Bioprobes pp 1-13 | Cite as

Trends in Bioprobe Research

  • Hiroyuki Osada


The term “Bioprobe” in this book is reserved for small molecular weight compounds mainly isolated from microbial secondary metabolites which are useful not only for biochemical research but also as a source of successful drugs with diverse activities. In general, bioprobes were discovered as inhibitors of specific functions of mammalian cells and afterwards their molecular targets in eukaryotic cells were determined (Fig. 1).


Nerve Growth Factor Okadaic Acid Nuclear Export Signal Microbial Metabolite Combinatorial Biosynthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Takatsuki A, Arima K, Tamura G (1971) Tunicamycin, a new antibiotic. I. Isolation and characterization of tunicamycin A. J Antibiot 24:215–223PubMedCrossRefGoogle Scholar
  2. 2.
    Shevach EM (1985) The effects of cyclosporine A on the immune system. Ann Rev Immunol 3:397–423CrossRefGoogle Scholar
  3. 3.
    Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987) FK-506, a novel immunosuppressant isolated from a streptomyces. I. fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot 40:1249–1255PubMedCrossRefGoogle Scholar
  4. 4.
    Endo A, Kuroda M, Tsujita Y (1976) ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J Antibiot 29:1346–1348PubMedCrossRefGoogle Scholar
  5. 5.
    Kwon HJ, Yoshida M, Fukui Y, Horinouchi S, Beppu T (1992) Potent and specific inhibition of p60<sup>v-src</sup> protein kinase both in vivo and in vitro by radicicol. Cancer Res 52:6926–6930PubMedGoogle Scholar
  6. 6.
    Cribbs DH, Glenney-Jr JR, Kaulfus P, Weber K, Lin S (1982) Interaction of cytochalasin B with actin filaments nucleated or fragmented by villin. J Biol Chem 257:395–399PubMedGoogle Scholar
  7. 7.
    Takatsuki A, Tamura G (1971) Tunicamycin, a new antibiotic. III Reversal of the antiviral activity of tunicamycin by aminosugars and their derivatives. J Antibiot 24:232–238PubMedCrossRefGoogle Scholar
  8. 8.
    Gahmberg CG, Jokinen M, Karhi KK, Andersson LC (1980) Effect of tunicamycin on the biosynthesis of the major human red cell sialoglycoprotein, glycophorin A, in the leukemia cell line K562. J Biol Chem 255:2169–2175PubMedGoogle Scholar
  9. 9.
    Hutchinson CR (1998) Combinatorial biosynthesis for new drug discovery. Curr Opin Microbiol 1:319–329PubMedCrossRefGoogle Scholar
  10. 10.
    Kondoh M, Usui T, Nishikiori T, Mayumi T, Osada H (1999) Apoptosis induction via microtubule disassembly by an antitumour compound, pironetin. Biochem J 340:411–416PubMedCrossRefGoogle Scholar
  11. 11.
    Ishihara H, Martin BL, Brautigan DL, Karaki H, Ozaki H, Kato Y, Fusetani N, Watabe S, Hasimoto K, Uemura D, Hartshorne DJ (1989) Calyculin A and okadaic acid: inhibitors of protein phosphatase activity. Biochem Biophys Res Commun 159:871–877PubMedCrossRefGoogle Scholar
  12. 12.
    Sako T, Yuspa SH, Harald CL, Pettit R, Blumberg PM (1987) Partial parallelism and partial blockade by bryostatin 1 of effects of phorbol ester tumor promoters on primary mouse epidermal cells. Cancer Res 47:5445–5450PubMedGoogle Scholar
  13. 13.
    Wender PA, Cribbs CM, Koehler KF, Sharkey NA, Harald CL, Kamano Y, Pettit GR, Blumberg PM (1988) Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C. Proc Natl Acad Sci USA 85:7197–7201PubMedCrossRefGoogle Scholar
  14. 14.
    Pettit GR, Kamano Y, Fujii Y, Herald CL, Inoue M, Brown P, Gust D, Kitahara K, Schmidt JM, Doubek DL, Michel C (1981) Marine animal biosynthetic constituents for cancer chemotherapy. J Nat Prod 44:482–485PubMedCrossRefGoogle Scholar
  15. 15.
