Fluoroalkene modification of mercaptoacetamide-based histone deacetylase inhibitors

Osada, Shinji; Сано, С.; Ueyama, Mariko; Chuman, Yoshiro; Kodama, Hiroaki; Sakaguchi, Kazuyasu

doi:10.1016/j.bmc.2009.12.005

Cited by 97 publications

(39 citation statements)

References 32 publications

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“…For example, (2S,3S)-3-(3-(2-chloro-4-(ethoxysulfinyl)phenyl)-1,2,4-oxadiazol-5-yl)-1-cyclopentylidene-1-fluorobutan-2-aminium 2a shows inhibitory activity of dipeptidylpeptidase IV (DPP-4) and (2E,4E,6E)-6-fluoro-7- (5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)octa-2,4,6-trienoic acid 2b can activate retinoid X receptor, both of which have potential therapeutic application in type 2 diabetes; N-((Z)-7-fluoro-8-mercaptooct-6-enyl)benzamide 5 can be used as a potent inhibitor of histone deacetylases. In light of the importance of fluoroalkenes, many efforts have been devoted towards the synthesis of these moieties.…”

Section: Introductionmentioning

confidence: 99%

Simple and convenient synthesis of fluoroalkenes via direct coupling of alcohols, alkynes and fluoroboric acid under metal-free conditions

Yan

Zhang

Wei

et al. 2014

Tetrahedron Letters

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Section: Introductionmentioning

confidence: 99%

Simple and convenient synthesis of fluoroalkenes via direct coupling of alcohols, alkynes and fluoroboric acid under metal-free conditions

Yan

Zhang

Wei

et al. 2014

Tetrahedron Letters

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“…In order to evaluate the effect of stereoisomerization on HDAC inhibitory activity, synthetic compounds were analyzed for HDAC inhibitory activity in vitro using a HeLa nuclear extract as described. 6 The inhibitory activity of 1(E) was very strong and comparable with that of SAHA. 1(Z) showed almost threefold stronger activity than SAHA (Table 1).…”

mentioning

confidence: 78%

“…The Z-isomer 1(Z) compound showed the stronger general HDAC inhibitory activity using HeLa extract than SAHA. 6 Here, we designed and synthesized the stereoisomer, E-isomer 1(E) to control the special configuration of thiol group. The effects of E-and Z-isomers on HDAC inhibitory activity and selectivity were analyzed against various HDAC-isoforms.…”

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confidence: 99%

Effects of E/Z Configuration of Fluoroalkene-containing HDAC Inhibitors on Selectivity for HDAC Isoforms

et al. 2013

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Histone deacetylase (HDAC) inhibitors belong to a new class of potential anticancer agents. It may be possible to reduce some of the toxicity by specifically targeting only the HDAC isoform. Here, stereoisomeric HDAC inhibitors containing fluoroalkene were analyzed for their specificity toward HDAC isoforms. Z-Form 1(Z) showed high affinity to HDACs whereas E-isoform 1(E) had lower affinity to HDAC1 and HDAC4. These data suggested that introduction of alkene with E/Z configuration to HDAC inhibitor can be a new strategy to develop the isoform-selective HDAC inhibitors.Histone deacetylases (HDACs) have crucial roles in numerous biological processes. There are eighteen encoded human HDACs, which are classified as class I (HDAC1, -2, -3, and -8), class II (HDAC4, -5, -6, -7, -9, and -10), class III (SIRT1-7), and class IV (HDAC11) enzymes. Recent studies of knockout mice lacking HDAC genes have revealed highly specific functions for individual HDAC isoforms.1 These facts emphasize the importance of developing HDAC-isoform specific inhibitors.A number of HDAC inhibitors have been reported to date, and they were used as anticancer drugs and reagents for serial animal cloning without clone-specific abnormalities.2,3 HDAC inhibitors, including SAHA, typically consist of a zinc-binding group that coordinates to the catalytic metal atom within the HDAC active site, a linker that accommodates the tubular access of the active site, and a capping group that interacts with the residues at the entrance of the active site. It is very important to have moieties to enhance isoform selectivity to reduce side effects. Replacement of hydroxamic acid as the zinc-binding group has been carried out to produce new types of HDAC isozyme-selective inhibitors.2 Recently, we developed HDAC inhibitors containing a sulfanylmethyl group attached with fluoroalkene. As the fluoroalkene is known for nonhydrolyzable amide mimetic, it is stable with respect to hydrolytic cleavage. 4 The thiol group may interact with zinc ion in a chelating manner 5 (Figure 1). The Z-isomer 1(Z) compound showed the stronger general HDAC inhibitory activity using HeLa extract than SAHA. 6 Here, we designed and synthesized the stereoisomer, E-isomer 1(E) to control the special configuration of thiol group. The effects of E-and Z-isomers on HDAC inhibitory activity and selectivity were analyzed against various HDAC-isoforms.The synthesis of 1(E) is outlined in Scheme 1. As outlined in Scheme 1, synthesis of the complementary 1(E) was started from bromide A, which was used for preparation of Z-isomer.

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“…[55] Osada also used this reaction to prepare histone deacetylase inhibitors. [56] Scheme 31. Synthesis of (Z)-α-fluoroalkenoates by use of an α-fluorinated phenylsulfinylacetate.…”

Section: Miscellaneous Reactionsmentioning

confidence: 99%

Synthetic Methods for Fluorinated Olefins

2011

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Fluoro‐olefin compounds, because of their favorable physicochemical properties, have been used as key materials in the fields of medicinal chemistry, chemical biology, and materials sciences. A number of the synthetic methodologies for applications of fluoro‐olefin compounds were developed simultaneously. This review article provides an overview not only of recent progress in syntheses of fluoro‐olefin compounds but also of some classical but still valuable synthetic reactions.

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Fluoroalkene modification of mercaptoacetamide-based histone deacetylase inhibitors

Cited by 97 publications

References 32 publications

Simple and convenient synthesis of fluoroalkenes via direct coupling of alcohols, alkynes and fluoroboric acid under metal-free conditions

Simple and convenient synthesis of fluoroalkenes via direct coupling of alcohols, alkynes and fluoroboric acid under metal-free conditions

Effects of E/Z Configuration of Fluoroalkene-containing HDAC Inhibitors on Selectivity for HDAC Isoforms

Synthetic Methods for Fluorinated Olefins

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