKC. Tetrahedron Lett., 1995, 36, 1067-1070.
34. Sodeoka, M.; Uotsu, K.; Shibasaki, M. Photoaffinity labeling of PKC with a phorbol derivative: importance of the 13-acyl group in phorbol ester-PKC interaction. Tetrahedron Lett., 1995, 36, 8795-8798.
35. Kazanietz, M. G.; Barchi, J. J.; Omichinski, J. G.; Blumberg, P. M. Low affinity binding of phorbol esters to protein kinase C and its recombinant cysteine-rich region in absence of phospholipids. J. Biol. Chem., 1995, 270, 14679-14684.
36. Hritz, J.; Ulicny, J.; Laaksonen, A.; Jancura, D.; Miskovsky, P. Molecular interaction model for the C1B domain of protein kinase C-γ in the complex with its activator phorbol-12-myristate-13-acetate in water solution and lipid bilayer. J. Med. Chem., 2004, 47, 6547-6555.
37. Xu, R. X.; Pawelczyk, T.; Xia, T. H.; Brown, S. C. NMR structure of a protein kinase C-γ phorbol-binding domain and study of protein-lipid micelle interactions. Biochemistry, 1997, 36, 10709-10717.
38. Fischer, S. M.; Patrick, K. E.; Lee, M. L.; Cameron, G. S. 4-β-and 4-α-12-O-tetradecanoylphorbol-13-acetate elicit arachidonate re lease from epidermal cells through different mechanisms. Cancer Res., 1991, 51, 850-856.
39. Tanaka, M.; Irie, K.; Nakagawa, Y.; Nakamura, Y.; Ohigashi, H.; Wender, P. A. The C4 hydroxyl group of phorbol esters is not necessary for protein kinase C binding. Bioorg. Med. Chem. Lett., 2001, 11, 719-722.
40. Canagarajah, B.; Leskow, F. C.; Ho, J. Y.; Mischak, H.; Saidi, L. F.; Kazanietz, M. G.; Hurley, J. H. Structural mechanism for lipid activation of the Rac-specific GAP, β2-chimaerin. Cell, 2004, 119, 407-418.
41. Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L. Isolation and structure of bryostatin 1. J. Am. Chem. Soc., 1982, 104, 6846-6848.
42. Davidson, S. K.; Allen, S. W.; Lim, G. E.; Anderson, C. M.; Haygood, M. G. Evidence for the biosynthesis of bryostatins by the bacterial symbiont "Candidatus Endobugula sertula" of the bryozoan Bugula neritina. Appl. Environ. Microbiol., 2001, 67, 4531-7.
43. Wender, P. A.; Verma, V. A. The design, synthesis, and evaluation of C7 diversified bryostatin analogs reveals a hot spot for PKC affinity. Org. Lett., 2008, 10, 3331-3334.
44. Mutter, R.; Wills, M. Chemistry and clinical biology of the bryostatins. Bioorg. Med. Chem., 2000, 8, 1841-60.
45. Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. Total synthesis of bryostatin 2. J. Am. Chem. Soc., 1999, 121, 7540-7552.
46. Hale, K. J.; Manaviazar, S. New approaches to the total synthesis of the bryostatin antitumor macrolides. Chem. Asian J., 2010, 5, 704-754.
47. Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.; Craske, M. L.; Horan, J. C.; Meyer, T. Function oriented synthesis: the design, synthesis, PKC binding and translocation activity of a new bryostatin analog. Curr. Drug Discov. Technol., 2004, 1, 1-11.
48. Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner, S. E.; Clarke, M. O.; Horan, J. C.; Kan, C.; Lacôte, E.; Lippa, B.; Nell, P. G.; Turner, T. M. The practical synthesis of a novel and highly potent analogue of bryostatin. J. Am. Chem. Soc., 2002, 124, 13648-13649.
49. Wender, P. A.; Brabander, J. D.; Harran, P. G.; Jimenez, J.; Koehler, M. F. T.; Lippa, B.; Park, C.; Shiozaki, M. Synthesis of the first members of a new class of biologically active bryostatin analogues. J. Am. Chem. Soc., 1998, 120, 4534-4535.
50. Keck, G. E.; Kraft, M. B.; Truong, A. P.; Li, W.; Sanchez, C. C.; Kedei, N.; Lewin, N. E.; Blumberg, P. M. Convergent assembly of highly potent analogues of bryostatin 1 via pyran annulation: bryostatin look-alikes that mimic phorbol ester function. J. Am. Chem. Soc., 2008, 130, 6660-6661.
51. Keck, G. E.; Li, W.; Kraft, M. B.; Kedei, N.; Lewin, N. E.; Blumberg, P. M. The bryostatin 1 A-ring acetate is not the critical determinant for antagonism of phorbol ester-induced biological responses. Org. Lett., 2009, 11, 2277-2280.
52. Keck, G. E.; Poudel, Y. B.; Welch, D. S.; Kraft, M. B.; Truong, A. P.; Stephens, J. C.; Kedei, N.; Lewin, N. E.; Blumberg, P. M. Substitution on the A-ring confers to bryopyran analogues the unique biological activity characteristic of bryostatins and distinct from that of the phorbol esters. Org. Lett., 2009, 11, 593-596.
53. Wender, P. A.; Dechristopher, B. A.; Schrier, A. J. Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins-driven macrocyclization strategy. J. Am. Chem. Soc., 2008, 130, 6658-6659.
54. Wender, P. A.; Horan, J. C.; Verma, V. A. Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs. Org. Lett., 2006, 8, 5299-5302.
55. Wender, P. A.; Baryza, J. L. Identification of a tunable site in bryostatin analogs: C20 Bryologs through late stage diversification. Org. Lett., 2005, 7, 1177-1180.
56. Kazanietz, M. G.; Lewin, N. E.; Gao, F.; Pettit, G. R.; Blumberg, P. M. Binding of [26-3H]bryostatin 1 and analogs to calciumdependent and calcium-independent protein kinase C isozymes. Mol. Pharmacol., 1994, 46, 374-379.
57. Dell'Aquila, M. L.; Nguyen, H. T.; Herald, C. L.; Pettit, G. R.; Blumberg, P. M. Inhibition by bryostatin 1 of the phorbol esterinduced blockage of differentiation in hexamethylene bisacetamide-treated Friend erythroleukemia cells. Cancer Res., 1987, 47, 6006-6009.
58. Kennedy, M. J.; Prestigiacomo, L. J.; Tyler, G.; May, W. S.; Davidson, N. E. Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res., 1992, 52, 1278-1283.
59. Szallasi, Z.; Denning, M. F.; Smith, C. B.; Dlugosz, A. A.; Yuspa, S. H.; Pettit, G. R.; Blumberg, P. M. Bryostatin 1 protects protein kinase C-aaafrom down-regulation in mouse keratinocytes in parallel with its inhibition of phorbol ester-induced differentiation. Mol. Pharmacol., 1994, 46, 840-850.
60. Szallasi, Z.; Smith, C. B.; Pettit, G. R.; Blumberg, P. M. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. J. Biol. Chem., 1994, 269, 2118-2124.
61. Lorenzo, P. S.; Bogi, K.; Acs, P.; Pettit, G. R.; Blumberg, P. M. The catalytic domain of protein kinase Ciiiconfers protection from down-regulation induced by bryostatin 1. J. Biol. Chem., 1997, 272, 33338-33343.
62. Lorenzo, P.S.; Bogi, K.; Hughes, K. M.; Beheshti, M.; Bhattacharyya, D.; Garfield, S. H.; Pettit, G. R.; Blumberg, P. M. Differential roles of the tandem C1 domains of protein kinase C rrrin the biphasic down-regulation induced by bryostatin 1. Cancer Res., 1999, 59, 6137-6144.
63. Choi, S. H.; Hyman, T.; Blumberg, P. M. Differential effect of bryostatin 1 and phorbol 12-myristate 13-acetate on HOP-92 cell proliferation is mediated by down-regulation of protein kinase Cpp. Cancer Res., 2006, 66, 7261-7269.
64. Tuthill, M. C.; Oki, C. E.; Lorenzo, P. S. Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes. Mol. Cancer Ther., 2006, 5, 602-610.
