Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

Abstract

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5''-epi-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia-Kocienski olefination of a 1,3-propanediol-derived sulfone and a L- or D-malic acid-derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)-3-hydroxy-7-mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5'' stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5''-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC(50)=2.4 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.

Total Synthesis of Thailandepsin B, a Potent HDAC Inhibitor Isolated from a Microorganism

“…The key macrolactonization precursor 9 could be prepared through the direct condensation of the D-allo-isoleucine-and D-cysteine-containing segment 10 with the D-norleucine-containing segment 11. Segment 11 could be formed by the condensation of commercially available D-norleucine methyl ester hydrochloride (12) with the known carboxylic acid 13 (previously prepared from L-malic acid in our laboratory 7,[9][10][11][12] ). Segment 10 was obtained as previously described in our total synthesis of 1 and 6.…”

“…7,9) We initially pursued the synthesis of the key segment 11, which is the coupling partner of 10, as shown in Chart 3. The condensation of 12 with 13 7,[9][10][11][12] afforded the desired coupling product 14 in excellent yield (98%). Subsequent saponification of the methyl ester moiety in 14 furnished the requisite segment 11 in 90% yield.…”

“…The crucial condensation of 10 with 11 proceeded well under the mild conditions [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.3 equiv), 1-hydroxy-7-azabenzotriazole (HOAt) (1.3 equiv), i-Pr 2 NEt (2.6 equiv), CH 2 Cl 2 , −30°C, 5 h] explored in our previous studies. 7,[9][10][11][12] The desired condensation product 15 was obtained in 90% yield without appreciable epimerization at the C2 stereogenic center (D-norleucine part in 15). In this condensation reaction, the use of a combination of HATU and HOAt at low temperature was critical to effectively suppress unfavorable epimerization event.…”

“…7) However, the total synthesis of thailandepsin B (2) has only been reported once in the patent literature. 8) During our efforts synthesizing and biologically evaluating bicyclic depsipeptide HDAC inhibitors including burkholdacs A (3), 7) B (1, thailandepsin A), 7) FK228 (4, romidepsin) 9) and spiruchostatins A (5), 9,10) B (6), 9,11) C (7) 12) and D (8), 12) we became interested in the synthesis of thailandepsin B (2) and its analogues with the aim of identifying novel mechanism-based anticancer agents. In this study, we describe our total synthesis of 2 using a synthetic strategy developed previously in our laboratory.…”

“…In this study, we describe our total synthesis of 2 using a synthetic strategy developed previously in our laboratory. 7,[9][10][11][12] …”