    Usui T, Kondoh M, Cui C-B, Mayumi T, Osada H (1998) Tryprostatin A, a specific and novel inhibitor of microtubule assembly. Biochem J 333:543–548PubMedGoogle Scholar
  16. 16.
    Bai R, Taylor GF, Cichacz ZA, Herald CL, Kepler JA, Pettit GR, Hamel E (1995) The spongistatins, potently cytotoxic inhibitors of tubulin polymerization, bind in a distinct region of the vinca domain. Biochemistry 34:9714–9721PubMedCrossRefGoogle Scholar
  17. 17.
    Owellen RJ, Hartke CA, Dickerson RM, Hains FO (1976) Inhibition of tubulin-microtubule polymerization by drugs of the Vinca alkaloid class. Cancer Res 36:1499–1502PubMedGoogle Scholar
  18. 18.
    Himes RH, Kersey RN, Heller-Bettinger I, Samson FE (1976) Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro. Cancer Res 36:3798–3802PubMedGoogle Scholar
  19. 19.
    Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 227:665–667CrossRefGoogle Scholar
  20. 20.
    Sherline P, Leung JT, Kipnis DM (1975) Binding of colchicine to purified microtubule protein. J Biol Chem 250:5481–5486PubMedGoogle Scholar
  21. 21.
    Owellen RJ, Jr AHO, Donigian DW (1972) The binding of vincristine, vinblastine and colchicine to tubulin. Biochem Biophys Res Commun 47:685–691PubMedCrossRefGoogle Scholar
  22. 22.
    Kumar N (1981) Taxol-induced polymerization of purified tubulin. Mechanism of action. J Biol Chem 256:10435–10441PubMedGoogle Scholar
  23. 23.
    Tsuruo T, Matsuzaki T M. M, Saito H, Yokokura T (1988) Antitumor effect of CPT-11, a new derivative of camptothecin, against pleiotropic drug-resistant tumors in vitro and in vivo. Cancer Chemother Pharmacol 21:71–74PubMedCrossRefGoogle Scholar
  24. 24.
    Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH (1993) The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85:271–291PubMedCrossRefGoogle Scholar
  25. 25.
    Rothenberg ML (1997) Topoisomerase I inhibitors: review and update. Ann Oncol 8:837–855PubMedCrossRefGoogle Scholar
  26. 26.
    Manfredi KP, Blunt JW, Cardellina-II JH, McMahon JB, Pannell LL, Cragg GM, Boyd MR (1991) Novel alkaloids from the tropical plant Ancistrocladus abbreviatus inhibit cell killing by HIV-1 and HIV-2. J Med Chem 34:3402–3405PubMedCrossRefGoogle Scholar
  27. 27.
    Boyd M, Hallock Y, Cardellina J, Manfredi K, Blunt J, McMahon J, Buckheit R, Jr., Bringmann G, Schaffer M, Cragg G (1994) Anti-HIV michellamines from Ancistrocladus korupensis. J Med Chem 37:1740–1745PubMedCrossRefGoogle Scholar
  28. 28.
    Nakamura A, Nagai K, Suzuki S, Ando K, Tamura G (1986) A novel method of screening for immunomodulating substances, establishment of an assay system and its application to culture broths of microorganisms. J Antibiot 39:1148–1154PubMedCrossRefGoogle Scholar
  29. 29.
    Osada H, Magae J, Watanabe C, Isono K (1988) Rapid screening method for inhibitors of protein kinase C. J Antibiot 41:925–931PubMedCrossRefGoogle Scholar
  30. 30.
    Osada H, Cui C-B, Onose R, Hanaoka F (1997) Screening of cell cycle inhibitors from microbial metabolites by a bioassay using a mouse cdc2 mutant cell line, tsFT210. Bioorg Med Chem 5:193–203PubMedCrossRefGoogle Scholar
  31. 31.
    Tomoda H, Omura S (1990) New strategy for discovery of enzyme inhibitors: screening with intact mammalian cells or intact microorganisms having special functions. J Antibiot 43:1207–1222PubMedCrossRefGoogle Scholar
  32. 32.
