Bryostatin

Bryostatin 1
Names
IUPAC name
(1S,3S,5Z,7R,8E,11S,12S,13E,15S,17R,20R,23R,25S)-25-Acetoxy-1,11,20-trihydroxy-17-[(1R)-1-hydroxyethyl]-5,13-bis(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate
Identifiers
ChemSpider 27022418
Jmol interactive 3D Image
Properties
C47H68O17
Molar mass 905.04 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Bryostatins are a group of macrolide lactones first isolated in the 1960s by George Pettit from extracts of a species of bryozoan, Bugula neritina based on research from samples originally provided by Jack Rudloe to Jonathan L. Hartwell’s anticancer drug discovery group at the National Cancer Institute (NCI).[1] The structure of bryostatin 1 was determined in 1982.[2] To date 20 different bryostatins have been isolated.[3] Bryostatins are potent modulators of protein kinase C. They are currently under investigation as anti-cancer agents, as anti-AIDS/HIV agents and as a memory-enhancing agent.

Biological effects

Bryostatin 1 is a potent modulator of protein kinase C (PKC). Short-term effects of bryostatin 1 include activation of classical or conventional PKCs and novel PKCs, whereas prolonged presence leads to lowered PKC activation. Bryostatin 1 effects on different isoforms of PKC vary. In in vitro tests bryostatin 1 was able to inhibit cell growth and angiogenesis and to excite cell differentiation and apoptosis. Bryostatin also shows immunomodulatory properties.[4]

In in vitro trials bryostatin 1 was able to induce apoptosis in HL-60 chronic lymphocytic leukaemia. It could be shown that bryostatin 1 acts synergistically in combination with other anti-cancer drugs. Drug combination was effective against a large variety of tumor cells including lung, prostate and non-Hodgkin's lymphoma tumor cells. Although animal studies were promising, bryostatin 1 as a single drug has failed to demonstrate significant activity in tumor patients in phase II trials in a wide range of tumor types, including melanoma and colorectal cancer. Additionally severe side-effects, mainly myalgia, were observed after bryostatin administration. As a consequence research focus has shifted to an investigation of combination therapy with other chemotherapeutic antitumor agents such as gemcitabine, vincristine, cisplatin, and paclitaxel.

Bryostatin 1 has appeared very promising in enhancing memory in animal models. It was able to increase the duration of memory retention of the marine slug Hermissenda crassicornis by over 500%.[5] Additionally it also increased the rate of learning in rats.[6] This makes it a possible drug candidate for the treatment of Alzheimer's disease. Currently bryostatin 1 is in clinical trial phase II for the treatment against Alzheimer's disease.[7]

The ability of bryostatin 1 to alleviate brain damage in ischaemically brain-injured rats also seems promising and may open another therapeutic field for bryostatins.[8][9]

Total synthesis

The low concentration in bryozoans (to extract one gram of bryostatin, roughly one tonne of the raw bryozoans is needed) makes extraction unviable for large scale production. Due to the structural complexity, total synthesis has proved difficult, with only a few total syntheses reported so far. Total syntheses have been published for bryostatins 1, 2, 3, 7, 9 and 16.[10][11][12][13][14][15][16] Among them, Krische’s total synthesis of bryostatin 7 via C-C bond forming hydrogenation[14] is the shortest synthesis of any bryostatin reported, to date.

A number of structurally simpler synthetic analogs also have been prepared which exhibit similar biological profile and in some cases greater potency, which may provide a practical supply for clinical use.[17]

Investigations on how bryostatin 1 behaves in a unique fashion are ongoing in several laboratories. The latest structure and activity relationship studies show that the northern hemisphere of bryostatin 1 plays a unique role.[18]

