Total Synthesis and Full Histone Deacetylase Inhibitory Profiling of Azumamides A–E as Well as β²- epi-Azumamide E and β³-epi-Azumamide E

Abstract

Cyclic tetrapeptide and depsipeptide natural products have proven useful as biological probes and drug candidates due to their potent activities as histone deacetylase (HDAC) inhibitors. Here, we present the syntheses of a class of cyclic tetrapeptide HDAC inhibitors, the azumamides, by a concise route in which the key step in preparation of the noncanonical disubstituted β-amino acid building block was an Ellman-type Mannich reaction. By tweaking the reaction conditions during this transformation, we gained access to the natural products as well as two epimeric homologues. Thus, the first total syntheses of azumamides B−D corroborated the originally assigned structures, and the synthetic efforts enabled the first full profiling of HDAC inhibitory properties of the entire selection of azumamides A−E. This revealed unexpected differences in the relative potencies within the class and showed that azumamides C and E are both potent inhibitors of HDAC10 and HDAC11.

Methyl Effect in Azumamides Provides Insight Into Histone Deacetylase Inhibition by Macrocycles

“…24 Analogous to the reported protocol, diastereoselective Ellman-type Mannich reaction between 15 (S-auxiliary) and 16 afforded the desired R-isomer (17) in 58% isolated yield (dr = 77:23) as shown in Figure 2c. The absolute stereochemistry was determined by X-ray crystallography upon desilylation with Bu 4 NF to give 18.…”

“…24 In said study, we observed a detrimental effect on inhibitory potency when changing the stereochemistry of either chiral center in the β-amino acid residue (gray shading in Figure 1a). Although this drastic effect was not particularly surprising when changing the stereochemistry of the extended Zn 2+ -binding side chain, which must be projected into the active site, the importance of the stereochemistry of the methyl group was less predictable.…”

“…We attribute these yields to two shortcomings in particular; first, the point of cyclization had previously been shown to have an effect on macrolactamization yield in a model system, 24 so synthesis of compound 7c was attempted by cyclizing between the β-amino acid and D-valine (Supporting Optimization of the Mannich reaction to give desmethylated building blocks. a Cumulative yield of both diastereomers.…”

“…The compounds chosen for investigation by NMR were azumamide A (5a), desmethylated azumamide C (9b), and the β 2 -epimer of azumamide E (36; Figure 3a), which was previously synthesized and reported to exhibit less than 50% inhibition across the full panel of HDACs at 50 μM inhibitor concentrations. 24 Azumamide A (5a) was chosen for structure determination over azumamide E (5e) due to more wellresolved NMR data, although compound 5a is less potent on account of its weak carboxamide Zn 2+ -binding group. 20 It can be assumed that this slight structural difference far away from the backbone would not influence the conformation in solution significantly, 38 and thus, compound 5a should provide a representative three-dimensional structure of the natural products that contain the same macrocycle.…”

Anticancer Drugs and Potential Anticancer Leads Inspired by Natural Products

“…5.14) is a cyclic tetrapeptide previously isolated in 1996 from the fungus, Fusarium pallidoroseum, and it was reported as an antimalarial agent [160]. Recent study revealed that the b-amino acid residue of azumamides has significant influence on the HDAC activities, and that azumamides C (92) and E (94) exhibited potent inhibitory activity of HDAC10 and HDAC11 [163]. Azumamides A-E (90-94) (Fig.…”