The Practical Synthesis of a Novel and Highly Potent Analogue of Bryostatin

Abstract

Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

“…93b,93c An additional, straightforward seven steps elaborated the pyran ring, including installation of the acyl octanoic acid side chain at C20, to give aldehyde 55 . The enal was installed at C15 through a zinc‐mediated addition of ( Z )‐bromo‐2‐ethoxyethene, followed by acid‐induced elimination and then Sharpless dihydroxylation, cleavage of the pyran ketal, and protection with a silyl group gave intermediate 56 , precursor to the recognition domain.…”

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

“…Another illustrative general example of successful modification of biologically active compounds, structurally unrelated to sesqiterpene quinones, is the attempt to simplify structures of bryostatin-1 (61, Figure 21), a powerful antineoplastic macrolide from a marine bryozoan (128,129) and to establish SAR requirements [128,129] for preserving its exceptional pharmacological properties. In a series of experiments, important discoveries and goals were achieved: a) the experimental data validate the design of the simplified pharmacological model structure; b) the newly developed analogues 62 and 63 ( Figure 21) have in vitro and in vivo biological activities similar or higher than bryostatin and c) by practical total synthesis, the analogues are made available in sufficient amounts for clinical trials.…”

Molecular Modeling, Total Synthesis, and Biological Evaluations of C9‐Deoxy Bryostatin 1

“…[10] Several analogues of bryostatin have also been prepared, primarily by the Wender group and by us. [1,11] Recently, our group has been focused on elucidating the structural features of bryostatin that are responsible for its function as a phorbol ester antagonist, as distinct from its activity simply as a ligand for PKC. We have previously reported on the synthesis of the bryopyran core structure [12] and of bryopyran analogues with greatly simplified A-and B-rings that function as phorbol ester mimics, [13] and have shown that functionality on the A-ring of bryostatin 1 is critical in preserving bryostatin-like biological effects.…”