Synthesis and Protein Kinase Inhibitory Activity of Balanol Analogues with Modified Benzophenone Subunits

Abstract

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.

Screening of natural compounds and their derivatives as potential protein kinase C inhibitors

“…As an example, (À)-balanol, a fungal metabolite of Verticillium balanoides, exhibits inhibition at nanomolar concentrations for most PKC kinase isozymes, but lacks isozyme/kinase selectivity and sufficient cellular activity [Hu, 1996]. Increased selectivity and cellular activity have been pursued by designing balanol analogues with modified benzophenone subunits [Lampe et al, 2002]. Hence, even if natural compounds do not show adequate potency or selectivity per se, they can provide a structural basis for the development of more specific inhibitors.…”

Spheciosterol Sulfates, PKCζ Inhibitors from a Philippine Sponge Spheciospongia sp.

“…(6) PKC has been implicated in the progression of numerous diseases, which makes PKC inhibitors attractive therapeutic agents. (8) In fact, inhibitors of PKCs are currently being tested in clinical trials for various disorders. (9) At least 11 closely related PKC isoforms have been reported that differ in structure, biochemical properties, tissue distribution, subcellular localization, and substrate specificity.…”

Reversed‐Polarity Synthesis of Diaryl Ketones through Palladium‐Catalyzed Direct Arylation of 2‐Aryl‐1,3‐dithianes

“…Dithianes 12d and 12g were obtained by coupling bromobenzene ( 2d ) and 4- N,N -dimethylamino bromobenzene ( 2g ) with 2-(2-fluorophenyl)-1,3-dithiane ( 7 ) in 92 and 83% yields, respectively, using NaN(SiMe 3 ) 2 at room temperature in 2 h. Reaction of dithiane 7 with 4-chloro bromobenzene ( 2k ) was rather sluggish, however, and reaction had to be performed in the presence of LiN(SiMe 3 ) 2 at 60 °C to furnish 12k in 78% yield in 2 h. Recently, the synthesis of diaryl ketones bearing ortho -substituents on both aryl groups under mild conditions has gained importance, [29] because many biologically active diaryl ketones are sterically congested. [10c-e] To explore the potential of our method for the construction of more hindered ketone precursors, 2-fluorophenyl substituted dithiane 7 was coupled with 1-bromonaphthalene ( 2f ) and 2-bromoanisole ( 2i ) to achieve dithianes 12f (93%) and 12i (63%), respectively. Furthermore, sterically more crowded 3-methylthiophene containing dithiane 8 was coupled with 1-bromo naphthalene to afford 13f in 81% yield.…”

“…It is noteworthy that diaryl ketones comprise a common structural core of a large number of biologically relevant compounds and have gained considerable attention as active components of marketed medications, such as Ketoprofen (Oruvail ® ), Suprofen (Profenal ® ) and Fenofibrate (TriCor ® ). [10] We have applied our method to the one-pot synthesis the anti-cholesterol drug Fenofibrate on 10.0 mmol scale.…”