180973-37-9Relevant articles and documents
A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling
Zhang, Bingbing,Liu,Gao, Dingding,Yu, Xiaolin,Wang, Jinlei,Lei, Xinsheng
, (2019/09/10)
Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a “fluorine scan” strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs. Unlike other modifications which often led to significant reduction or complete loss of activity as reported in the literature, most of these fluoro thiols have displayed comparable or enhanced activity and selectivity in enzymatic assays. Two of the sulfhydryl esters have also exhibited excellent inhibitory activity in cellular assays with a few selected cell lines. The C19-fluorinated analogue has been further studied by immunoblot analysis, confirming that it is a potent selective class I HDAC inhibitor and supporting that the potent cellular antiproliferative activity is due to HDAC inhibition. The molecular docking study reveals that introducing fluorine at the C19 position does not change the original interactions, but might have made a subtle change in binding conformation, resulting in an obvious improvement in activity.
Study for diastereoselective aldol reaction in flow: synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid, a key component of cyclodepsipeptide HDAC inhibitors
Doi, Takayuki,Otaka, Hiroyuki,Umeda, Koji,Yoshida, Masahito
, p. 6463 - 6470 (2015/08/18)
Abstract Flow synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (5), a key component of cyclodepsipeptide histone deacetylase inhibitors was achieved. An efficient flow system for the synthesis of α, β-unsaturated ester 8 was established using a flow reactor column packed with polymer-supported 1,4-diazabicyclo[2.2.2]octane and a fast mixing accessible flow reactor (Comet X-01). Enal 9 was efficiently prepared by a partial reduction of the α, β-unsaturated ester 8 using diisobutylaluminium hydride in the flow system, and the continuous-flow diastereoselective aldol reaction was performed at low temperature, giving a good yield and diastereoselectivity of the desired aldol 10.
Total synthesis of spiruchostatin B aided by an automated synthesizer
Fuse, Shinichiro,Okada, Kumiko,Iijima, Yusuke,Munakata, Asami,MacHida, Kazuhiro,Takahashi, Takashi,Takagi, Motoki,Shin-Ya, Kazuo,Doi, Takayuki
experimental part, p. 3825 - 3833 (2011/06/21)
The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.