65. Bogi, K.; Lorenzo, P. S.; Szallasi, Z.; Acs, P.; Wagner, G. S.; Blumberg, P. M. Differential selectivity of ligands for the C1a and C1b phorbol ester binding domains of protein kinase CCC: possible correlation with tumor-promoting activity. Cancer Res., 1998, 58, 1423-1428.
66. Lee, H. W.; Smith, L.; Pettit, G. R.; Bingham Smith, J. Dephosphorylation of activated protein kinase C contributes to downregulation by bryostatin. Am. J. Physiol., 1996, 271, C304-311.
67. Isakov, N.; Galron, D.; Mustelin, T.; Pettit, G. R.; Altman, A. Inhibition of phorbol ester-induced T cell proliferation by bryostatin is associated with rapid degradation of protein kinase C. J. Immunol., 1993, 150, 1195-1204.
68. Sredni, B.; Kalechman, Y.; Albeck, M.; Gross, O.; Aurbach, D.; Sharon, P.; Sehgal, S. N.; Gurwith, M. J.; Michlin, H. Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin. Immunology, 1990, 70, 473-477.
69. Basu, A.; Akkaraju, G. R. Regulation of caspase activation and cisdiamminedichloroplatinum(II)-induced cell death by protein kinase C. Biochemistry, 1999, 38, 4245-4251.
70. Matthews, S. A.; Pettit, G. R.; Rozengurt, E. Bryostatin 1 induces biphasic activation of protein kinase D in intact cells. J. Biol. Chem., 1997, 272, 20245-20250.
71. Jaggi, M.; Chauhan, S. C.; Du, C.; Balaji, K. C. Bryostatin 1 modulates β-catenin subcellular localization and transcription activity through protein kinase D1 activation. Mol. Cancer Ther., 2008, 7, 2703-2712.
72. Lorenzo, P. S.; Beheshti, M.; Pettit, G. R.; Stone, J. C.; Blumberg, P. M. The guanine nucleotide exchange factor RasGRP is a high-affinity target for diacylglycerol and phorbol esters. Mol. Pharmacol., 2000, 57, 840-846.
73. Stone, J. C.; Stang, S. L.; Zheng, Y.; Dower, N. A.; Brenner, S. E.; Baryza, J. L.; Wender, P. A. Synthetic bryostatin analogues activate the RasGRP1 signaling pathway. J. Med. Chem., 2004, 47, 6638-6644.
74. Caloca, M. J.; Wang, H.; Delemos, A.; Wang, S.; Kazanietz, M. G. Phorbol esters and related analogs regulate the subcellular localization of β2-chimaerin, a non-protein kinase C phorbol ester receptor. J. Biol. Chem., 2001, 276, 18303-18312.
75. Trost, B.M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S. Synthesis of a ring-expanded bryostatin analogue. J. Am. Chem. Soc., 2007, 129, 2206-2207.
76. Jones, R. J.; Sharkis, S. J.; Miller, C. B.; Rowinsky, E. K.; Burke, P. J.; May, W. S. Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro. Blood, 1990, 75, 1319-1323.
77. Jones, R. J.; Sharkis, S. J.; Miller, C. B.; Rowinsky, E. K.; Burke, P. J.; May, W. S. Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro. Blood, 1990, 75, 1319-1323.
78. Roddie, P. H.; Horton, Y.; Turner, M. L. Primary acute myeloid leukaemia blasts resistant to cytokine-induced differentiation to dendritic-like leukaemia cells can be forced to differentiate by the addition of bryostatin-1. Leukemia, 2002, 16, 84-93.
79. Hayun, M.; Okun, E.; Hayun, R.; Gafter, U.; Albeck, M.; Longo, D. L.; Sredni, B. Synergistic effect of AS101 and Bryostatin-1 on myeloid leukemia cell differentiation in vitro and in an animal model. Leukemia, 2007, 21, 1504-1513.
80. Thomas, A.; Pepper, C.; Hoy, T.; Bentley, P. Bryostatin induces protein kinase C modulation, Mcl-1 up-regulation and phosphorylation of Bcl-2 resulting in cellular differentiation and resistance to drug-induced apoptosis in B-cell chronic lymphocytic leukemia cells. Leuk. Lymphoma, 2004, 45, 997-1008.
81. Szallasi, Z; Du, L.; Levine, R.; Lewin, N. E.; Nguyen, P. N.; Williams, M. D.; Pettit, G. R.; Blumberg, P. M. The bryostatins inhibit growth of B16/F10 melanoma cells in vitro through a protein kinase C-independent mechanism: dissociation of activities using 26-epi-bryostatin 1. Cancer Res., 1996, 56, 2105-2111.
82. Stang, S. L.; Lopez-Campistrous, A.; Song, X.; Dower, N. A.; Blumberg, P. M.; Wender, P. A.; Stone, J. C. A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells. Exp. Hematol., 2009, 37, 122-134.
83. Jørgensen, H. G.; Allan, E. K.; Mountford, J. C.; Richmond, L.; Harrison, S.; Elliott, M. A.; Holyoake, T. L. Enhanced CML stem cell elimination in vitro by bryostatin priming with imatinib mesylate. Exp. Hematol., 2005, 33, 1140-1146.
84. Al-Katib, A. M.; Smith, M. R.; Kamanda, W. S.; Pettit, G. R.; Hamdan, M.; Mohamed, A. N.; Chelladurai, B.; Mohammad, R. M. Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin. Cancer Res., 1998, 4, 1305-1314.
85. Wang, S.; Wang, Z.; Dent, P.; Grant, S. Induction of tumor necrosis factor by bryostatin 1 is involved in synergistic interactions with paclitaxel in human myeloid leukemia cells. Blood, 2003, 101, 3648-3657.
86. Trenn, G.; Pettit, G. R.; Takayama, H.; Hu-Li, J.; Sitkovsky, M. V. Immunomodulating properties of a novel series of protein kinase C activators. The bryostatins. J. Immunol., 1988, 140, 433-439.
87. Garcia, C. S.; Curiel, R. E.; Mwatibo, J. M.; Pestka, S.; Li, H.; Espinoza-Delgado, I. The antineoplastic agent bryostatin-1 differentially regulates IFN-γ receptor subunits in monocytic cells: transcriptional and posttranscriptional control of IFN-γ R2. J. Immunol., 2006, 177, 2707-2716.
88. Bosco, M. C.; Rottschafer, S.; Taylor, L. S.; Ortaldo, J. R.; Longo, D. L.; Espinoza-Delgado, I. The antineoplastic agent bryostatin-1 induces proinflammatory cytokine production in human monocytes: synergy with interleukin-2 and modulation of interleukin-2Rγ chain expression. Blood, 1997, 89, 3402-3411.
89. Shaha, S. P.; Tomic, J.; Shi, Y.; Pham, T.; Mero, P.; White, D.; He, L.; Baryza, J. L.; Wender, P. A.; Booth, J. W.; Spaner, D. E. Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells. Clin. Exp. Immunol., 2009, 158, 186-198.
90. Swannie, H. C.; Kaye, S. B. Protein kinase C inhibitors. Curr. Oncol. Rep., 2002, 4, 37-46.
91. Kortmansky, J.; Schwartz, G. K. Bryostatin-1: a novel PKC inhibitor in clinical development. Cancer Invest., 2003, 21, 924-936.
92. Pavlick, A.C.; Wu, J.; Roberts, J.; Rosenthal, M. A.; Hamilton, A.; Wadler, S.; Farrell, K.; Carr, M.; Fry, D.; Murgo, A. J.; Oratz, R.; Hochster, H.; Liebes, L.; Muggia, F. Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors. Cancer Chemother. Pharmacol., 2009, 64, 803-810.
93. Barr, P.M.; Lazarus, H. M.; Cooper, B. W.; Schluchter, M. D.; Panneerselvam, A.; Jacobberger, J. W.; Hsu, J. W.; Janakiraman, N.; Simic, A.; Dowlati, A.; Remick, S. C. Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant. Am. J. Hematol., 2009, 84, 484-487.
