180973-22-2Relevant academic research and scientific papers
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.
Radical-Mediated Thiol-Ene Strategy: Photoactivation of Thiol-Containing Drugs in Cancer Cells
Sun, Shuang,Oliveira, Bruno L.,Jiménez-Osés, Gonzalo,Bernardes, Gon?alo J. L.
, p. 15832 - 15835 (2018/11/10)
Photoactivated drugs provide an opportunity to improve efficacy alongside reducing side-effects in the treatment of severe diseases such as cancer. Described herein is a photoactivation decaging method of isobutylene-caged thiols through a UV-initiated thiol-ene reaction. The method was demonstrated with an isobutylene-caged cysteine, cyclic disulfide-peptide, and thiol-containing drug, all of which were rapidly and efficiently released under mild UV irradiation in the presence of thiol sources and a photoinitiator. Importantly, it is shown that the activity of histone deacetylase inhibitor largazole can be switched off when stapled, but selectively switched on within cancer cells when irradiated with non-phototoxic light.
AN IMPROVED PROCESS FOR THE PREPARATION OF (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ETHYLIDENE-4,21-BIS(1-METHYLETHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TETRAAZABICYCLO[8.7.6]TRICOS-16-ENE-3, 6, 9, 19, 22-PENTONE
-
, (2017/05/19)
The present invention is relates to an improved process for the preparation (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I.
NOVEL HDAC INHIBITORS AND METHODS OF TREATMENT USING THE SAME
-
Paragraph 000162, (2017/03/21)
Disclosed herein are novel HDAC inhibitors. The HDAC inhibitors may be used in methods of treating cancer. The HDAC inhibitors may be used in methods of treating a neurological disorder.
METHOD FOR PREPARING LARGAZOLE ANALOGS AND USES THEREOF
-
Paragraph 00323, (2016/09/26)
Analogs of largazole are described herein. Methods of treating cancer and blood disorders using largazole and largazole analogs and pharmaceutical compositions comprising the same are additionally described herein. Methods for preparing largazole analogs are likewise described.
Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
Almaliti, Jehad,Al-Hamashi, Ayad A.,Negmeldin, Ahmed T.,Hanigan, Christin L.,Perera, Lalith,Pflum, Mary Kay H.,Casero, Robert A.,Tillekeratne, L. M. Viranga
, p. 10642 - 10660 (2016/12/16)
A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-a-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.
Modular synthesis and biological activity of pyridyl-based analogs of the potent Class i Histone Deacetylase Inhibitor Largazole
Clausen, Dane J.,Smith, William B.,Haines, Brandon E.,Wiest, Olaf,Bradner, James E.,Williams, Robert M.
, p. 5061 - 5074 (2015/08/03)
The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein.
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.
HDAC Inhibitors as Anti-Cancer Agents
-
Paragraph 0142, (2016/01/15)
Largazole analogues, methods of making the same, and methods of using the same, are described.
An efficient partial reduction of α,β-unsaturated esters using DIBAL-H in flow
Yoshida, Masahito,Otaka, Hiroyuki,Doi, Takayuki
, p. 6010 - 6016 (2015/03/30)
The partial reduction of α,β-unsaturated esters and benzoate derivatives to form the corresponding aldehydes was achieved using a flow reactor system within 1 s at a high flow rate (18 mL min-1) under cryogenic conditions (-97°C). Commercially available diisobutylaluminium hydride (DIBAL-H) was used as the reductant. The desired enals and benzaldehyde derivatives, except for 4-methoxycinnamate and 4-methoxybenzoate, were formed selectively and redox economically in moderate to high yields.
