bryostatin-7 and bryostatin-1

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.

Topics: Bryostatins; Cell Line, Tumor; Down-Regulation; Humans; Isoenzymes; Lipids; Male; Membrane Potential, Mitochondrial; Protein Kinase C; Real-Time Polymerase Chain Reaction; Subcellular Fractions; U937 Cells

A method with tandem high performance liquid chromatography (HPLC) and Q-Tof mass spectrometry (MS) has been established for the qualitative assay of bryostatins in Bugula neritina extracts. Ten bryostatins were well separated on a Polaris C18-5 column (4.6 mm i.d. x 200 mm, 5 microm) with methanol and water (80:20, v/v) as mobile phase. The bryostatins were qualitatively detected with the mass spectrometric detection. Ten bryostatins were found in the Bugula neritina collected from Gulf of Dayawan (Shenzhen, China). Mass spectra of the peaks led to the identification of nine known bryostatins that were bryostatins 4, 5, 6(9), 7, 8, 10, 16, 17, 18. Bryostatins 4, 5, 8, 10 could be further verified by the retention times of the corresponding standards. The two trace constituents, bryostatin 7 and 17, were for the first time found in Bugula neritina inhabiting in China sea. It is interesting that the result indicated the existence of a possibly new bryostatin in the mixture. The work above provides a quick and accurate assay method for the qualitative identification of the bryostatins in Bugula neritina extracts.

Topics: Animals; Bryostatins; Bryozoa; Chromatography, High Pressure Liquid; Lactones; Macrolides; Mass Spectrometry

[reaction: see text] The "Southern Hemisphere" intermediate 2, used by Masamune and co-workers for their asymmetric total synthesis of bryostatin 7 (1), has been synthesized from (E)-1,4-hexadiene (11) by a 24-step pathway that has a longest linear sequence of only 20 steps. This is the shortest synthesis of 2 so far recorded, and moreover, it is fully stereocontrolled.

Topics: Alkenes; Antineoplastic Agents; Bryostatins; Lactones; Macrolides; Organometallic Compounds