94. Lam, A. P.; Sparano, J. A.; Vinciguerra, V.; Ocean, A. J.; Christos, P.; Hochster, H.; Camacho, F.; Goel, S.; Mani, S.; Kaubisch, A. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am. J. Clin. Oncol., 2010, 33, 121-124.
95. Ku, G.Y.; Ilson, D. H.; Schwartz, L. H.; Capanu, M.; O'Reilly, E.; Shah, M. A.; Kelsen, D. P.; Schwartz, G. K. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol., 2008, 62, 875-880.
96. Roberts, J.D.; Smith, M. R.; Feldman, E. J.; Cragg, L.; Millenson, M. M.; Roboz, G. J.; Honeycutt, C.; Thune, R.; Padavic-Shaller, K.; Carter, W. H.; Ramakrishnan, V.; Murgo, A. J.; Grant, S. Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma. Clin. Cancer Res., 2006, 12, 5809-5816.
97. El-Rayes, B.F.; Gadgeel, S.; Shields, A. F.; Manza, S.; Lorusso, P.; Philip, P. A. Phase I study of bryostatin 1 and gemcitabine. Clin. Cancer Res., 2006, 12, 7059-7062.
98. Peterson, A.C.; Harlin, H.; Karrison, T.; Vogelzang, N. J.; Knost, J. A.; Kugler, J. W.; Lester, E.; Vokes, E.; Gajewski, T. F.; Stadler, W. M. A randomized phase II trial of interleukin-2 in combination with four different doses of bryostatin-1 in patients with renal cell carcinoma. Invest. New Drugs, 2006, 24, 141-149.
99. Ajani, J.A.; Jiang, Y.; Faust, J.; Chang, B. B.; Ho, L.; Yao, J. C.; Rousey, S.; Dakhil, S.; Cherny, R. C.; Craig, C.; Bleyer, A. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest. New Drugs, 2006, 24, 353-357.
100. Khan, T.K.; Nelson, T. J.; Verma, V. A.; Wender, P. A.; Alkon, D. L. A cellular model of Alzheimer's disease therapeutic efficacy: PKC activation reverses Aβ-induced biomarker abnormality on cultured fibroblasts. Neurobiol. Dis., 2009, 34, 332-339.
101. Etcheberrigaray, R.; Tan, M.; Dewachter, I.; Kuiperi, C.; Van der Auwera, I.; Wera, S.; Qiao, L.; Bank, B.; Nelson, T. J.; Kozikowski, A. P.; Van Leuven, F.; Alkon, D. Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc. Natl. Acad. Sci. USA, 2004, 101, 11141-11146.
102. US National Institutes of Health. Clinical trials. gov. http://clinicaltrials.gov/ (Accessed June 29, 2010).
103. Pascale, A.; Amadio, M.; Quattrone, A. Defining a neuron: neuronal ELAV proteins. Cell Mol. Life Sci., 2008, 65, 128-140.
104. Pascale, A.; Amadio, M.; Scapagnini, G.; Lanni, C.; Racchi, M.; Provenzani, A.; Govoni, S.; Alkon, D. L.; Quattrone, A. Neuronal ELAV proteins enhance mRNA stability by a PKCα-dependent pathway. Proc. Natl. Acad. Sci. USA, 2005, 102, 12065-12070.
105. Sun, M.K.; Hongpaisan, J.; Nelson, T. J.; Alkon, D. L. Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains. Proc. Natl. Acad. Sci. USA, 2008, 105, 13620-13625.
106. Sun, M. K.; Hongpaisan, J.; Alkon, D. L. Postischemic PKC activation rescues retrograde and anterograde long-term memory. Proc. Natl. Acad. Sci. USA, 2009, 106, 14676-14680.
107. Jassbi, A. R. Chemistry and biological activity of secondary metabolites in Euphorbia from Iran. Phytochemistry, 2006, 67, 1977-1984.
108. Ogbourne, S.M.; Hampson, P.; Lord, J. M.; Parsons, P.; De Witte, P.A.; Suhrbier, A. Proceedings of the first international conference on PEP005. Anticancer Drugs, 2007, 18, 357-362.
109. Hohmann, J.; Evanics, F.; Berta, L.; Bartok, T. Diterpenoids from Euphorbia peplus. Planta Med., 2000, 66, 291-294.
110. Kedei, N.; Lundberg, D. J.; Toth, A.; Welburn, P.; Garfield, S. H.; Blumberg, P. M. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res., 2004, 64, 3243-3255.
111. Krauter, G.; Von der Lieth, C. W.; Schmidt, R.; Hecker, E. Structure/ activity relationships of polyfunctional diterpenes of the tigliane type. A pharmacophore model for protein-kinase-C activators based on structure/activity studies and molecular modeling of the tumor promoters 12-O-tetradecanoylphorbol 13-acetate and 3-O-tetradecanoylingenol. Eur. J. Biochem., 1996, 242, 417-427.
112. Winkler, J. D.; Hong, B.; Bahador, A.; Kazanietz, M. G.; Blumberg, P. M. Synthesis of ingenol analogues with affinity for protein kinase C. Bioorg. Med. Chem. Lett., 1993, 3, 577-580.
113. Hampson, P.; Chahal, H.; Khanim, F.; Hayden, R.; Mulder, A.; Assi, L. K.; Bunce, C. M.; Lord, J. M. PEP005, a selective smallmolecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood, 2005, 106, 1362-1368.
114. Hampson, P.; Kavanagh, D.; Smith, E.; Wang, K.; Lord, J. M.; Ed Rainger, G. The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-δdependent manner. Cancer Immunol. Immunother., 2008, 57, 1241-1251.
115. Blanco-Molina, M.; Tron, G. C.; Macho, A.; Lucena, C.; Calzado, M. A.; Munoz, E.; Appendino, G. Ingenol esters induce apoptosis in Jurkat cells through an AP-1 and NF-κB independent pathway. Chem. Biol., 2001, 8, 767-778.
116. Zayed, S. M.; Farghaly, M.; Taha, H.; Gotta, H.; Hecker, E. Dietary cancer risk conditional cancerogens in produce of livestock fed on species of spurge (Euphorbiaceae). I. Skin irritant and tumorpromoting ingenane-type diterpene esters in E. peplus, one of several herbaceous Euphorbia species contaminating fodder of livestock. J. Cancer Res. Clin. Oncol., 1998, 124, 131-140.
117. Gillespie, S. K.; Zhang, X. D.; Hersey, P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. Mol. Cancer Ther., 2004, 3, 1651-1658.
118. Lee, W. Y.; Hampson, P.; Coulthard, L.; Ali, F.; Salmon, M.; Lord, J. M.; Scheel-Toellner, D. Novel anti-leukemic compound ingenol 3-angelate inhibits T cell apoptosis by activating PKC θ. J. Biol. Chem., 2010, 285, 23889-23898.
119. Ogbourne, S. M.; Suhrbier, A.; Jones, B.; Cozzi, S.; Boyle, G. M.; Morris, M.; McAlpine, D.; Johns, J.; Scott, T. M.; Sutherland, K. P.; Gardner, J. M.; Le, T. T.; Lenarczyk, A.; Aylward, J. H.; Parsons, P. G. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res., 2004, 64, 2833-2839.
120. Benhadji, K. A.; Serova, M.; Ghoul, A.; Cvitkovic, E.; Le Tourneau, C.; Ogbourne, S. M.; Lokiec, F.; Calvo, F.; Hammel, P.; Faivre, S.; Raymond, E. Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells. Br. J. Cancer, 2008, 99, 1808-1815.
121. Serova, M.; Ghoul, A.; Benhadji, K. A.; Faivre, S.; Le Tourneau, C.; Cvitkovic, E.; Lokiec, F.; Lord, J.; Ogbourne, S. M.; Calvo, F.; Raymond, E. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol. Cancer Ther., 2008, 7, 915-922.
122. Hampson, P.; Wang, K.; Milverton, L.; Ersvaer, E.; Bruserud, O.; Lord, J. M. Kinetics of ERK1/2 activation determine sensitivity of acute myeloid leukaemia cells to the induction of apoptosis by the novel small molecule ingenol 3-angelate (PEP005). Apoptosis, 2010, 15, 946-955.
