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Bryostatins

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Margo G Haygood – One of the best experts on this subject based on the ideXlab platform.

  • Bryostatins biological context and biotechnological prospects
    Current Opinion in Biotechnology, 2010
    Co-Authors: Amaro E Trindadesilva, Grace E Limfong, Koty H Sharp, Margo G Haygood

    Abstract:

    Bryostatins are a family of protein kinase C modulators that have potential applications in biomedicine. Found in miniscule quantities in a small marine invertebrate, lack of supply has hampered their development. In recent years, Bryostatins have been shown to have potent bioactivity in the central nervous system, an uncultivated marine bacterial symbiont has been shown to be the likely natural source of the Bryostatins, the bryostatin biosynthetic genes have been identified and characterized, and bryostatin analogues with promising biological activity have been developed and tested. Challenges in the development of Bryostatins for biomedical and biotechnological application include the cultivation of the bacterial symbiont and heterologous expression of bryostatin biosynthesis genes. Continued exploration of the biology as well as the symbiotic origin of the Bryostatins presents promising opportunities for discovery of additional Bryostatins, and new functions for Bryostatins.

  • localization of candidatus endobugula sertula and the Bryostatins throughout the life cycle of the bryozoan bugula neritina
    The ISME Journal, 2007
    Co-Authors: Seana K Davidson, Koty H Sharp, Margo G Haygood

    Abstract:

    ‘Candidatus Endobugula sertula,’ the uncultivated γ-proteobacterial symbiont of the marine bryozoan Bugula neritina, synthesizes Bryostatins, complex polyketides that render B. neritina larvae unpalatable to predators. Although the symbiosis is well described, little is known about the locations of ‘E. sertula’ or the Bryostatins throughout larval settlement, metamorphosis and early development. In this study, we simultaneously localized ‘E. sertula’ and the Bryostatins in multiple stages of the B. neritina life cycle, using a novel bryostatin detection method based on its known ability to bind mammalian protein kinase C. Our results suggest that the Bryostatins are deposited onto the exterior of B. neritina larvae during embryonic development, persist on the larval surface throughout metamorphosis and are shed prior to cuticle formation. During metamorphosis, ‘E. sertula’ remains adhered to the larval pallial epithelium and is incorporated into the preancestrula cystid tissue layer, which ultimately develops into a bud and gives rise to the next zooid in the colony. Colocalization of bryostatin signal with aggregates of ‘E. sertula’ in buds of ancestrulae suggested new synthesis of Bryostatins in ancestrulae. In adult B. neritina colonies, symbiont microcolonies were observed in the funicular cords of rhizoids, which likely result in asexual transmission of ‘E. sertula’ to regenerated colonies. Furthermore, bryostatin signal was detected on the surface of the rhizoids of adult B. neritina colonies. Through simultaneous localization of the Bryostatins and the ‘E. sertula,’ we determined how ‘E. sertula’ is transmitted, and identified shifts in bryostatin localization throughout the life cycle of the host B. neritina.

  • evidence for the biosynthesis of Bryostatins by the bacterial symbiont candidatus endobugula sertula of the bryozoan bugula neritina
    Applied and Environmental Microbiology, 2001
    Co-Authors: Margo G Haygood, Seana K Davidson, Scott W Allen, Christine Anderson

    Abstract:

    The marine bryozoan, Bugula neritina, is the source of the Bryostatins, a family of macrocyclic lactones with anticancer activity. Bryostatins have long been suspected to be bacterial products. B. neritina harbors the uncultivated gamma proteobacterial symbiont “Candidatus Endobugula sertula.” In this work several lines of evidence are presented that show that the symbiont is the most likely source of Bryostatins. Bryostatins are complex polyketides similar to bacterial secondary metabolites synthesized by modular type I polyketide synthases (PKS-I). PKS-I gene fragments were cloned from DNA extracted from the B. neritina-“E. sertula” association, and then primers specific to one of these clones, KSa, were shown to amplify the KSa gene specifically and universally from total B. neritina DNA. In addition, a KSa RNA probe was shown to bind specifically to the symbiotic bacteria located in the pallial sinus of the larvae of B. neritina and not to B. neritina cells or to other bacteria. Finally, B. neritina colonies grown in the laboratory were treated with antibiotics to reduce the numbers of bacterial symbionts. Decreased symbiont levels resulted in the reduction of the KSa signal as well as the bryostatin content. These data provide evidence that the symbiont E. sertula has the genetic potential to make Bryostatins and is necessary in full complement for the host bryozoan to produce normal levels of Bryostatins. This study demonstrates that it may be possible to clone bryostatin genes from B. neritina directly and use these to produce Bryostatins in heterologous host bacteria.

Eric J Thomas – One of the best experts on this subject based on the ideXlab platform.