    Omura S, Sasaki Y, Iwai Y, Takeshima H (1995) Staurosporine, a potentially important gift from a microorganism. J Antibiot 48:535–548PubMedCrossRefGoogle Scholar
  33. 33.
    Osada H, Takahashi H, Tsunoda K, Kusakabe H, Isono K (1990) A new inhibitor of protein kinase C, RK-286C (4’-demethylamino-4’-hydroxystaurosporine). I. Screening, taxonomy, fermentation and biological activity. J Antibiot 43:163–167PubMedCrossRefGoogle Scholar
  34. 34.
    Osada H, Satake M, Koshino H, Onose R, Isono K (1992) A new indolocarbazole antibiotic, RK-286D. J Antibiot 45:278–279PubMedCrossRefGoogle Scholar
  35. 35.
    Osada H, Koshino H, Kudo T, Onose R, Isono K (1992) A new inhibitor of protein kinase C, RK-1409 (7-oxostaurosporine). I. Taxonomy and biological activity. J Antibiot 45:189–194PubMedCrossRefGoogle Scholar
  36. 36.
    Koshino H, Osada H, Amano S, Onose R, Isono K (1992) A new inhibitor of protein kinase C, RK-1409B (4’-demethylamino-4’-hydroxy-3’-epistaurosporine). J Antibiot 45:1428–1432PubMedCrossRefGoogle Scholar
  37. 37.
    Alvarez MA, Fu H, Khosla C, Hopwood DA, Bailey JE (1996) Engineered biosynthesis of novel polyketides: Properties of the whiE aromatase/cyclase. Nature Biotech 14:335–338CrossRefGoogle Scholar
  38. 38.
    Martin JF (1998) New aspects of genes and enzymes for beta-lactam antibiotic biosynthesis. Appl Microbiol Biotech 50:1–15CrossRefGoogle Scholar
  39. 39.
    Seow KT, Meure G, Gerlitz M, Wendt-Pienkowski E, Hutchinson CR, Davies J (1997) A study of iterative type II polyketide synthases, using bacterial genes cloned from soil DNA: A means to access and use genes from uncultured microorganisms. J Bacteriol 179:7360–7368PubMedGoogle Scholar
  40. 40.
    Meijer L (1996) Chemical inhibitors of cyclin-dependent kinases. Trend Cell Biol 6:393–397CrossRefGoogle Scholar
  41. 41.
    Usui T, Yoshida M, Abe K, Osada H, Isono K, Beppu T (1991) Uncoupled cell cycle without mitosis induced by a protein kinase inhibitor, K-252a. J Cell Biol 115:1275–1282PubMedCrossRefGoogle Scholar
  42. 42.
    Abe K, Yoshida M, Usui T, Horinouchi S, Beppu T (1991) Highly synchronous culture of fibroblasts from G2 block caused by staurosporine, a potent inhibitor of protein kinases. Exp Cell Res 192:122–127PubMedCrossRefGoogle Scholar
  43. 43.
    Gadbois DM, Hamaguchi JR, Swank RA, Bradbury EM (1992) Staurosporine is a potent inhibitor of p34cdc2 and p34cdc2-like kinases. Biochem Biophys Res Commun 184:80–85PubMedCrossRefGoogle Scholar
  44. 44.
    Kitagawa M, Higashi H, Takahashi IS, Okabe T, Ogino H, Taya Y, Nishimura S, Okuyama A (1994) A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. Oncogene 9:2549–2557PubMedGoogle Scholar
  45. 45.
    Deguchi A, Imoto M, Umezawa K (1996) Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin, a phosphatidylinositol synthesis inhibitor. J Biochem 120:1118–1122PubMedCrossRefGoogle Scholar
  46. 46.
    Bollag DM, McQueney PA, Zhu J, Hensens 0, Koupal L, Liesch J, Goetz M, Lazarides E, Woods CM (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55:2325–2333PubMedGoogle Scholar
  47. 47.
    Hamaguchi T, Sudo T, Osada H (1995) RK-682, a potent inhibitor of tyrosine phosphatase, arrested the mammalian cell cycle progression at GI phase. FEBS Lett 372:54–58PubMedCrossRefGoogle Scholar
  48. 48.