123. Cozzi, S. J.; Parsons, P. G.; Ogbourne, S. M.; Pedley, J.; Boyle, G. M. Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway. Cancer Res., 2006, 66, 10083-10091.
124. Olsnes, A. M.; Ersvaer, E.; Ryningen, A.; Paulsen, K.; Hampson, P.; Lord, J. M.; Gjertsen, B. T.; Kristoffersen, E. K.; Bruserud, O. The protein kinase C agonist PEP005 increases NF-κB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells. Br. J. Haematol., 2009, 145, 761-774.
125. Mason, S. A.; Cozzi, S. J.; Pierce, C. J.; Pavey, S. J.; Parsons, P. G.; Boyle, G. M. The induction of senescence-like growth arrest by protein kinase C-activating diterpene esters in solid tumor cells. Invest. New Drugs, 2010, 28, 575-586.
126. Ersvaer, E.; Hampson, P.; Hatfield, K.; Ulvestad, E.; Wendelbo, O.; Lord, J. M.; Gjertsen, B. T.; Bruserud, O. T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-γ that can be further increased by a novel protein kinase C agonist PEP005. Cancer Immunol. Immunother., 2007, 56, 913-925.
127. Challacombe, J. M.; Suhrbier, A.; Parsons, P. G.; Jones, B.; Hampson, P.; Kavanagh, D.; Rainger, G. E.; Morris, M.; Lord, J. M.; Le, T. T. T.; Hoang-Le, D.; Ogbourne, S. M. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J. Immunol., 2006, 177, 8123-8132.
128. Le, T. T.; Gardner, J.; Hoang-Le, D.; Schmidt, C. W.; MacDonald, K. P.; Lambley, E.; Schroder, W. A.; Ogbourne, S. M.; Suhrbier, A. Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies. Vaccine, 2009 27, 3053-3062.
129. Siller, G.; Gebauer, K.; Welburn, P.; Katsamas, J.; Ogbourne, S. M. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehiclecontrolled, multicentre, phase IIa study. Australas. J. Dermatol., 2009, 50, 16-22.
130. Anderson, L.; Schmieder, G. J.; Werschler, W. P.; Tschen, E. H.; Ling, M. R.; Stough, D. B.; Katsamas, J. Randomized, doubleblind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J. Am. Acad. Dermatol., 2009, 60, 934-943.
131. Takashima, M.; Sakai, H. A new toxic substance, teleocidin produced by Streptomyces. Part I. Production, isolation, and chemical studies. Bull. Agric. Chem. Soc. Jpn, 1960, 24, 647-651.
132. Fujiki, H.; Mori, M.; Nakayasu, M.; Terada, M.; Sugimura, T.; Moore, R. E. Indole alkaloids: dihydroteleocidin B, teleocidin, and lyngbyatoxin A as members of a new class of tumor promoters. Proc. Natl. Acad. Sci. USA, 1981, 78, 3872-3876.
133. Umezawa, K.; Weinstein, I. B.; Horowitz, A.; Fujiki, H.; Matsushima, T.; Sugimura, T. Similarity of teleocidin B and phorbol ester tumour promoters in effects on membrane receptors. Nature, 1981, 290, 411-413.
134. Irie, K.; Nakagawa, Y.; Ohigashi, H. Toward the development of new medicinal leads with selectivity for protein kinase C isozymes. Chem. Rec., 2005, 5, 185-195.
135. Kozikowski, A. P.; Chen, Y.; Subhasish, T.; Lewin, N. E.; Blumberg, P. M.; Zhong, Z.; D'Annibale, M. A.; Wang, W.; Shen, Y.; Langley, B. Searching for disease modifiers-PKC activation and HDAC inhibition-a dual drug approach to Alzheimer's disease that decreases Aβ production while blocking oxidative stress. ChemMedChem, 2009, 4, 1095-1105.
136. Endo, Y.; Takehana, S.; Ohno, M.; Driedger, P. E.; Stabel, S.; Mizutani, M. Y.; Tomioka, N.; Itai, A.; Shudo, K. Clarification of the binding mode of teleocidin and benzolactams to the Cys2 domain of protein kinase Coooby synthesis of hydrophobically modified, teleocidin-mimicking benzolactams and computational docking simulation. J. Med. Chem., 1998, 41, 1476-1496.
137. Rong, S. B.; Enyedy, I. J.; Qiao, L.; Zhao, L.; Ma, D.; Pearce, L. L.; Lorenzo, P. S.; Stone, J. C.; Blumberg, P. M.; Wang, S.; Kozikowski, A. P. Structural basis of RasGRP binding to high-affinity PKC ligands. J. Med. Chem., 2002, 45, 853-860.
138. Kozikowski, A. P.; Nowak, I.; Petukhov, P. A.; Etcheberrigaray, R.; Mohamed, A.; Tan, M.; Lewin, N.; Hennings, H.; Pearce, L. L.; Blumberg, P. New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPPα. J. Med. Chem., 2003, 46, 364-373.
139. Yanagita, R. C.; Nakagawa, Y.; Yamanaka, N.; Kashiwagi, K.; Saito, N.; Irie, K. Synthesis, conformational analysis, and biological evaluation of 1-hexylindolactam-V10 as a selective activator for novel protein kinase C isozymes. J. Med. Chem., 2008, 51, 46-56.
140. Nakagawa, Y.; Irie, K.; Nakamura, Y.; Ohigashi, H. The amide hydrogen of (-)-indolactam-V and benzolactam-V8's plays a critical role in protein kinase C binding and tumor-promoting activities. Bioorg. Med. Chem. Lett., 2001, 11, 723-728.
141. Nakagawa, Y.; Irie, K.; Yanagita, R. C.; Ohigashi, H.; Tsuda, K. Indolactam-V is involved in the CH/pi interaction with Pro-11 of the PKCtttC1B domain: application for the structural optimization of the PKCoooligand. J. Am. Chem. Soc., 2005, 127, 5746-5747.
142. Irie, K.; Nakagawa, Y.; Ohigashi, H. Indolactam and benzolactam compounds as new medicinal leads with binding selectivity for C1 domains of protein kinase C isozymes. Curr. Pharm. Des., 2004, 10, 1371-1385.
143. Mach, U.R.; Lewin, N. E.; Blumberg, P. M.; Kozikowski, A. P. Synthesis and pharmacological evaluation of 8-and 9-substituted benzolactam-V8 derivatives as potent ligands for protein kinase C, a therapeutic target for Alzheimer's disease. ChemMedChem, 2006, 1, 307-314.
144. Ma, D.; Zhang, T.; Wang, G.; Kozikowski, A. P.; Lewin, N. E.; Blumberg, P. M. Synthesis of 7,8-disubstituted benzolactam-V8 and its binding to protein kinase C. Bioorg. Med. Chem. Lett., 2001, 11, 99-101.
145. Ma, D.; Tang, G.; Kozikowski, A. P. Synthesis of 7-substituted benzolactam-V8s and their selectivity for protein kinase C isozymes. Org. Lett., 2002, 4, 2377-2380.
146. Ma, D.; Tang, W.; Kozikowski, A. P.; Lewin, N. E.; Blumberg, P. M. General and Stereospecific route to 9-substituted, 8,9-disubstituted, and 9,10-disubstituted analogues of benzolactam-V8. J. Org. Chem., 1999, 64, 6366-6373.
147. Endo, Y.; Yamaguchi, M.; Hirano, M.; Shudo, K. Role of the hydrophobic moiety of tumor promoters. Synthesis and activity of 9-alkylated benzolactams. Chem. Pharm. Bull., 1996, 44, 1138-1140.
148. Endo, Y.; Ohno, M.; Hirano, M.; Itai, A.; Shudo, K. Synthesis, conformation, and biological activity of teleocidin mimics, benzolactams. A clarification of the conformational flexibility problem in structure-activity studies of teleocidins. J. Am. Chem. Soc., 1996, 118, 1841-1855.
149. Endo, Y.; Yokoyama, A. Role of the hydrophobic moiety of tumor promoters. Synthesis and activity of 2-alkylated benzolactams. Bioorg. Med. Chem. Lett., 2000, 10, 63-66.
