Late-Stage Intermolecular CH Activation for Lead Diversification: A Highly Chemoselective Oxyfunctionalization of the C-9 Position of Potent Bryostatin Analogues

Q1 · CHEMISTRY

Article

Author: Hilinski, Michael K. ; Wender, Paul A. ; Mayweg, Alexander V. W.

Treatment of highly potent and densely functionalized bryostatin analogue 1 with dimethyldioxirane afforded the C-9 hydroxylated hemiketal 2 via oxyfunctionalization of the C9-CH bond, one of 12 CH bonds geminal to an oxygen substituent in 1. When bryostatin analogue 3 was subjected to identical conditions, oxidation of a C-26 secondary hydroxyl group was found to compete with C-9 hydroxylation. Complete selectivity for C-9 hydroxylation was restored upon acylation of the C-26 secondary alcohol.

01 Dec 2004·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthetic Bryostatin Analogues Activate the RasGRP1 Signaling Pathway

Q1 · MEDICINE

Article

Author: Dower, Nancy A. ; Stang, Stacey L. ; Zheng, Yong ; Baryza, Jeremy L. ; Brenner, Stacey E. ; Stone, James C. ; Wender, Paul A.

The functional properties of four diacylglycerol (DAG) analogues were compared using cell-signaling assays based on the protein RasGRP1, a DAG-regulated Ras activator. Compounds 1 and 2, synthetic analogues of bryostatin 1, were compared to authentic bryostatin 1 and phorbol 12-myristate-13-acetate (PMA). The two "bryologues" were able to activate RasGRP1 signaling rapidly in cultured cells and isolated mouse thymocytes. They elicited expression of the T cell activation marker CD69 in human T cells. DAG analogues promptly recruited RasGRP1 to cell membranes, but they did not induce RasGRP1 proteolysis. Bryostatin 1 and compounds 1 and 2 appeared to be less potent than PMA at inducing aggregation of mouse thymocytes, a PKC-dependent, RasGRP1-independent response. In addition to sharing potential anticancer properties with bryostatin 1, compounds 1 and 2 might be clinically useful as modulators of the immune system.

01 Sep 2004·Chemistry & Biology

Simplified Analogs of Bryostatin with Anticancer Activity Display Greater Potency for Translocation of PKCδ-GFP

Article

Author: Madeleine L. Craske ; Paul A. Wender ; Stacey E. Brenner ; Jeremy L. Baryza ; Tobias Meyer

Structurally simplified analogs of bryostatin 1, a marine natural product in clinical trials for the treatment of cancer, have been shown to be up to 50 times more potent than bryostatin 1 at inducing the translocation of PKCdelta-GFP from the cytosol of rat basophilic leukemia (RBL) cells. The end distribution of the protein is similar for all three compounds, despite a significant difference in translocation kinetics. The potency of the compounds for inducing the translocation response appears to be only qualitatively related to their binding affinity for PKC, highlighting the importance of using binding affinity in conjunction with real-time measurements of protein localization for the pharmacological profiling of biologically active agents.

100 Deals associated with Synthetic bryostatin analogues compounds 1(University of Alberta)

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Indication	Highest Phase	Country/Location	Organization	Date
Immune System Diseases	Preclinical	Canada	University of Alberta	16 Nov 2004
Neoplasms	Preclinical	Canada	University of Alberta	16 Nov 2004

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Synthetic bryostatin analogues compounds 1(University of Alberta)

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