Bryostatins

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Bryostatins are organic compounds from the group of macrolactones . The compounds are found predominantly in bryozoa ( Latin : bryozoa ); the majority of research focuses on bryostatin 1 .

Occurrence

Structural formula of bryostatin 1

Bryostatins occur in very small amounts in members of the genus Bryozoa , especially in Bugula neritina . Smaller occurrences in other marine organisms such as Lissodendoryx isodictyalis were also reported, but in each of these cases the biomass also contained Bugula neritina . For example, 120 mg of bryostatin 1 were obtained from 500 kg of Bugula neritina , and another group was able to extract 18 g of bryostatin 1 from 14 t. There is a dependency not only on the region, but also on the water depth and time of year in which samples of Bugula neritina were taken. This is possibly due to a symbiosis with the bacterium Candidatus Endobugula sertula . Bugula neritina samples, which were taken from below 9 m water depth, produce the bryostatins 1–3, whereas these bryostatins were not produced for samples from lower water depths. Differences in the gene sequence for mitochondrial caboxylase I from Candidatus Endobuula sertula were found, which may explain this observation.

history

In the meantime, the total synthesis of a large number of representatives of this group has been successful: in 1999 this was successful for bryostatin 2, in 2000 the first total synthesis of bryostatin 3, in 2008 of bryostatin 16 and 2011 of bryostatin 9 and bryostatin 7

The structure was first elucidated in 1982 for bryostatin 1 and in 1983 for bryostatin 2 and bryostatin 3 after extraction from Bugula neritina . One year later, bryostatin 4 was isolated and in 1985 the isolation and structure elucidation of bryostatins 5-7 took place. Other bryostatins were bryostatin 9 in 1986, bryostatin 10-11 and 12-13 in 1987, bryostatin 14-15 in 1991 and finally bryostatins 16-18 in 1996 and the respective structure was elucidated.

properties

The bryostatins 1–12 can be isolated by inverse HPLC , an acetonitrile- water gradient is used as the eluent . In research, the various potential medical applications of bryostatins are examined, in particular bryostatin 1 is being investigated more intensively. Activation of protein kinase C (PKC) was observed after short-term exposure to bryostatin 1, but long-term exposure causes a decrease in PKC activity. Using a bryostatin analogue, the CRD2 domain of PKCα was identified as the binding site for bryostatin 1 . For example, bryostatin 1 was administered intravenously to patients with advanced cancer in a 1993 Phase I study . This was followed by a phase II study in 1998. A total of over 80 clinical studies had been carried out by 2004, 20 of which were phase I and phase II stages, but research into bryostatins as a possible cancer drug stagnated at this stage.