150. Kozikowski, A. P.; Ma, D.; Pang, Y.; Shum, P.; Likic, V.; Mishra, P. K.; Macura, S.; Basu, A.; Lazo, J. S.; Ball, R. G. Synthesis, molecular modeling, 2-D NMR, and biological evaluation of ILV mimics as potential modulators of protein kinase C. J. Am. Chem. Soc., 1993, 115, 3957-3965.
151. Ma, D.; Wang, G.; Wang, S.; Kozikowski, A. P.; Lewin, N. E.; Blumberg, P. M. Synthesis and protein kinase C binding activity of benzolactam-V7. Bioorg. Med. Chem. Lett., 1999, 9, 1371-1374.
152. Sridhar, J.; Wei, Z. L.; Nowak, I.; Lewin, N. E.; Ayres, J. A.; Pearce, L. V.; Blumberg, P. M.; Kozikowski, A. P. New bivalent PKC ligands linked by a carbon spacer: enhancement in binding affinity. J. Med. Chem., 2003, 46, 4196-4204.
153. Kozikowski, A. P.; Wang, S.; Ma, D.; Yao, J.; Ahmad, S.; Glazer, R. I.; Bogi, K.; Acs, P.; Modarres, S.; Lewin, N. E.; Blumberg, P. M. Modeling, chemistry, and biology of the benzolactam analogues of indolactam V (ILV). 2. Identification of the binding site of the benzolactams in the CRD2 activator-binding domain of PKCbbband discovery of an ILV analogue of improved isozyme selectivity. J. Med. Chem., 1997, 40, 1316-1326.
154. Nakagawa, Y.; Irie, K.; Yanagita, R. C.; Ohigashi, H.; Tsuda, K.; Kashiwagi, K.; Saito, N. Design and synthesis of 8-octylbenzolactam-V9, a selective activator for protein kinase C VVVand aa. J. Med. Chem., 2006, 49, 2681-2688.
155. Nakagawa, Y.; Irie, K.; Masuda, A.; Ohigashi, H. Synthesis, conformation and PKC isozyme surrogate binding of new lactone analogues of benzolactame-V8s. Tetrahedron, 2002, 58, 2101-2115.
156. Bhagavan, S.; Ibarreta, D.; Ma, D.; Kozikowski, A. P.; Etcheberrigaray, R. Restoration of TEA-induced calcium responses in fibroblasts from Alzheimer's disease patients by a PKC activator. Neurobiol. Dis., 1998, 5, 177-187.
157. Ibarreta, D.; Duchen, M.; Ma, D.; Qiao, L.; Kozikowski, A. P.; Etcheberrigaray, R. Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells. Neuroreport, 1999, 10, 1035-1040.
158. Yang, H.; Pan, J.; Ba, M.; Sun, Z.; Ma, G.; Lu, G.; Xiao, Q. C., S. New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing α-secretase activity. Eur. J. Neurosci., 2007, 26, 381-391.
159. Chen, S.; Borowiak, M.; Fox, J. L.; Maehr, R.; Osafune, K.; Davidow, L.; Lam, K.; Peng, L. F.; Schreiber, S. L.; Rubin, L. L.; Melton, D. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat. Chem. Biol., 2009, 5, 258-265.
160. Marquez, V. E.; Blumberg, P. M. Synthetic diacylglycerols (DAG) and DAG-lactones as activators of protein kinase C (PK-C). Acc. Chem. Res., 2003, 36, 434-443.
161. Kang, J. H.; Siddiqui, M. A.; Sigano, D. M.; Krajewski, K.; Lewin, N. E.; Pu, Y.; Blumberg, P. M.; Lee, J.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol. 24. Asymmetric synthesis of a chiral (R)-DAG-lactone template as a versatile precursor for highly functionalized DAG-lactones. Org. Lett., 2004, 6, 2413-2416.
162. Duan, D.; Lewin, N. E.; Sigano, D. M.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol. 21. A solid-phase method of synthesis of diacylglycerol lactones as a prelude to a combinatorial approach for the synthesis of protein kinase C isozyme-specific ligands. J. Med. Chem., 2004, 47, 3248-3254.
163. Kang, J. H.; Peach, M. L.; Pu, Y.; Lewin, N. E.; Nicklaus, M. C.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C. J. Med. Chem., 2005, 48, 5738-5748.
164. Nacro, K.; Bienfait, B.; Lee, J.; Han, K. C.; Kang, J. H.; Benzaria, S.; Lewin, N. E.; Bhattacharyya, D. K.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C? J. Med. Chem., 2000, 43, 921-944.
165. Kang, J. H.; Benzaria, S.; Sigano, D. M.; Lewin, N. E.; Pu, Y.; Peach, M. L.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol. 26. Exploring the chemical space surrounding the C1 domain of protein kinase C with DAG-lactones containing aryl groups at the sn-1 and sn-2 positions. J. Med. Chem., 2006, 49, 3185-3203.
166. Comin, M. J.; Czifra, G.; Kedei, N.; Telek, A.; Lewin, N. E.; Kolusheva, S.; Velasquez, J. F.; Kobylarz, R.; Jelinek, R.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths. J. Med. Chem., 2009, 52, 3274-3283.
167. Malolanarasimhan, K.; Kedei, N.; Sigano, D. M.; Kelley, J. A.; Lai, C. C.; Lewin, N. E.; Surawski, R. J.; Pavlyukovets, V. A.; Garfield, S. H.; Wincovitch, S.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). 27. modulation of membrane translocation of protein kinase C (PKC) Isozymes α and β by diacylglycerol lactones (DAG-lactones) containing rigid-rod acyl groups. J. Med. Chem., 2007, 50, 962-978.
168. Nacro, K.; Lee, J.; Barchi, J. J.; Lewin, N. E.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). Part 19: Asymmetric syntheses of (3R)-and (3S)-3-hydroxy-4,4-disubstituted heptono-1,4-lactones as protein kinase C (PK-C) with increased hydrophilicity. Tetrahedron, 2002, 58, 5335-5345.
169. Tamamura, H.; Sigano, D. M.; Lewin, N. E.; Peach, M. L.; Nicklaus, M. C.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). 23. Hydrophobic ligand-protein interactions versus ligand-lipid interactions of DAGlactones with protein kinase C (PK-C). J. Med. Chem., 2004, 47, 4858-4864.
170. Baba, Y.; Ogoshi, Y.; Hirai, G.; Yanagisawa, T.; Nagamatsu, K.; Mayumi, S.; Hashimoto, Y.; Sodeoka, M. Design, synthesis, and structure-activity relationship of new isobenzofuranone ligands of protein kinase C. Bioorg. Med. Chem. Lett., 2004, 14, 2963-2967.
171. Choi, Y.; Pu, Y.; Peach, M. L.; Kang, J. H.; Lewin, N. E.; Sigano, D. M.; Garfield, S. H.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol (DAG). 28. DAG-dioxolanones reveal a new additional interaction site in the C1b domain of PKC CC. J. Med. Chem., 2007, 50, 3465-3481.
172. Lee, J.; Han, K. C.; Kang, J. H.; Pearce, L. L.; Lewin, N. E.; Yan, S.; Benzaria, S.; Nicklaus, M. C.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol. 18. The incorporation of a hydroxamate moiety into diacylglycerol-lactones reduces lipophilicity and helps discriminate between sn-1 and sn-2 binding modes to protein kinase C (PK-C). Implications for isozyme specificity. J. Med. Chem., 2001, 44, 4309-4312, and erratum J. Med. Chem. 2003, 46, 2794.
173. Tamamura, H.; Sigano, D. M.; Lewin, N. E.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol.20. The search for an elusive binding site on protein kinase C through relocation of the carbonyl pharmacophore along the sn-1 side chain of 1,2-diacylglycerol lactones. J. Med. Chem., 2004, 47, 644-655.
174. Kang, J. H.; Kim, S. Y.; Lee, J.; Marquez, V. E.; Lewin, N. E.; Pearce, L. V.; Blumberg, P. M. Macrocyclic diacylglycerol-bislactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C. J. Med. Chem., 2004, 47, 4000-4007.
