Heterocyclic anthracene ketone histone methyltransferase inhibitor and medical application thereof
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A heterocycle and methoxy technology, applied in the field of medicinal chemistry, can solve problems that have not been studied clearly
Inactive Publication Date: 2015-12-30
CHINA PHARM UNIV
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So far, the specific mechanism of histone lysine methylation affecting gene transcription h
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Embodiment 1
[0052] Preparation of 3,5-dibromo-6H-anthracene[1,9-cd]isoxazol-6-one
[0053]
[0054] 6H-Anthracene[1,9-cd]isoxazol-6-one (5g, 22.60mmol) was dissolved in AcOH (50mL), and bromine (2.90mL, 56.51mmol) in acetic acid solution was added dropwise to the reaction solution During TLC detection, the reaction was terminated. The reaction solution was adjusted to weak alkalinity with saturated sodium bicarbonate, extracted with dichloromethane (3×50 mL), the organic layer was dried with anhydrous sodium sulfate, the solvent was spin-dried, and the yellow 3,5-bis Bromo-6H-anthracene[1,9-cd]isoxazol-6-one (7.26g, 73%).m.p.247-248℃. 1 HNMR (300MHz, CDCl 3 ): δ8.45(d, J=7.71Hz, 1H, ArH), 8.08(d, J=7.5Hz, 1H, ArH), 7.97(s, 1H, ArH), 7.82(t, J=7.23Hz, 1H,ArH),7.72(t,J=7.35Hz,ArH).HRMS(ESI):calcdforC 14 h 5 Br 2 NO 2 [M+H] + 377.8760,found 377.8752.
Embodiment 2
[0056]
[0057] Differently substituted ammonia was dissolved in anhydrous aluminum chloride in dichloromethane solution, the compound of Example 1 was added to the mixture, stirred at 40° C. for 12 h, detected by TLC, and the reaction was stopped. The reaction was extracted with water (2 x 30 mL). The organic layer was dried with anhydrous sodium sulfate, and the solvent was spin-dried to obtain a red solid.
Embodiment 3
[0060] Preparation of 3-bromo-5-((4-methoxyphenyl)amino)-6H-anthracene[1,9-cd]isoxazol-6-one
[0061]
[0062] 3,5-dibromo-6H-anthracene[1,9-cd]isoxazol-6-one (0.10g, 0.26mmol) and p-methoxyaniline (0.19g, 1.58mmol) were synthesized according to the method in Example 2 . m.p.156-157℃. 1 HNMR (300MHz, CDCl 3 ):δ11.32(s,1H,NH),8.58(d,J=7.23Hz,1H,ArH),8.18(d,J=7.23Hz,ArH),7.82(t,J=7.47Hz,1H, ArH), 7.70(t, J=8.01Hz, 1H, ArH), 7.62(s, 1H, ArH), 7.30(d, J=8.79Hz, 2H, ArH), 7.05(d, J=8.85Hz, 2H ,ArH),3.91(s,3H,CH3).HRMS(ESI):calcdforC 21 h 13 BrN 2 o 3 [M+H] + 421.0182,found 421.0186.
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a heterocyclic anthracene ketone histone methyltransferase inhibitor and a preparation method and application of the heterocyclic anthracene ketone histone methyltransferase inhibitor. It is proved by pharmacology experiments that the compound has a good inhibiting effect on histone methyltransferase from the molecular level to the cell level, has good antiproliferative activity on tumor cell strains and has reasonable medicinal parameters, such as a proper dissociation constant (pKa), a lipid-aqueous partition coefficient (LogD, pH=7.4), water solubility and film transmittance. It is testified by research on pharmacokinetics that the compound is wide in distribution in a body of a rat, the plasma clearance can be within an acceptable range, and good bioavailability is achieved. The compound and the pharmaceutic preparation of the compound can be used for treating a series of diseases caused by disorder of enzyme activity of the histone methyltransferase, such as solid tumor, leucocythemia, malaria and neurodegenerative diseases.
Description
technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of heterocyclic anthrone-type histone methyltransferase inhibitors, a preparation method and medical application thereof. Background technique [0002] Histone methylation modification is an important epigenetic regulation mode, which is involved in the regulation of chromatin conformation, gene transcription and expression. The methylation level of histone is closely related to a variety of proto-oncogenes and tumor suppressor genes. The abnormal expression of these proto-oncogenes and tumor suppressor genes may lead to the occurrence of tumors. Therefore, by regulating the methylation level of histones, some important genes can be transcribed to achieve the purpose of treating tumors. Histone methylation regulatory proteins have become the latest and most popular targets in the field of cancer drug development. [0003] The main substrates of histone methyltransfera...
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