Individual evidence

  1. ↑ a b Bethany Halford: The Bryostatins' Tale . In: Chemical & Engineering News Archive . tape 89 , no. 43 , 2011, p. 10-17 , doi : 10.1021 / cen-v089n043.p010 .
  2. ↑ External identifiers or database links for bryostatin 1 : CAS number: 83314-01-6, PubChem : 5280757 , ChemSpider : 10196541 , Wikidata : Q27095907 .
  3. ^ Roger Mutter, Martin Wills: Chemistry and Clinical Biology of the Bryostatins . In: Bioorg. Med. Chem. Band 8 , no. 8 , August 2000, p. 1841-1860 , doi : 10.1016 / S0968-0896 (00) 00150-4 .
  4. ^ A b George R. Pettit, Cherry L. Herald, Dennis L. Doubek, Delbert L. Herald, Edward Arnold, Jon Clardy: Isolation and structure of bryostatin 1 . In: J. Am. Chem. Soc. tape 104 , no. 24 , p. 6846-6848 , doi : 10.1021 / ja00388a092 .
  5. ↑ Daniel E. Schaufelberger, Mary P. Koleck, John A. Beutler, Angel M. Vatakis, A. Belinda Alvarado, Pamela Andrews, LV Marzo, GM Muschik, John Roach, John T. Ross, William B. Lebherz, Marie P Reeves, Robert M. Eberwein, Lori L. Rodgers, Robert P. Testerman, Kenneth M. Snader, Salvatore Forenza: The Large-Scale Isolation of Bryostatin 1 from Bugula neritina Following Current Good Manufacturing Practices . In: J Nat Prod . tape 54 , no. 5 , 1991, pp. 1265-1270 , doi : 10.1021 / np50077a004 .
  6. ↑ SK Davidson, SW Allen, GE Lim, CM Anderson, MG Haygood: Evidence for the Biosynthesis of Bryostatins by the Bacterial Symbiont “Candidatus Endobugula sertula” of the Bryozoan Bugula neritina . In: Appl. Environ. Microbiol. October 2001, p. 4531-4537 , doi : 10.1128 / AEM.67.10.4531-4537.2001 ( Open Access ).
  7. ^ A b David J. Newman, Gordon M. Cragg: Marine Natural Products and Related Compounds in Clinical and Advanced Preclinical Trials . In: J Nat Prod . tape 67 , 2004, pp. 121-1238 , doi : 10.1021 / np040031y .
  8. ↑ David A. Evans, Percy H. Carter, Erick M. Carreira, André B. Charette, Joëlle A. Prunet, Mark Lautens: Total Synthesis of Bryostatin 2 . In: J. Am. Chem. Soc. tape 121 , no. 33 , 1999, pp. 7540-7552 , doi : 10.1021 / ja990860j .
  9. ↑ Ken Ohmori, Yasuyuki Ogawa, Tetsuo Obitsu, Yuichi Ishikawa, Shigeru Nishiyama, Shosuke Yamamura: Total Synthesis of Bryostatin 3 . In: Angew. Chem. Int. Ed. tape 39 , no. 13 , 2000, pp. 2290-2294 , doi : 10.1002 / 1521-3773 (20000703) 39:13 <2290 :: AID-ANIE2290> 3.0.CO; 2-6 .
  10. ↑ Barry M. Trost , Guangbin Dong: Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches . In: Nature . tape 456 , 2008, p. 485-488 , doi : 10.1038 / nature07543 .
  11. ↑ Paul A. Wender, Adam J. Schrier: Total synthesis of bryostatin 9 . In: J. Am. Chem. Soc. tape 133 , no. 24 , 2011, p. 9228-9231 , doi : 10.1021 / ja203034k .
  12. ↑ Yu Lu, Sang Kook Woo, Michael J. Krische: Total Synthesis of Bryostatin 7 via C – C Bond-Forming Hydrogenation . In: J. Am. Chem. Soc. tape 133 , no. 35 , 2011, p. 13876-13879 , doi : 10.1021 / ja205673e , PMC 3164899 (free full text).
  13. ↑ George R. Pettit, Cherry L. Herald, Yoshiaki Kamano, Devens Gust, Reiko Aoyagi: The Structure of Bryostatin 2 from the Marine Bryozoan Bugula neritina . In: J Nat Prod . tape 46 , no. 4 , July 1983, p. 528-531 , doi : 10.1021 / np50028a017 .
  14. ↑ George R. Pettit, Cherry L. Herald, Yoshiaki Kamano: Structure of the Bugula neritina (Marine Bryozoa) Antineoplastic Component Bryostatin 3 . In: J. Org. Chem. Date = 1983-04 . tape 48 , p. 5354-5356 , doi : 10.1021 / jo00174a037 .
