Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of 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.
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Noemi
N
Kedei
Nancy E
NE
Lewin
Tamás
T
Géczy
Julia
J
Selezneva
Derek C
DC
Braun
Jinqiu
J
Chen
Michelle A
MA
Herrmann
Madeleine R
MR
Heldman
Langston
L
Lim
Poonam
P
Mannan
Susan H
SH
Garfield
Yam B
YB
Poudel
Thomas J
TJ
Cummins
Arnab
A
Rudra
Peter M
PM
Blumberg
Gary E
GE
Keck
D054713:Bryostatins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000201:enzymology; D020298:U937 Cells
D054713:Bryostatins; D007527:Isoenzymes; D008055:Lipids; C475531:bryostatin 7; C046785:bryostatin 1; D011493:Protein Kinase C