Anacardic Acid Derivatives Isolated from Fungal Species Tyromyces fissilis as New Histone Acetyltransferase Inhibitors

Abstract

Anacardic acid (AA) was first detected in the shells of cashew nuts, Anacardium occidentale, and is known to possess inhibitory activity against acetyltransferases. Recently, several anacardic acid derivatives (AAds) were isolated from the wild fungus, Tyromyces fissilis, which has been reported as xanthine oxidase inhibitors. In the present study, we investigated whether nine AAds function as acetyltransferase inhibitors. Screening analyses were performed by incubating the enzyme protein (P300/CBP-associated factor; PCAF) and the substrate protein (histone H1) with radioisotope-marked acetyl-CoA, showing that two of the nine derivatives, namely, AAd7 and AAd11, inhibited the acetyltransferase activity of PCAF at concentrations of 50 and 100 µM, respectively. The inhibition intensities were similar to those of the original compound, AA, and the inhibitory effects of these derivatives increased in a concentration-dependent manner. Docking simulations suggested the possibility that AA, AAd7, and AAd11 might bind the same active pocket of PCAF. These results suggest that the AAds can be used as acetyltransferase inhibitors. In contrast, there were no significant differences in the molecular structure of AA and its derivatives; however, these small differences in the functional groups on the alkyl side chain on salicylic acid reduced the acetyltransferase inhibitor activity or newly produced proteolytic activity.