175. Pu, Y.; Perry, N. A.; Yang, D.; Lewin, N. E.; Kedei, N.; Braun, D. C.; Choi, S. H.; Blumberg, P. M.; Garfield, S. H.; Stone, J. C.; Duan, D.; Marquez, V. E. A novel diacylglycerol-lactone shows marked selectivity in vitro among C1 domains of protein kinase C (PKC) isoforms α and δ well as selectivity for RasGRP compared with PKCα. J. Biol. Chem., 2005, 280, 27329-27338.
176. Duan, D.; Sigano, D. M.; Kelley, J. A.; Lai, C. C.; Lewin, N. E.; Kedei, N.; Peach, M. L.; Lee, J.; Abeyweera, T. P.; Rotenberg, S. A.; Kim, H.; Kim, Y. H.; El Kazzouli, S.; Chung, J. U.; Young, H. A.; Young, M. R.; Baker, A.; Colburn, N. H.; Haimovitz-Friedman, A.; Truman, J. P.; Parrish, D. A.; Deschamps, J. R.; Perry, N. A.; Surawski, R. J.; Blumberg, P. M.; Marquez, V. E. Conformation ally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities. J. Med. Chem., 2008, 51, 5198-5220.
177. El Kazzouli, S.; Lewin, N. E.; Blumberg, P. M.; Marquez, V. E. Conformationally constrained analogues of diacylglycerol. 30. An investigation of diacylglycerol-lactones containing heteroaryl groups reveals compounds with high selectivity for Ras guanyl nucleotide-releasing proteins. J. Med. Chem., 2008, 51, 5371-5386.
178. Garcia-Bermejo, M. L.; Leskow, F. C.; Fujii, T.; Wang, Q.; Blumberg, P. M.; Ohba, M.; Kuroki, T.; Han, K. C.; Lee, J.; Marquez, V. E.; Kazanietz, M. G. Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCα. J. Biol. Chem., 2002, 277, 645-655, and erratum J. Biol. Chem. 2004, 279, 23846
179. Truman, J. P.; Rotenberg, S. A.; Kang, J. H.; Lerman, G.; Fuks, Z.; Kolesnick, R.; Marquez, V. E.; Haimovitz-Friedman, A. PKCα activation downregulates ATM and radio-sensitizes androgensensitive human prostate cancer cells in vitro and in vivo. Cancer. Biol. Ther., 2009, 8, 54-63.
180. Kang, J. H.; Kim, Y.; Won, S. H.; Park, S. K.; Lee, C. W.; Kim, H. M.; Lewin, N. E.; Perry, N. A.; Pearce, L. V.; Lundberg, D. J.; Surawski, R. J.; Blumberg, P. M.; Lee, J. Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-γ-lactones as protein kinase C ligands and antitumor agents. Bioorg. Med. Chem. Lett., 2010, 20, 1008-1012.
181. Lee, J.; Kang, J. H.; Han, K. C.; Kim, Y.; Kim, S. Y.; Youn, H. S.; Mook-Jung, I.; Kim, H.; Lo Han, J. H.; Ha, H. J.; Kim, Y. H.; Marquez, V. E.; Lewin, N. E.; Pearce, L. V.; Lundberg, D. J.; Blumberg, P. M. Branched diacylglycerol-lactones as potent protein kinase C ligands and α-secretase activators. J. Med. Chem., 2006, 49, 2028-2036.
182. Sigano, D. M.; Peach, M. L.; Nacro, K.; Choi, Y.; Lewin, N. E.; Nicklaus, M. C.; Blumberg, P. M.; Marquez, V. E. Differential binding modes of diacylglycerol (DAG) and DAG lactones to protein kinase C (PK-C). J. Med. Chem., 2003, 46, 1571-1579.
183. Hamer, D. H.; Bocklandt, S.; McHugh, L.; Chun, T. W.; Blumberg, P. M.; Sigano, D. M.; Marquez, V. E. Rational design of drugs that induce human immunodeficiency virus replication. J. Virol., 2003, 77, 10227-10236.
184. Raifman, O.; Kolusheva, S.; Comin, M. J.; Kedei, N.; Lewin, N. E.; Blumberg, P. M.; Marquez, V. E.; Jelinek, R. Membrane anchoring of diacylglycerol lactones substituted with rigid hydrophobic acyl domains correlates with biological activities. FEBS J., 2010, 277, 233-243.
185. Arcamone, F.; Cassinelli, G.; Fantini, G.; Grein, A.; Orezzi, P.; Pol, C.; Spalla, C. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol. Bioeng., 1969, 11, 1101-1110.
186. Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev., 2004, 56, 185-229.
187. Frederick, C. A.; Williams, L. D.; Ughetto, G.; van der Marel, G. A.; van Boom, J. H.; Rich, A.; Wang, A. H. Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin. Biochemistry, 1990, 29, 2538-2549.
188. Israel, M.; Seshadri, R.; Idriss, J. M. N-Benzyladriamycin-14-valerate (AD198), a promising new adriamycin (ADR) analog. Proc. Am. Assoc. Cancer Res., 1985, 26, 220.
189. Roaten, J. B.; Kazanietz, M. G.; Sweatman, T. W.; Lothstein, L.; Israel, M.; Parrill, A. L. Molecular models of N-benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-δ. J. Med. Chem., 2001, 44, 1028-1034.
190. Lothstein, L.; Israel, M.; Sweatman, T. W. Anthracycline drug targeting: cytoplasmic versus nuclear--a fork in the road. Drug Resist. Updat, 2001, 4, 169-177.
191. Roaten, J. B.; Kazanietz, M. G.; Caloca, M. J.; Bertics, P. J.; Lothstein, L.; Parrill, A. L.; Israel, M.; Sweatman, T. W. Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14-valerate with the C1-regulatory domain of protein kinase C: structural requirements, isoform specificity, and correlation with drug cytotoxicity. Mol. Cancer. Ther., 2002, 1, 483-492.
192. Barrett, C. M.; Lewis, F. L.; Roaten, J. B.; Sweatman, T. W.; Israel, M.; Cleveland, J. L.; Lothstein, L. Novel extranuclear-targeted anthracyclines override the antiapoptotic functions of Bcl-2 and target protein kinase C pathways to induce apoptosis. Mol. Cancer. Ther., 2002, 1, 469-481.
193. Harstrick, A.; Vanhoefer, U.; Schleucher, N.; Schroeder, J.; Baumgart, J.; Scheulen, M. E.; Wilke, H.; Seeber, S. Activity of Nbenzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines. Anticancer Drugs, 1995, 6, 681-685.
194. Traganos, F.; Israel, M.; Silber, R.; Seshadri, R.; Kirschenbaum, S.; Potmesil, M. Effects of new N-alkyl analogues of adriamycin on in vitro survival and cell cycle progression of L1210 cells. Cancer Res., 1985, 45, 6273-6279.
195. Lothstein, L.; Savranskaya, L.; Sweatman, T. W. NBenzyladriamycin-14-valerate (AD 198) cytotoxicty circumvents Bcr-Abl anti-apoptotic signaling in human leukemia cells and also potentiates imatinib cytotoxicity. Leuk. Res., 2007, 31, 1085-1095.
196. He, Y.; Liu, J.; Durrant, D.; Yang, H. S.; Sweatman, T.; Lothstein, L.; Lee, R. M. N-benzyladriamycin-14-valerate (AD198) induces apoptosis through protein kinase C-aa-induced phosphorylation of phospholipid scramblase 3. Cancer Res., 2005, 65, 10016-10023.
197. Ganapathi, R.; Grabowski, D.; Sweatman, T. W.; Seshadri, R.; Israel, M. N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo. Br. J. Cancer, 1989, 60, 819-826.
198. Sweatman, T. W.; Seshadri, R.; Israel, M. Pharmacology of Nbenzyladriamycin-14-valerate in the rat. Cancer Chemother. Pharmacol., 1999, 43, 419-426.
199. He, Y.; Liu, J.; Grossman, D.; Durrant, D.; Sweatman, T.; Lothstein, L.; Epand, R. F.; Epand, R. M.; Lee, R. M. Phosphorylation of mitochondrial phospholipid scramblase 3 by protein kinase C-oo induces its activation and facilitates mitochondrial targeting of tBid. J. Cell. Biochem., 2007, 101, 1210-1221.
