This renewal project seeks to continue and expand a program of synthesis, biology, and computational chemistry based on the exciting profile of biological activity displayed by the natural product bryostatin 1. This marine natural product has been shown to have anticancer activity, and has been in over 80 clinical trials in man. In addition, bryostatin 1 has demonstrated effects on memory, on stimulation of the immune system, and on Alzheimer's disease. Moreover, recent studies in rats have shown that bryostatin 1 offers promise in the treatment of stroke, in that rescue of damaged neural tissue can be effected for up to 24 hours following the ischemic event. The mode of action of bryostatin is only partially understood, but it is known to involve interaction with a family of signaling proteins containing C1 domains. Amongst the known ligands for this Protein Kinase C superfamily, bryostatin 1 is unique in being a functional antagonist to the tumor-promoting phorbol esters. The studies proposed are aimed at realizing the therapeutic potential of this agent. We propose to continue our studies of structure-function relationships in bryostatin 1, in an attempt to define the structural features responsible for the various biological activities already established for bryostatin 1. We also propose to prepare this agent on gram scale, to provide more material for further studies. We plan to continue to investigate the biology of analogues of bryostatin 1, both in the hope of identifying selective new agents with unique patterns of biological activity, and also in terms of using these agents as tools to study the underlying biology of the signaling mechanisms. We have already established, during the preceding grant period, proof of concept in each of these areas. New analogues of bryostatin 1 will be prepared to investigate various hypotheses regarding mechanisms of action and structure activity relationships, and evaluated in detail for their effects in living cells of various types. Detailed biological investigations will be pursued to establish the underlying mechanisms for the biological endpoints observed in the various systems. Computational methods will be employed both to help interpret the structural effects observed and to suggest promising new avenues for structural exploration. Ongoing collaborations with leading experts in the biology of bryostatin and PKC signaling, and in computational investigations of these same systems will be continued.
This project seeks to realize the potential of a very promising substance, bryostatin 1, which was originally isolated from a marine (ocean) source. This material has shown fascinating activity against a variety of diseases including cancer, Alzheimers'disease, and stroke, and has been in clinical trials in man. Our dual approach is to develop a laboratory synthesis of this agent (there is no supply from natural sources) as well as to use this compound as a lead structure. Thus we are developing other structures, similar to that of bryostatin, and studying their biology. The hopes are to identify new and more easily prepared structures for use in therapy, and also to use these structures as biological tools for study of the underlying disease.
|Kedei, Noemi; Chen, Jin-Qiu; Herrmann, Michelle A et al. (2014) Molecular systems pharmacology: isoelectric focusing signature of protein kinase C? provides an integrated measure of its modulation in response to ligands. J Med Chem 57:5356-69|
|Kraft, Matthew B; Poudel, Yam B; Kedei, Noemi et al. (2014) Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core. J Am Chem Soc 136:13202-8|
|Kedei, N; Telek, A; Michalowski, A M et al. (2013) Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action. Biochem Pharmacol 85:313-24|
|Kedei, Noemi; Lewin, Nancy E; Géczy, Tamás et al. (2013) Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of bryostatin 1. ACS Chem Biol 8:767-77|
|Keck, Gary E; Poudel, Yam B; Cummins, Thomas J et al. (2011) Total synthesis of bryostatin 1. J Am Chem Soc 133:744-7|
|Kedei, Noemi; Lubart, Emanuel; Lewin, Nancy E et al. (2011) Some phorbol esters might partially resemble bryostatin 1 in their actions on LNCaP prostate cancer cells and U937 leukemia cells. Chembiochem 12:1242-51|
|Kedei, Noemi; Telek, Andrea; Czap, Alexandra et al. (2011) The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line. Biochem Pharmacol 81:1296-308|
|Keck, Gary E; Poudel, Yam B; Rudra, Arnab et al. (2010) Molecular modeling, total synthesis, and biological evaluations of C9-deoxy bryostatin 1. Angew Chem Int Ed Engl 49:4580-4|
|Keck, Gary E; Li, Wei; Kraft, Matthew B et al. (2009) The bryostatin 1 A-ring acetate is not the critical determinant for antagonism of phorbol ester-induced biological responses. Org Lett 11:2277-80|
|Keck, Gary E; Poudel, Yam B; Welch, Dennie S et al. (2009) Substitution on the A-ring confers to bryopyran analogues the unique biological activity characteristic of bryostatins and distinct from that of the phorbol esters. Org Lett 11:593-6|
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