References

  1. ↑ B Halford The Bryostatins’ Tale VOLUME 89, NUMBER 43 PP. 10-17, Oct 24, 2011 Chemical and Engineering News
  2. ↑ Pettit GR, Cherry Herald L, Doubek DL, Herald DL, Arnold E, Clardy J (1982). "Isolation and structure of bryostatin 1". J. Am. Chem. Soc. 104 (24): 6846–6848. doi:10.1021/ja00388a092.
  3. ↑ Hale KJ, Manviazar S (2010). "New approaches to the Total Synthesis of Bryostatin Antitumor Macrolides". Chem. Asian J. 5 (4): 704–54. doi:10.1002/asia.200900634. PMID 20354984.
  4. ↑ Mackay HJ, Twelves CJ (July 2007). "Targeting the protein kinase C family: are we there yet?". Nat. Rev. Cancer 7 (7): 554–62. doi:10.1038/nrc2168. PMID 17585335.
  5. ↑ Kuzirian AM, Epstein HT, Gagliardi CJ, Nelson TJ, Sakakibara M, Taylor C, Scioletti AB, Alkon DL (June 2006). "Bryostatin enhancement of memory in Hermissenda". Biol. Bull. 210 (3): 201–14. doi:10.2307/4134558. PMID 16801495.
  6. ↑ Sun MK, Alkon DL (April 2005). "Dual effects of bryostatin-1 on spatial memory and depression". Eur. J. Pharmacol. 512 (1): 43–51. doi:10.1016/j.ejphar.2005.02.028. PMID 15814089.
  7. ↑ "Clinical trial at Blanchette Rockefeller Neurosciences Institute at West Virginia University".
  8. ↑ Sun MK, Hongpaisan J, Alkon DL (August 2009). "Postischemic PKC activation rescues retrograde and anterograde long-term memory". Proc. Natl. Acad. Sci. U.S.A. 106 (34): 14676–80. Bibcode:2009PNAS..10614676S. doi:10.1073/pnas.0907842106. PMC 2732881. PMID 19667190.
  9. ↑ "Drug Given 24 Hours After Stroke Helps Repair Brain Tissue". Bio-medicine.org. March 2008. Retrieved 2010-04-24.
  10. ↑ G. E. Keck, Y. B. Poudel, T. J. Cummins, A. Rudra, and J. A. Covel (2010). "Total Synthesis of Bryostatin 1". J. Am. Chem. Soc. 133 (4): 744–747. doi:10.1021/ja110198y.
  11. ↑ D. A. Evans, P. H. Carter, E. M. Carreira, A. B. Charette, J. A. Prunet, and M. Lautens (1999). "Total Synthesis of Bryostatin 2". J. Am. Chem. Soc. 121 (33): 7540–7552. doi:10.1021/ja990860j.
  12. ↑ Ohmori K, Ogawa Y, Obitsu T, Ishikawa Y, Nishiyama S, Yamamura S (July 2000). "Total Synthesis of Bryostatin 3". Angew. Chem. Int. Ed. Engl. 39 (13): 2290–4. doi:10.1002/1521-3773(20000703)39:13<2290::AID-ANIE2290>3.0.CO;2-6. PMID 10941067.
  13. ↑ M. Kageyama, T. Tamura, M. H. Nantz, J. C. Roberts, P. Somfai, D. C. Whritenour and S. Masamune (1990). "Synthesis of Bryostatin 7". J. Am. Chem. Soc. 112 (20): 7407–7408. doi:10.1021/ja00176a058.
  14. 1 2 Lu, Y.; Woo, S. K.; Krische, M. J. (2011). "Total Synthesis of Bryostatin 7 via C–C Bond-Forming Hydrogenation". J. Am. Chem. Soc. 133 (35): 13876–13879. doi:10.1021/ja205673e. PMC 3164899. PMID 21780806.
  15. ↑ P.A. Wender, A.J. Schrier (2011). "Total Synthesis of Bryostatin 9". J. Am. Chem. Soc. 133 (24): 9228–9231. doi:10.1021/ja203034k.
  16. ↑ Trost BM, Dong G (November 2008). "Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches". Nature 456 (7221): 485–8. Bibcode:2008Natur.456..485T. doi:10.1038/nature07543. PMC 2728752. PMID 19037312.
  17. ↑ Wender PA, Baryza JL, Bennett CE, Bi FC, Brenner SE, Clarke MO, Horan JC, Kan C, Lacôte E, Lippa B, Nell PG, Turner TM (November 2002). "The practical synthesis of a novel and highly potent analogue of bryostatin". J. Am. Chem. Soc. 124 (46): 13648–9. doi:10.1021/ja027509. PMID 12431074.
  18. ↑ Keck GE, Poudel YB, Rudra A, Stephens JC, Kedei N, Lewin NE, Peach ML, Blumberg PM (June 2010). "Molecular modeling, total synthesis, and biological evaluations of C9-deoxy bryostatin 1". Angew. Chem. Int. Ed. Engl. 49 (27): 4580–4. doi:10.1002/anie.201001200. PMC 3269168. PMID 20491108.

External links

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