200. Hofmann, P. A.; Israel, M.; Koseki, Y.; Laskin, J.; Gray, J.; Janik, A.; Sweatman, T. W.; Lothstein, L. N-Benzyladriamycin-14-valerate (AD 198): a non-cardiotoxic anthracycline that is cardioprotective through PKC-tttactivation. J. Pharmacol. Exp. Ther., 2007, 323, 658-664.
201. Kashfi, K.; Israel, M.; Sweatman, T. W.; Seshadri, R.; Cook, G. A. Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues. Biochem. Pharmacol., 1990, 40, 1441-1448.
202. Lameh, J.; Chuang, L. F.; Israel, M.; Chuang, R. Y. Mechanistic studies on N-benzyladriamycin-14-valerate (AD 198), a highly lipophilic alkyl adriamycin analog. Anticancer Res., 1988, 8, 689-693.
203. Chuang, L. F.; Kung, H. F.; Israel, M.; Chuang, R. Y. Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32). Biochem. Pharmacol., 1992, 43, 865-872.
204. Markman, M.; Homesley, H.; Norberts, D. A.; Schink, J.; Abbas, F.; Miller, A.; Soper, J.; Teng, N.; Hammond, N.; Muggia, F.; Israel, M.; Sweatman, T. Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies. Gynecol. Oncol., 1996, 61, 90-93.
205. Iida, T.; Kobayashi, E.; Yoshida, M.; Sano, H. Calphostins, novel and specific inhibitors of protein kinase C. II. Chemical structures. J. Antibiot., (Tokyo) 1989, 42, 1475-1481.
206. Kobayashi, E.; Nakano, H.; Morimoto, M.; Tamaoki, T. Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C. Biochem. Biophys. Res. Commun., 1989, 159, 548-553.
207. Rotenberg, S. A.; Huang, M. H.; Zhu, J.; Su, L.; Riedel, H. Deletion analysis of protein kinase C inactivation by calphostin C. Mol. Carcinog., 1995, 12, 42-49.
208. Bruns, R. F.; Miller, F. D.; Merriman, R. L.; Howbert, J. J.; Heath, W. F.; Kobayashi, E.; Takahashi, I.; Tamaoki, T.; Nakano, H. Inhibition of protein kinase C by calphostin C is light-dependent. Biochem. Biophys. Res. Commun., 1991, 176, 288-293.
209. Gopalakrishna, R.; Chen, Z. H.; Gundimeda, U. Irreversible oxidative inactivation of protein kinase C by photosensitive inhibitor calphostin C. FEBS Lett., 1992, 314, 149-154.
210. Redman, C.; Lefevre, J.; MacDonald, M. L. Inhibition of diacylglycerol kinase by the antitumor agent calphostin C. Evidence for similarity between the active site of diacylglycerol kinase and the regulatory site of protein kinase C. Biochem. Pharmacol., 1995, 50, 235-241.
211. Areces, L. B.; Kazanietz, M. G.; Blumberg, P. M. Close similarity of baculovirus-expressed n-chimaerin and protein kinase Cα as phorbol ester receptors. J. Biol. Chem., 1994, 269, 19553-19558.
212. Kazanietz, M. G.; Lewin, N. E.; Bruns, J. D.; Blumberg, P. M. Characterization of the cysteine-rich region of the Caenorhabditis elegans protein Unc-13 as a high affinity phorbol ester receptor. Analysis of ligand-binding interactions, lipid cofactor requirements, and inhibitor sensitivity. J. Biol. Chem., 1995, 270, 10777-10783.
213. Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A. Carbene complexes in the synthesis of complex natural products: total synthesis of the calphostins. J. Am. Chem. Soc., 2000, 122, 3224-3225.
214. Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A.; Mammen, J. Total synthesis of the calphostins: application of fischer carbene complexes and thermodynamic control of atropisomers. J. Org. Chem., 2001, 66, 1297-1309.
215. Morgan, B. J.; Dey, S.; Johnson, S. W.; Kozlowski, M. C. Design, synthesis, and investigation of protein kinase C inhibitors: total syntheses of (+)-calphostin D, (+)-phleichrome, cercosporin, and new photoactive perylenequinones. J. Am. Chem. Soc., 2009, 131, 9413-9425.
216. Kobayashi, E.; Ando, K.; Nakano, H.; Iida, T.; Ohno, H.; Morimoto, M.; Tamaoki, T. Calphostins (UCN-1028), novel and specific inhibitors of protein kinase C. I. Fermentation, isolation, physico-chemical properties and biological activities. J. Antibiot., (Tokyo) 1989, 42, 1470-1474.
217. Chiarini, A.; Whitfield, J. F.; Pacchiana, R.; Armato, U.; Dal Pra, I. Photoexcited calphostin C selectively destroys nuclear lamin B1 in neoplastic human and rat cells-a novel mechanism of action of a photodynamic tumor therapy agent. Biochim. Biophys. Acta, 2008, 1783, 1642-1653.
218. Dubauskas, Z.; Beck, T. P.; Chmura, S. J.; Kovar, D. A.; Kadkhodaian, M. M.; Shrivastav, M.; Chung, T.; Stadler, W. M.; Rinker-Schaeffer, C. W. Activated calphostin C cytotoxicity is independent of p53 status and in vivo metastatic potential. Clin. Cancer Res., 1998, 4, 2391-2398.
219. Pollack, I. F.; Kawecki, S. The effect of calphostin C, a potent photodependent protein kinase C inhibitor, on the proliferation of glioma cells in vitro. J. Neurooncol., 1997, 31, 255-266.
220. Guo, B.; Hembruff, S. L.; Villeneuve, D. J.; Kirwan, A. F.; Parissenti, A. M. Potent killing of paclitaxel-and doxorubicin-resistant breast cancer cells by calphostin C accompanied by cytoplasmic vacuolization. Breast Cancer Res. Treat., 2003, 82, 125-141.
221. Kaul, A.; Maltese, W. A. Killing of cancer cells by the photoactivatable protein kinase C inhibitor, calphostin C, involves induction of endoplasmic reticulum stress. Neoplasia, 2009, 11, 823-834.
222. Alonso, M.; Muniz, M.; Hall, C.; Velasco, A.; Hidalgo, J. Calphostin C induces selective disassembly of the Golgi complex by a protein kinase C-independent mechanism. Eur. J. Cell Biol., 1998, 76, 93-101.
223. Morgado-Diaz, J. A.; Montesano, G.; De Souza Fernandes, S.; Redondo, P. A.; Fernandes de Souza, W.; Albuquerque-Xavier, A. C.; Leve, F.; Tanaka, M. N.; Martins de Araujo, W.; Oliveira, S. S.; Benchimol, M.; De Souza, W. Golgi complex disassembly caused by light-activated calphostin C involves MAPK and PKA. Tissue Cell, 2007, 39, 161-169.
224. Sciorra, V. A.; Hammond, S. M.; Morris, A. J. Potent direct inhibition of mammalian phospholipase D isoenzymes by calphostin-c. Biochemistry, 2001, 40, 2640-2646.
225. Chiarini, A.; Whitfield, J. F.; Pacchiana, R.; Marconi, M.; Armato, U.; Dal Pra, I. Calphostin C, a remarkable multimodal photodynamic killer of neoplastic cells by selective nuclear lamin B1 destruction and apoptogenesis (Review). Oncol. Rep., 2010, 23, 887-892.
226. Lown, J. W. 1996 Hoffman-LaRoche Award Lecture Photochemistry and photobiology of perylenequinones. Can. J. Chem., 1997, 75, 99-119.
227. Wender, P. A.; Kee, J. M.; Warrington, J. M. Practical synthesis of prostratin, DPP, and their analogs, adjuvant leads against latent HIV. Science, 2008, 320, 649-652.
228. Marquez, N.; Calzado, M. A.; Sanchez-Duffhues, G.; Perez, M.; Minassi, A.; Pagani, A.; Appendino, G.; Diaz, L.; Munoz-Fernandez, M. A.; Munoz, E. Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation. Biochem. Pharmacol., 2008, 75, 1370-1380.