  15. ↑ George R. Pettit, Yoshiaki Kamano, Cherry L. Herald, Machiko Tozawa: Structure of bryostatin. 4. An important antineoplastic constituent of geographically diverse Bugula neritina (Bryozoa) . In: J. Am. Chem. Soc. tape 106 , no. October 22 , 1984, p. 6768-6771 , doi : 10.1021 / ja00334a050 .
  16. ↑ George R. Pettit ,, Yoshiaki Kamano, Cherry L. Herald, Machiko Tozawa: Isolation and structure of bryostatins 5-7 . In: Can. J. Chem. Volume 63 , no. 6 , 1985, pp. 1204-1208 , doi : 10.1139 / v85-205 .
  17. ↑ George R. Pettit ,, Yoshiaki Kamano, Cherry L. Herald: ANTINEOPLASTIC AGENTS 118. ISOLATION AND STRUCTURE OF BRYOSTATIN 9 . In: J Nat Prod . tape 49 , no. 4 , July 1986, p. 661-664 , doi : 10.1021 / np50046a017 .
  18. ↑ George R. Pettit, Yoshiaki Kamano, Cherry L. Herald: Isolation and Structure of Bryostatin 10 and 11 . In: J. Org. Chem. Band 52 , 1987, pp. 2848-2854 , doi : 10.1021 / jo00389a036 .
  19. ↑ George R. Pettit, John E. Leet, Cherry L. Herald, Yoshiaki Kamano, Fred E. Boettner, Lubomir Baczynskyi, Ronald A. Nieman: Isolation and Structure of Bryostatins 12 and 13 . In: J. Org. Chem. Band 52 , 1987, pp. 2854-2860 , doi : 10.1021 / jo00389a037 .
  20. ↑ GR Pettit, F. Gao, D .Sengupta, JC Coll, CL Herald, DL Doubek, JM Schmidt, JR van Camp, JJ Rudloe, RA Nieman: Isolation and structure of bryostatins 14 and 15 . In: Tetrahedron . tape 47 , no. 22 , 1991, pp. 3601-3610 , doi : 10.1016 / S0040-4020 (01) 80873-5 .
  21. ↑ George R. Pettit, Feng Gao, Peter M. Blumberg, Cherry L. Herald, John C. Coll, Yoshiaki Kamano, Nancy E. Lewin, Jean M. Schmidt, Jean-Charles Chapuis: Antineoplastic Agents. 340. Isolation and Structural Elucidation of bryostatins 16 -18 . In: J Nat Prod . tape 59 , no. 3 , March 1996, p. 286-289 , doi : 10.1021 / np960100b .
  22. ↑ George R. Pettit, Yoshiaki Kamano, Daniel Schaufelberger, Cheery L. Herald, Peter M. Blumberg, Stratford W. May: High Performance Liquid Chromatographic Separation of Bryostatins 1-12 . In: Journal of Liquid Chromatography . tape 12 , no. 4 , 1989, pp. 553-561 , doi : 10.1080 / 01483918908051757 .
  23. ↑ Jeremy Kortsmansky, Gary K. Schwartz: Bryostatin-1 . A Novel PKC Inhibitor in Clinical Development. tape 21 , no. 6 , 2003, p. 924-936 , doi : 10.1081 / CNV-120025095 .
  24. Jump up ↑ Karl J. Hale, Mark Frigerio, Soraya Manaviazar, Marc G. Hummersone, Ian J. Fillingham, Igor G. Barsukov, Christian F. Damblon, Andreas Gescher, Gordon CK Roberts: Synthesis of a Simplified Bryostatin C-Ring Analogue That Binds to the CRD2 of Human PKC-α and Construction of a Novel BC-Analogue by an Unusual Julia Olefination Process . In: Org. Lett. tape 5 , no. 4 , January 2003, p. 499-502 , doi : 10.1021 / ol027392u .
  25. ↑ J. Prendivillel, D. Crowther, N. Thatcher, PJ Woll, BW Fox, A. McGown, N. Testa, P. Stem, R. McDermott, M. Potter, GR Pettit: A phase I study of intravenous bryostatin 1 in patients with advanced cancer . In: Br J Cancer . tape 68 , 1993, pp. 418-424 , PMC 1968558 (free full text).
  26. ↑ DJ Propper, V- Macaulay, KJ O'Byrne, JP Braybrooke, SM Wilner, TS Ganesan, DC Talbot, AL Harris: A phase II study of bryostatin 1 in metastatic malignant melanoma . In: Br J Cancer . tape 78 , 1998, pp. 1337-1341 , doi : 10.1038 / bjc.1998.680 .