1137735-74-0Relevant articles and documents
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.
supporting information, 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
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Page/Page column 25, (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.
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.
Design, synthesis, and biological evaluation of largazole derivatives: Alteration of the zinc-binding domain
Su, Jinyue,Qiu, Yatao,Ma, Kun,Yao, Yiwu,Wang, Zhen,Li, Xianling,Zhang, Dayong,Tu, Zhengchao,Jiang, Sheng
, p. 7763 - 7769 (2014/12/10)
A new series of largazole analogues in which the side chain was replaced with disulfide groups were synthesized, and their biological activities were evaluated. Compound 8 bearing an octyl moiety showed much better selectivity for HDAC1 over HDAC7 than largazole (320-fold). Structure-activity relationships suggested that the length in the disulfide chain of largazole is important for the selectivity toward HDAC1 over HDAC7.
Biological evaluation of new largazole analogues: Alteration of macrocyclic scaffold with click chemistry
Li, Xianlin,Tu, Zhenchao,Li, Hua,Liu, Chunping,Li, Zheng,Sun, Qiao,Yao, Yiwu,Liu, Jinsong,Jiang, Sheng
supporting information, p. 132 - 136 (2013/03/13)
We report the design, synthesis, and biological evaluation of a new series of largazole analogues in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, respectively. Compound 7 bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole molecular scaffold.
Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability
Benelkebir, Hanae,Marie, Sabrina,Hayden, Annette L.,Lyle, Jason,Loadman, Paul M.,Crabb, Simon J.,Packham, Graham,Ganesan
supporting information; experimental part, p. 3650 - 3658 (2011/08/03)
The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life ≤5 min) to the thiol which has a half-life of 51 min.
Method for preparing largazole analogs and uses thereof
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Page/Page column 29, (2010/03/02)
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.
Synthesis and histone deacetylase inhibitory activity of largazole analogs: Alteration of the zinc-binding domain and macrocyclic scaffold
Bowers, Albert A.,West, Nathan,Newkirk, Tenaya L.,Troutman-Youngman, Annie E.,Schreiber, Stuart L.,Wiest, Olaf,Bradner, James E.,Williams, Robert M.
supporting information; experimental part, p. 1301 - 1304 (2009/09/06)
Fourteen analogs of the marine natural product largazole have been prepared and assayed against histone deacetylases (HDACs) 1, 2, 3, and 6. Olefin cross-metathesis was used to efficiently access six variants of the side-chain zinc-binding domain, while adaptation of our previously reported modular synthesis allowed probing of the macrocyclic cap group.
Macrolactamization versus macrolactonization: Total synthesis of FK228, the depsipeptide histone deacetylase inhibitor
Wen, Shijun,Packham, Graham,Ganesan
experimental part, p. 9353 - 9361 (2009/04/05)
(Chemical Equation Presented) The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.
Total synthesis and biological mode of action of largazole: A potent class I histone deacetylase inhibitor
Bowers, Albert,West, Nathan,Taunton, Jack,Schreiber, Stuart L.,Bradner, James E.,Williams, Robert M.
supporting information; experimental part, p. 11219 - 11222 (2009/02/05)
The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.