229. Gulakowski, R. J.; McMahon, J. B.; Buckheit, R. W., Jr; Gustafson, K. R.; Boyd, M. R. Antireplicative and anticytopathic activities of prostratin, a non-tumor-promoting phorbol ester, against human immunodeficiency virus (HIV). Antiviral Res., 1997, 33, 87-97.
230. Hezareh, M.; Moukil, M. A.; Szanto, I.; Pondarzewski, M.; Mouche, S.; Cherix, N.; Brown, S. J.; Carpentier, J. L.; Foti, M. Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and novel PKC isoforms. Antivir. Chem. Chemother., 2004, 15, 207-222.
231. Kulkosky, J.; Culnan, D. M.; Roman, J.; Dornadula, G.; Schnell, M.; Boyd, M. R.; Pomerantz, R. J. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood, 2001, 98, 3006-3015.
232. Williams, S. A.; Chen, L. F.; Kwon, H.; Fenard, D.; Bisgrove, D.; Verdin, E.; Greene, W. C. Prostratin antagonizes HIV latency by activating NF-κB. J. Biol. Chem., 2004, 279, 42008-42017.
233. Kato, Y.; Scheuer, P. J. Aplysiatoxin and debromoaplysiatoxin, constituents of the marine mollusk Stylocheilus longicauda (Quoy and Gaimard, 1824). J. Am. Chem. Soc., 1974, 96, 2245-2246.
234. Fujiki, H.; Suganuma, M.; Nakayasu, M.; Hoshino, H.; Moore, R. E.; Sugimura, T. The third class of new tumor promoters, polyacetates (debromoaplysiatoxin and aplysiatoxin), can differentiate biological actions relevant to tumor promoters. Gann, 1982, 73, 495-497.
235. Horowitz, A. D.; Fujiki, H.; Weinstein, I. B. Comparative effects of aplysiatoxin, debromoaplysiatoxin, and teleocidin on receptor binding and phospholipid metabolism. Cancer Res., 1983, 43, 1529-1535.
236. Nakagawa, Y.; Yanagita, R. C.; Hamada, N.; Murakami, A.; Takahashi, H.; Saito, N.; Nagai, H.; Irie, K. A simple analogue of tumor-promoting aplysiatoxin is an antineoplastic agent rather than a tumor promoter: development of a synthetically accessible protein kinase C activator with bryostatin-like activity. J. Am. Chem. Soc., 2009, 131, 7573-7579.
237. Marner, F.; Krick, W.; Gellrich, B.; Jaenicke, L. Irigermanal and Iridogermanal: Two New Triterpenoids from Rhizomes of Iris germanica L. J. Org. Chem., 1982, 47, 2531-2536.
238. Takahashi, K.; Suzuki, S.; Hano, Y.; Nomura, T. Protein kinase C activation by iridal type triterpenoids. Biol. Pharm. Bull. 2002, 25, 432-436.
239. Shao, L.; Lewin, N. E.; Lorenzo, P. S.; Hu, Z.; Enyedy, I. J.; Garfield, S. H.; Stone, J. C.; Marner, F. J.; Blumberg, P. M.; Wang, S. Iridals are a novel class of ligands for phorbol ester receptors with modest selectivity for the RasGRP receptor subfamily. J. Med. Chem., 2001, 44, 3872-3880.
240. Corbu, A.; Aquino, M.; Pratap, T. V.; Retailleau, P.; Arseniyadis, S. Enantioselective synthesis of iridal, the parent molecule of the iridal triterpenoid class. Org. Lett., 2008, 10, 1787-1790.
241. Shakibaei, M.; Harikumar, K. B.; Aggarwal, B. B. Resveratrol addiction: to die or not to die. Mol. Nutr. Food Res., 2009, 53, 115-128.
242. Stewart, J. R.; Ward, N. E.; Ioannides, C. G.; O'Brian, C. A. Resveratrol preferentially inhibits protein kinase C-catalyzed phosphorylation of a cofactor-independent, arginine-rich protein substrate by a novel mechanism. Biochemistry, 1999, 38, 13244-13251.
243. Aggarwal, B. B.; Bhardwaj, A.; Aggarwal, R. S.; Seeram, N. P.; Shishodia, S.; Takada, Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res., 2004, 24, 2783-2840.
244. Shih, A.; Zhang, S.; Cao, H. J.; Boswell, S.; Wu, Y. H.; Tang, H. Y.; Lennartz, M. R.; Davis, F. B.; Davis, P. J.; Lin, H. Y. Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-α. Mol. Cancer. Ther., 2004, 3, 1355-1364.
245. Atten, M. J.; Godoy-Romero, E.; Attar, B. M.; Milson, T.; Zopel, M.; Holian, O. Resveratrol regulates cellular PKC α and δ inhibit growth and induce apoptosis in gastric cancer cells. Invest. New Drugs, 2005, 23, 111-119.
246. Majhi, A.; Rahman, G. M.; Panchal, S.; Das, J. Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C. Bioorg. Med. Chem., 2010, 18, 1591-1598.
247. Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. Curcumin inhibits formation of amy loid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem., 2005, 280, 5892-5901.
248. Begum, A. N.; Jones, M. R.; Lim, G. P.; Morihara, T.; Kim, P.; Heath, D. D.; Rock, C. L.; Pruitt, M. A.; Yang, F.; Hudspeth, B.; Hu, S.; Faull, K. F.; Teter, B.; Cole, G. M.; Frautschy, S. A. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease. J. Pharmacol. Exp. Ther., 2008, 326, 196-208.
249. Conboy, L.; Foley, A. G.; O'Boyle, N. M.; Lawlor, M.; Gallagher, H. C.; Murphy, K. J.; Regan, C. M. Curcumin-induced degradation of PKCooois associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats. Biochem. Pharmacol., 2009, 77, 1254-1265.
250. Woo, M. S.; Jung, S. H.; Kim, S. Y.; Hyun, J. W.; Ko, K. H.; Kim, W. K.; Kim, H. S. Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells. Biochem. Biophys. Res. Commun., 2005, 335, 1017-1025.
251. Epstein, J.; Sanderson, I. R.; Macdonald, T. T. Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. Br. J. Nutr., 2010, 103, 1545-1557.
252. Boijeaf Gennäs, G.; Talman, V.; Aitio, O.; Ekokoski, E.; Finel, M.; Tuominen, R. K.; Yli-Kauhaluoma, J. Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C. J. Med. Chem., 2009, 52, 3969-3981.
253. Galkin, A.; Surakka, A.; Boijeaf Gennäs, G.; Ruotsalainen, T.; Kreander, K.; Tammela, P.; Yli-Kauhaluoma, J.; Vuorela, P. Hydrophobic derivatives of 5-(hydroxymethyl)isophthalic acid that selectively induce apoptosis in leukemia cells but not in fibroblasts. Drug Dev. Res., 2008, 69, 185-195.
254. Appendino, G.; Jakupovic, S.; Tron, G. C.; Jakupovic, J.; Milon, V.; Ballero, M. Macrocyclic diterpenoids from Euphorbia semiperfoliata. J. Nat. Prod., 1998, 61, 749-756.
255. Bedoya, L. M.; Marquez, N.; Martinez, N.; Gutierrez-Eisman, S.; Alvarez, A.; Calzado, M. A.; Rojas, J. M.; Appendino, G.; Munoz, E.; Alcami, J. SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro. Biochem. Pharmacol., 2009, 77, 965-978.
256. Ghoul, A.; Serova, M.; Astorgues-Xerri, L.; Bieche, I.; Bousquet, G.; Varna, M.; Vidaud, M.; Phillips, E.; Weill, S.; Benhadji, K. A.; Lokiec, F.; Cvitkovic, E.; Faivre, S.; Raymond, E. Epithelial-tomesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. Cancer Res., 2009, 69, 4260-4269.
257. Dries, D. R.; Gallegos, L. L.; Newton, A. C. A single residue in the C1 domain sensitizes novel protein kinase C isoforms to cellular diacylglycerol production. J. Biol. Chem., 2007, 282, 826-830.
258. Dries, D. R.; Gallegos, L. L.; Newton, A. C. A single residue in the C1 domain sensitizes novel protein kinase C isoforms to cellular diacylglycerol production. J. Biol. Chem., 2007, 282, 826-830.