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Substituted o-benzoylsulfonylimide histone deacetylase inhibitor, preparation method and application
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A technology of benzoylsulfonimide and sirtuin, which is applied in the field of medicine and can solve problems such as ineffectiveness of solid tumors, limitations of clinical application, and existence of cardiotoxicity
Active Publication Date: 2017-10-17
SHANDONG UNIV
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However, the marketed HDACs inhibitors still have many shortcomings, especially ineffective against solid tumors and cardiotoxicity at normal doses, which greatly limits the clinical application of such drugs
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[0098] The present invention will be further described below in conjunction with the examples, but not limited thereto.
Embodiment 14-
[0099] Example 1.4-[3-[1,1-dioxo-3-oxobenzo[d]isothiazol-2(3H)-yl]propionamido]-N-hydroxybenzamide (4AA) synthesis
[0100] Synthesis of 4-[3-[1,1-dioxo-3-oxobenzo[d]isothiazol-2(3H)-yl]propionamido]benzoic acid (3AA)
[0101] Compound o-benzoylsulfonimide (1A, 0.73 g, 4 mmol) was dissolved in 5 mL of DMF and NaHCO was added 3 (0.34g, 4mmol) and 4-(3-bromopropionamido)benzoic acid (2A, 1.09g, 4mmol), reacted at 80°C for 4h, poured the reaction solution into 50mL water, a white precipitate precipitated, filtered, and recrystallized from methanol A white solid (0.90 g, 60%) was obtained. Mp:>250℃. 1 H NMR (300MHz, DMSO-d 6 )δ12.71(s,1H),10.40(s,1H),8.31(dd,J=6.9Hz,1.2Hz,1H),8.13(dd,J=6.9Hz,1.2Hz,1H),8.09-7.98 (m,2H),7.70(d,J=8.7Hz,2H),7.63(d,J=8.7Hz,2H),4.05(t,J=7.2Hz,2H),2.87(t,J=7.2Hz ,2H).MS(ESI)m / z:373.0[M-H] - .
[0102] Compounds 3B-3R were synthesized according to the method of 3A.
[0103] Synthesis of 4-[3-[1,1-dioxo-3-oxobenzo[d]isothiazol-2(3H)-yl]propionamid...
Embodiment 23-3
[0108] Example 2.3-[3-[1,1-dioxo-3-oxobenzo[d]isothiazol-2(3H)-yl]propionamido]-N-hydroxybenzamide (4AB) synthesis
[0109] The preparation methods of intermediates and target compounds are as in Example 1. Yield 20%; m.p.199-201°C; 1 H NMR (300MHz, DMSO-d 6 )δ: 11.16(s, 1H), 10.22(s, 1H), 9.00(d, J=1.8Hz, 1H), 8.31(dd, J=6.9Hz, 0.9Hz, 1H), 8.14-8.12(m, 1H), 8.09-7.98(m, 2H), 7.96(s, 1H), 7.76-7.72(m, 1H), 7.40-7.32(m, 2H), 4.05(t, J=7.2Hz, 2H), 2.86 (t,J=7.2Hz,2H),2.11-2.01(m,2H).HRMS(AP-ESI)m / z calcd forC 17 h 15 N 3 o 6 S[M+H] + 390.0754, found 390.0750.
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Abstract
The invention discloses a preparation method and an application for a histone deacetylases inhibitor capable of replacing saccharin. A chemical compound is of the general formula I structure. The chemical compound has a strong inhibitory activity for histone deacetylases (HDAC). The chemical compound can be used for preparing medicine for preventing and treating related mammalian diseases caused by abnormal expression of the histone deacetylases. The invention further relates to a medicine preparation purpose of a composition of the chemical compound with the general formula I structure.
Description
technical field [0001] The invention relates to a substituted o-benzoylsulfonimide histone deacetylase inhibitor, a preparation method and application thereof, and belongs to the technical field of medicine. Background technique [0002] Histones are an important part of the nucleosome, the basic structure of chromatin. The covalent modification of histone acetylation / deacetylation is an important regulation method of chromosome modification and gene expression, which is mainly composed of histone acetyl transferases (histone acetyl transferases, HATs) and histone deacetylases (histone deacetylases, HDACs) co-catalyze the completion. In cancer cells, the expression of HDACs is abnormally increased, the dynamic balance between HATs and HDACs is broken, and the cell cycle inhibitor p21 WAF1 / CIP1 The expression of HIF-1 (hypoxia-inducible factor-1) and VEGF (vascular endothelial growth factor) which promote tumor angiogenesis are increased. Therefore, HDACs have become popul...
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