323581-08-4Relevant academic research and scientific papers
Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models
Shen, Sida,Hadley, Melissa,Ustinova, Kseniya,Pavlicek, Jiri,Knox, Tessa,Noonepalle, Satish,Tavares, Mauricio T.,Zimprich, Chad A.,Zhang, Guiping,Robers, Matthew B.,Ba?inka, Cyril,Kozikowski, Alan P.,Villagra, Alejandro
, p. 8557 - 8577 (2019/10/02)
Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.
ISOXAZOLE HYDROXAMIC ACIDS AS HISTONE DEACETYLASE 6 INHIBITORS
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Paragraph 0244, (2018/10/25)
The present disclosure provides compounds represented by Formula (I): (Formula(I) and pharmaceutically acceptable salts, solvates, e.g., hydrates, and prodrugs thereof, wherein X and n are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I) for use to treat diseases and conditions, e.g., cancer, wherein inhibition of HDAC provides a benefit.
The oxidative dealkylation of tertiary amides: Mechanistic aspects
Iley, Jim,Tolando, Roberto
, p. 2328 - 2336 (2007/10/03)
N-(But-3-enyl)-N-methylbenzamide 14a undergoes microsomal oxidation by rat liver microsomes to yield both N-methyl- and N-(but-3-enyl)benzamides 18a and 19, the products of N-dealkylation. Cyclic products, that could be derived from a carbon-centered radical formed by hydrogen atom abstraction from the N-methyl group, were not observed. When generated independently, this carbon-centred radical underwent cyclisation, the 5-exo-trig mode being preferred to 6-endo-trig by a factor of 5. In contrast, N-(but-3-ynyl)-N-methylbenzamide 15 undergoes microsomal oxidation to yield the products of dealkylation 18a and 23 and also N-benzoylpiperidone 24. Dealkylation is preferred by factor of 3 and the piperidone accounts for ca. 45% of the reaction at the N-methyl group. Piperidone formation is consistent with the generation of a carbon-centred radical α- to the amide nitrogen atom during dealkylation and implies that cyclisation proceeds preferentially via the 6-endo-dig mode. Generated independently the radical undergoes cyclisation by both 5-exo-dig and 6-endo-dig modes, the former being favoured by a factor of 10. Similarly, N,N-dimethylacrylamide 26 and N-methyl-N-(3-pyridyl)acrylamide 27 undergo microsomal oxidation to form, via the 5-endo-trig cyclisation mode, 3-hydroxy-N-methyl-2-pyrrolidone 33 and 3-hydroxycotinine ? 34, respectively, confirming the intermediacy of a carbon-centred radical in the dealkylation process. Attempts to trap N-acyliminium ions during microsomal dealkylation failed. Thus, although N,N-dimethylaniline 35 reacts in the presence of NaCN to form N-cyanomethyl-N-methylaniline 37 (Nu=CN), N,N-dimethylbenzamide undergoes dealkylation without forming N-cyanomethyl-N-methylbenzamide. Similarly, microsomal reaction of N,N-dimethylaniline in the presence of NaBD4 gives rise to multiple incorporation of deuterium atoms into the methyl groups of the starting material, whereas N,N-dimethylbenzamide undergoes dealkylation but with no such deuterium incorporation into the starting material. Further, microsomal oxidation of N,N-dimethylsalicylamide 38 yields N-methylsalicylamide 40 with no evidence for the formation of N-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one 39, the potential product of intramolecular cyclisation of the phenolic oxygen atom onto the putative N-aroylmethylene iminium ion.