    Usui T, Marriott G, Inagaki M, Schwarp G, Osada H (1999) Protein phosphatase 2A inhibitors, phoslactomycins. Effects on the cytoskeleton in NIH/3T3 cells. J Biochem 125:960–965PubMedCrossRefGoogle Scholar
  49. 49.
    Kagamizono T, Hamaguchi T, Ando T, Sugawara K, Adachi T, Osada H (1999) Phosphatoquinones A and B, novel tyrosine phosphatase inhibitors produced by Streptomyces sp. J Antibiot 52:75–80PubMedCrossRefGoogle Scholar
  50. 50.
    Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci, USA 73:2424–2428PubMedCrossRefGoogle Scholar
  51. 51.
    Troppmair J, Bruder JT, App H, Cai H, Liptak L, Szeberenyi J, Cooper GM, Rapp UR (1992) Ras controls coupling of growth factor receptors and protein kinase C in the membrane to Raf-1 and B-Raf protein serine kinases in the cytosol. Oncogene 7:1867–73PubMedGoogle Scholar
  52. 52.
    Yao R, Cooper GM (1995) Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267:2003–2006PubMedCrossRefGoogle Scholar
  53. 53.
    Omura S, Fujimoto T, Otoguro K, Matsuzaki K, Moriguchi R, Tanaka H, Sasaki Y (1991) Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. J Antibiot 44:113–116PubMedCrossRefGoogle Scholar
  54. 54.
    Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL (1995) Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268:726–731PubMedCrossRefGoogle Scholar
  55. 55.
    Koizumi S, Contreras ML, Matsuda Y, Hama T, Lazarovici P, Guroff G (1988) K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells. J Neurosci 8:715–721PubMedGoogle Scholar
  56. 56.
    Berg MM, Sternberg DW, Parada LF, Chao MV (1992) K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity. J Biol Chem 267:13–16PubMedGoogle Scholar
  57. 57.
    Kakeya H, Takahashi I, Okada G, Isono K, Osada H (1995) Epolactaene, a novel neuritogenic compound in human neuroblastoma cells, produced by a marine fungus. J Antibiot 48:733–735PubMedCrossRefGoogle Scholar
  58. 58.
    Kakeya H, Onozawa C, Sato M, Arai K, Osada H (1997) Neuritogenic effect of epolactaene derivatives on human neuroblastoma cells which lack high affinity nerve growth factor receptors. J Med Chem 40:391–394PubMedCrossRefGoogle Scholar
  59. 59.
    Green D, Kroemer G (1998) The central executioners of apoptosis : caspases or mitochondria ? Trend Cell Biol 8:267–271CrossRefGoogle Scholar
  60. 60.
    Jacobson MD (1996) Reactive oxygen species and programmed cell death. Trend Biol Sci 21:83–86Google Scholar
  61. 61.
    Korsmeyer SJ, Yin XM, Oltvai ZN, Veis-Novack DJ, Linette GP (1995) Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family. Biochim Biophys Acta 1271:63–66PubMedGoogle Scholar
  62. 62.
    Schlapbach R, Fontana A (1997) Differential activity of bcl-2 and ICE enzyme family protease inhibitors on Fas and puromycin-induced apoptosis of glioma cells. Biochim Biophys Acta 1359:174–180PubMedCrossRefGoogle Scholar
  63. 63.
    Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331PubMedCrossRefGoogle Scholar
  64. 64.
    Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DKM, Wright M, Chernoff J, Clark EA, Krebs EG (1998) Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mstl. EMBO J 17:2224–2234PubMedCrossRefGoogle Scholar
  65. 65.
    Kakeya H, Onose R, Osada H (1998) Caspase-mediated activation of a 36-kDa myelin basic protein kinase during anticancer drug-induced apoptosis. Cancer Res 58:4888–4894PubMedGoogle Scholar
  66. 66.
    Watabe M, Kakeya H, Osada H (1999) Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis. Oncogene 18:5211–5220PubMedCrossRefGoogle Scholar
  67. 67.
    Elliott JF, Lin Y, Mizel SB, Bleackley RC, Harnish DG, Paetkau V (1984) Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science 226:1439–1441PubMedCrossRefGoogle Scholar
  68. 68.
    Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S, Degudicibus S, Siekierka JJ, Chin J, Huchinson N (1989) The immunosuppressant FK-506 selectively inhibits expression of early cell activation genes. J Immunol 143:718–726PubMedGoogle Scholar
  69. 69.
    Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot 28:721–726PubMedCrossRefGoogle Scholar
  70. 70.
    Bierer BE, Mattila PS, Standaert RF, Herzenberg LA, Burakoff SJ, Crabtree G, Schreiber SL (1990) Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci USA 87:9231–9235PubMedCrossRefGoogle Scholar
  71. 71.
    Masuda T, Mizutani S, Iijima M, Odai H, Suda H, Ishizuka M, Takeuchi T, Umezawa H (1987) Immunosuppressive activity of 15-deoxyspergualin and its effect on skin allografts in rats. J Antibiot 40:1612–1618PubMedCrossRefGoogle Scholar
  72. 72.
    Nemoto K, Hayashi M, Abe F, Nakamura T, Ishizuka M, Umezawa H (1987) Immunosuppressive activities of 15-deoxyspergualin in animals. J Antibiot 40:561–562PubMedCrossRefGoogle Scholar
  73. 73.
    Nadler SG, Tepper MA, Schacter B, Mazzucco CE (1992) Interaction of the immunosuppressant deoxyspergualin with a member of the Hsp70 family of heat shock proteins. Science 258:484–486PubMedCrossRefGoogle Scholar
  74. 74.
    Endo A (1979) Monacolin K, a new hypo-cholesterolemic agent produced by a-Monascus species. J Antibiot 32:852–854PubMedCrossRefGoogle Scholar
  75. 75.
    Matsuoka T, Miyakoshi S, Tanzawa K, Nakahara K, Hosobuchi M, Serizawa N (1989) Purification and characterization of cytochrome P-450sca from Streptomyces carbophilus. Eur J Biochem 184:707–713PubMedCrossRefGoogle Scholar
  76. 76.
    Dawson MJ, Farthing JE, Marshall PS, Middleton RF, O’Neill MJ, Shuttleworth A, Stylli C, Tait RM, Taylor PM, Wildman HG, Buss AD, Langley D, Hayes MV (1992) The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma: I. Taxonomy, fermentation, isolation, physicochemical properties and biological activity. J Antibiot 45:639–647PubMedCrossRefGoogle Scholar
  77. 77.
    Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, et al., & Alberts AW (1993) Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci, USA 90:80–84PubMedCrossRefGoogle Scholar
  78. 78.
    Tomoda H, Tabata N, Yang D-J, Takayanagi H, Nishida H, Omura S (1995) Pyripyropenes, novel ACAT inhibitors produced by Aspergillus fumigatus. III. Structure elucidation of pyripyropenes E to L. J Antibiot 48:495–503PubMedCrossRefGoogle Scholar
  79. 79.
    Cui H, Matsui K, Omura S, Schauer SL, Matulka RA, Sonenshein GE, Ju S (1997) Proteasome regulation of activation-induced T cell death. Proc Natl Acad Sci USA 94:7515–7520PubMedCrossRefGoogle Scholar
  80. 80.
    Hamamoto T, Gunji S, Tsuji H, Beppu T (1983) Leptomycins A and B, new antifungal antibiotics. I. Taxonomy of the producing strain and their fermentation, purification and characterization. J Antibiot 36:639–645PubMedCrossRefGoogle Scholar
  81. 81.
    Kudo N, Khochbin S, Nishi K, Kitano K, Yanagida M, Yoshida M, Horinouchi S (1997) Molecular cloning and cell cycle-dependent expression of mammalian CRM I, a protein involved in nuclear export of proteins. J Biol Chem 272:29742–29751PubMedCrossRefGoogle Scholar
  82. 82.
    Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M, Nishida E (1997) CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 390:308–311PubMedCrossRefGoogle Scholar
  83. 83.
    Fornerod M, Ohno M, Yoshida M, Mattaj IW (1997) CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 90:1051–1060PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2000

Authors and Affiliations

  • Hiroyuki Osada

There are no affiliations available

Personalised recommendations