- Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy
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Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin’s target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.
- Hardman, Clayton,Ho, Stephen,Luu-Nguyen, Quang,Marsden, Matthew D.,Shimizu, Akira,Sloane, Jack L.,Soliman, Mohamed S. A.,Wender, Paul A.,Zack, Jerome A.
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- BRYOSTATIN COMPOUNDS AND METHODS OF PREPARING THE SAME
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Methods for preparing a variety of bryostatin compounds are provided. The subject methods provide for preparation of bryostatin 1 in multi-gram quantities in a low and unprecedented number of convergent synthetic steps from commercially available materials. The subject methods are scalable with low estimated material costs and can provide enough material to meet clinical needs. Also provided are a variety of bryostatin analog compounds, and prodrug forms thereof, which are synthetically accessible via the subject methods and pharmaceutical compositions including the same.
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Page/Page column 90-92
(2018/04/21)
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- Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV
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Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer’s disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.
- Wender, Paul A.,Hardman, Clayton T.,Ho, Stephen,Jeffreys, Matthew S.,Maclaren, Jana K.,Quiroz, Ryan V.,Ryckbosch, Steven M.,Shimizu, Akira J.,Sloane, Jack L.,Stevens, Matthew C.
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p. 218 - 223
(2017/10/19)
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- Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of bryostatin 1
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The bryostatins are a group of 20 macrolides isolated by Pettit and co-workers from the marine organism Bugula neritina. Bryostatin 1, the flagship member of the family, has been the subject of intense chemical and biological investigations due to its remarkably diverse biological activities, including promising indications as therapy for cancer, Alzheimer's disease, and HIV. Other bryostatins, however, have attracted far less attention, most probably due to their relatively low natural abundance and associated scarcity of supply. Among all macrolides in this family, bryostatin 7 is biologically the most potent protein kinase C (PKC) ligand (in terms of binding affinity) and also the first bryostatin to be synthesized in the laboratory. Nonetheless, almost no biological studies have been carried out on this agent. We describe herein the total synthesis of bryostatin 7 based on our pyran annulation technology, which allows for the first detailed biological characterizations of bryostatin 7 with side-by-side comparisons to bryostatin 1. The results suggest that the more easily synthesized and less lipophilic bryostatin 7 may be an effective surrogate for bryostatin 1.
- Kedei, Noemi,Lewin, Nancy E.,Geczy, Tamas,Selezneva, Julia,Braun, Derek C.,Chen, Jinqiu,Herrmann, Michelle A.,Heldman, Madeleine R.,Lim, Langston,Mannan, Poonam,Garfield, Susan H.,Poudel, Yam B.,Cummins, Thomas J.,Rudra, Arnab,Blumberg, Peter M.,Keck, Gary E.
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p. 767 - 777
(2013/06/27)
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- Total synthesis of bryostatin 1
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Bryostatin 1 is a marine natural product that is a very promising lead compound because of the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic rout
- Keck, Gary E.,Poudel, Yam B.,Cummins, Thomas J.,Rudra, Arnab,Covel, Jonathan A.
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p. 744 - 747
(2011/03/23)
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- Synthetic conversion of bryostatin 2 into bryostatin 1
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Bryostatin 2 is converted to bryostatin 1 by a selective protection and dotection strategy involving the C-26 hydroxyl group.
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- Macrocyclic lactones
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New and exceptionally potent antineoplastic agents designated bryostatin 1, bryostatin 2 and bryostatin 3 have been isolated from the marine animal Bugula neritina L. (Bryozoan phylum). An x-ray crystallographic analysis led to the assignment of novel structures shown in Charts I, II and III.
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