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
3D model (JSmol)
ChemSpider
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 isolated from the marine organism, Bugula neritina. Bryostatins are potent modulators of protein kinase C. They have been studied in clinical trials as anti-cancer agents, as anti-AIDS/HIV agents and in people with Alzheimer's disease.

Biological effects of bryostatin 1

Bryostatin 1 is a potent modulator of protein kinase C (PKC).[1]

It showed activity in laboratory tests in cells and model animals, so it was brought into clinical trials. As of 2014 over thirty clinical trials had been conducting, using bryostatin alone and in combination with other agents, in both solid tumors and blood tumors; it did not show a good enough risk:benefit ratio to be advanced further.[1]

It showed enough promise in animal models of Alzheimer's disease that a Phase II trial was started by 2010;[2] the trial was sponsored by the Blanchette Rockefeller Neurosciences Institute.[3] Scientists from that institute started a company called Neurotrope,[4] and launched another clinical trial in Alzheimer's disease,[5] preliminary results of which were released in 2017.[6]

Bryostatin has also been studied in people with HIV.[1]

Chemistry

Bryostatin 1 was 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).[7] The structure of bryostatin 1 was determined in 1982.[8] As of 2010 20 different bryostatins had been isolated.[9]

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]

References

  1. 1 2 3 Kollár, P; Rajchard, J; Balounová, Z; Pazourek, J (February 2014). "Marine natural products: bryostatins in preclinical and clinical studies.". Pharmaceutical biology. 52 (2): 237–42. PMID 24033119. doi:10.3109/13880209.2013.804100.
  2. ↑ Trindade-Silva, AE; Lim-Fong, GE; Sharp, KH; Haygood, MG (December 2010). "Bryostatins: biological context and biotechnological prospects.". Current Opinion in Biotechnology. 21 (6): 834–42. PMC 4497553 Freely accessible. PMID 20971628.
  3. ↑ "Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics Study of Bryostatin 1 in Patients With Alzheimer's Disease - Full Text View - ClinicalTrials.gov". Clinicaltrials.gov. Retrieved 4 May 2017.
  4. ↑ "Alzheimer's Researchers Discover Bryostatin Can Slow, Reverse Disease Progression". Alzheimer's News Today. 19 August 2014.
  5. ↑ "A Study Assessing Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease - Full Text View - ClinicalTrials.gov". Clinicaltrials.gov. Retrieved 4 May 2017.
  6. ↑ Taylor, Nick Paul (May 1, 2017). "Neurotrope misses primary endpoint in Alzheimer’s trial". FierceBiotech.
  7. ↑ B Halford (Oct 24, 2011). "The Bryostatins’ Tale". Chemical & Engineering News. 89 (43): 10–17.
  8. ↑ 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.
  9. ↑ Hale KJ, Manviazar S (2010). "New approaches to the Total Synthesis of Bryostatin Antitumor Macrolides". Chem. Asian J. 5 (4): 704–54. PMID 20354984. doi:10.1002/asia.200900634.
  10. ↑ G. E. Keck; Y. B. Poudel; T. J. Cummins; A. Rudra & 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 & 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. PMID 10941067. doi:10.1002/1521-3773(20000703)39:13<2290::AID-ANIE2290>3.0.CO;2-6.
  13. ↑ M. Kageyama; T. Tamura; M. H. Nantz; J. C. Roberts; P. Somfai; D. C. Whritenour & 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. PMC 3164899 Freely accessible. PMID 21780806. doi:10.1021/ja205673e.
  15. ↑ P.A. Wender; A.J. Schrier (2011). "Total Synthesis of Bryostatin 9". J. Am. Chem. Soc. 133 (24): 9228–9231. PMC 3129979 Freely accessible. PMID 21618969. 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. PMC 2728752 Freely accessible. PMID 19037312. doi:10.1038/nature07543.
  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. PMID 12431074. doi:10.1021/ja027509.
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