Yakushinamides, Polyoxygenated Fatty Acid Amides That Inhibit HDACs and SIRTs, from the Marine Sponge Theonella swinhoei

Abstract

Yakushinamides A (1) and B (2), prolyl amides of polyoxygenated fatty acids, have been isolated from the marine sponge Theonella swinhoei as inhibitors of HDACs and SIRTs. Their planar structures were determined by interpretation of the NMR data of the intact molecules and tandem FABMS data of the methanolysis products. For the assignment of the relative configurations of the three contiguous oxymethine carbons in 1 and 2, Kishi's universal NMR database was applied to the methanolysis products. During the assignments of relative configurations of the isolated 1-hydroxy-3-methyl moiety in 1 and the isolated 1-hydroxy-2-methyl moiety in 2, we found diagnostic NMR features to distinguish each pair of diastereomers. The absolute configurations of 1 and 2 were determined by a combination of the modified Mosher's method and Marfey's method. Although the modified Mosher's method was successfully applied to the methanolysis product of 1, this method gave an ambiguous result at C-20 when applied to the methanolysis product of 2, even after oxidative cleavage of the C-14 and C-15 bond.

Marine natural products

“…A number of new glyceride (788 and 789) and ceramide (790-793) lipids have been reported from species of Theonella and Erylus, 394,395 while branched fatty acids (794 and 795), polyoxygenated fatty acid amides (796 and 797) and N-acyldopamine glycosides 798-801 were sourced from Asteropus, Melonanchora, Myxilla and Theonella sponges. [396][397][398][399] Unusually, only one new polyacetylene 802 was reported in 2016, from Halichondria panicea. 400 Examination of the two-sponge association between Xestospongia deweerdtae and Plakortis halichondrioides, in addition to P. zyggompha, resulted in the isolation of 6-epi-7,8dihydroplakortide K 803, plakortide AA 804, and three chemically unstable plakinic acids N-P 805-807.…”

Identification of the 216kbp gene cluster and structure elucidation of gargantulides B and C, new complex 52-membered macrolides fromAmycolatopsissp

“…We then focused on chiral centers whose stereochemistry had not previously been determined for 3 . The syn configuration for C-6/C-7 was deduced from the Kishi’s NMR database for the 4-methylnonan-5-ol isomers (45) ( SI Appendix , Fig. S12), based on the chemical shift of the branched methyl Me-6 at δ C 14.5 ppm.…”

Histone Deacetylase Inhibitors from Marine Invertebrates

“…Theonella swinhoei (Gray, 1868; Demospongiae, Tetractinellida: Theonellidae, Figure 8) is a sessile, hermaphrodite, and filter-feeder species typical of the Indo-West Pacific area, where it populates the tropical environments in a depth range between 20 and 188 m. Its covering dimensions range from 2.0 to 200 mm, and it is regarded as a remarkable component of the sponge population in coral reef communities, much studied because it represents a suitable microenvironment for the development of different types of autotrophic and heterotrophic organisms that inhabit different parts of its body [57]. From this demosponge, Takada et al [58] isolated two prolyl amides of polyoxygenated fatty acid, i.e., yakushinamide A (Figure 9), which displayed a moderate inhibitory effect on HDACs and sirtuins. In particular, yakushinamide A inhibited HDAC1, SIRT1, and -3 at 26, 16, and 79 µM, respectively, whereas yakushinamide B at 29, 75, 52, 34, 150, and 78 µM, respectively.…”

“…They can have a granular, smooth, or glassy shape, and their colors can vary according to the depth of the waters in which they are located, being white-grey in deep and greener in shallow waters thanks to the presence of light that allows the development of symbiotic algae in the latter case [59]. From this demosponge, Takada et al [58] isolated two prolyl amides of polyoxygenated fatty acid, i.e., yakushinamide A (Figure 9), which displayed a moderate inhibitory effect on HDACs and sirtuins. In particular, yakushinamide A inhibited HDAC1, SIRT1, and -3 at 26, 16, and 79 µM, respectively, whereas yakushinamide B at 29, 75, 52, 34, 150, and 78 µM, respectively.…”

“…In particular, yakushinamide A inhibited HDAC1, SIRT1, and -3 at 26, 16, and 79 µM, respectively, whereas yakushinamide B at 29, 75, 52, 34, 150, and 78 µM, respectively. From this demosponge, Takada et al [58] isolated two prolyl amides of polyoxygenated fatty acid, i.e., yakushinamide A (Figure 9), which displayed a moderate inhibitory effect on HDACs and sirtuins. In particular, yakushinamide A inhibited HDAC1, SIRT1, and -3 at 26, 16, and 79 µM, respectively, whereas yakushinamide B at 29, 75, 52, 34, 150, and 78 µM, respectively.…”