  • synthesis of vinylic iodides for incorporation into the c17 c27 fragment of Bryostatins
    Tetrahedron, 2017
    Co-Authors: Thomas J Gregson, Eric J Thomas

    Abstract:

    Abstract Vinylic iodides were identified as useful intermediates for the synthesis of the C17-C27 fragment of the Bryostatins with control of the geometry of the exocyclic methoxycarbonylmethylene group. Following literature precedent, the Piers ( E )-stereoselective addition of tributyltin hydride to an alkynoate followed by ester reduction and tin-iodine exchange gave vinylic iodides that could be used to form the C20-C21 bond of the Bryostatins. Chelation controlled addition of lithiated 3-silyloxypropynes to 2-alkoxyaldehydes followed by reductive iodination was used to prepare vinylic iodides that could be used in the complementary assembly of the C21-C22 bond of the Bryostatins. Initial studies of the synthesis of intermediates for metathesis studies using metal catalysed reactions of a vinylic iodide for C21-C22 bond formation were complicated by cyclisation reactions.

  • some limitations of an approach to the assembly of Bryostatins by ring closing metathesis
    Organic and Biomolecular Chemistry, 2017
    Co-Authors: Raphael Dumeunier, Thomas J Gregson, Somhairle Maccormick, Hiroki Omori, Eric J Thomas

    Abstract:

    Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of Bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1–C16 and C17–C27 fragments. However, studies of the formation of the C16–C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1–C16 acid and modified C17–C25 alcohols were prepared and their use for the synthesis of analogues of Bryostatins was investigated. Although only low yields were obtained, it appeared that macrolides analogous to the Bryostatins can be prepared by RCM, using the Grubbs II catalyst, if the precursors lack the two methyl groups at C18. RCM was not observed, however, for substrates in which these methyl groups were present.

  • synthesis of c16 c27 fragments of Bryostatins modified by 20 20 difluorination
    Tetrahedron Letters, 2015
    Co-Authors: Paul R Mears, Eric J Thomas

    Abstract:

    2-Hydroxytetrahydropyrans corresponding to the C16–C27 fragment of Bryostatins which have been difluorinated at C20 (bryostatin numbering) have been synthesised. The fluorine substituents were introduced by difluoroallylation. An (E)-selective Wittig reaction using a stabilised ylide provided the required methoxycarbonylmethylene substituent with excellent stereoselectivity.

Peter M. Blumberg – One of the best experts on this subject based on the ideXlab platform.

  • Munc13 Is a Molecular Target of Bryostatin 1.
    Biochemistry, 2019
    Co-Authors: Francisco A. Blanco, Noemi Kedei, Agnes Czikora, Gary A. Mitchell, Satyabrata Pany, Anamitra Ghosh, Peter M. Blumberg

    Abstract:

    Bryostatin 1 is a natural macrolide shown to improve neuronal connections and enhance memory in mice. Its mechanism of action is largely attributed to the modulation of novel and conventional protein kinase Cs (PKCs) by binding to their regulatory C1 domains. Munc13-1 is a C1 domain-containing protein that shares common endogenous and exogenous activators with novel and conventional PKC subtypes. Given the essential role of Munc13-1 in the priming of synaptic vesicles and neuronal transmission overall, we explored the potential interaction between bryostatin 1 and Munc13-1. Our results indicate that in vitro bryostatin 1 binds to both the isolated C1 domain of Munc13-1 (Ki = 8.07 ± 0.90 nM) and the full-length Munc13-1 protein (Ki = 0.45 ± 0.04 nM). Furthermore, confocal microscopy and immunoblot analysis demonstrated that in intact HT22 cells bryostatin 1 mimics the actions of phorbol esters, a previously established class of Munc13-1 activators, and induces plasma membrane translocation of Munc13-1, a h…

  • Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin.
    Molecular Carcinogenesis, 2016
    Co-Authors: Jessica S. Kelsey, Jin-qiu Chen, Michelle A. Herrmann, Mark E. Petersen, Gary E. Keck, Christophe Cataisson, Stuart H. Yuspa, David O. Baumann, Kevin M. Mcgowan, Peter M. Blumberg

    Abstract:

    : Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12-myristate 13-acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic efforts are currently underway to develop simplified bryostatin analogs that preserve the critical functional features of bryostatin 1, including its lack of tumor promoting activity. The degree to which bryostatin analogs maintain the unique pattern of biological behavior of bryostatin 1 depends on the specific cellular system and the specific response. Merle 23 is a significantly simplified bryostatin analog that retains bryostatin like activity only to a limited extent. Here, we show that in mouse epidermal cells the activity of Merle 23 was either similar to bryostatin 1 or intermediate between bryostatin 1 and PMA, depending on the specific parameter examined. We then examined the hyperplastic and tumor promoting activity of Merle 23 on mouse skin. Merle 23 showed substantially reduced hyperplasia and was not tumor promoting at a dose comparable to that for PMA. These results suggest that there may be substantial flexibility in the design of bryostatin analogs that retain its lack of tumor promoting activity. © 2016 Wiley Periodicals, Inc.

  • Neristatin 1 provides critical insight into bryostatin 1 structure-function relationships.
    Journal of Natural Products, 2015
    Co-Authors: Noemi Kedei, George R. Pettit, Cherry L. Herald, Matthew B. Kraft, Gary E. Keck, Noeleen Melody, Peter M. Blumberg

    Abstract:

    Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses …