Nucleoside and base hydroxamic acid derived compound and preparation method and applications thereof

A nucleoside base hydroxamic and hydroxamic acid functional technology, applied in the field of medicine, can solve the problems of drug resistance of tumor cells, toxic side effects, and reduced therapeutic effect

Active Publication Date: 2017-06-23
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, studies have found that when DNMTs or HDACs inhibitors are used alone, the high expression of another enzyme can still lead to the silencing of tumor suppressor genes. This compensatory mechanism makes tumor cells resistant to drugs and reduces the therapeutic effect.
Although the combined use has the advantage of synergistic effect, it also has some disadvantages, such as complicating the pharmacokinetics, generating drug interactions, and causing more toxic side effects, etc.

Method used

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  • Nucleoside and base hydroxamic acid derived compound and preparation method and applications thereof
  • Nucleoside and base hydroxamic acid derived compound and preparation method and applications thereof
  • Nucleoside and base hydroxamic acid derived compound and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] 6-(4-((4-Amino-2-oxopyrimidin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyhexanamide

[0102]

Embodiment 1A

[0104] Ethyl 6-Azidohexanoate

[0105]

[0106] Ethyl 6-bromohexanoate (1eq) was dissolved in DMF, sodium azide (3eq) was added, the temperature was slowly raised from room temperature to 80°C and reacted at this temperature overnight. Ethyl acetate was then added, excess sodium azide was removed by filtration, water was added and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. Filtration and spin off the solvent on a rotary evaporator afforded the title compound. 1H NMR (400MHz, DMSO-d6) δ4.05 (q, J = 7.1Hz, 2H), 3.31 (t, J = 6.8Hz, 2H), 2.29 (t, J = 7.3Hz, 2H), 1.60–1.47 (m,4H),1.38–1.27(m,2H),1.18(t,J=7.1Hz,3H). 13 CNMR (101MHz, DMSO) δ173.26, 60.18, 51.05, 33.91, 28.46, 26.16, 24.52, 14.64.

Embodiment 1B

[0108] 4-Amino-1-(prop-2-yn-1-alk)pyrimidin-2(1H)-one

[0109]

[0110] Dissolve cytosine (1eq) and 3-bromopropyne (3eq) in anhydrous DMF, add anhydrous cesium carbonate (2eq), heat to 80°C and react overnight. After the reaction was completed, water was added and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by column separation after removing the solvent of the organic phase. 1 H NMR (400MHz, DMSO-d6) δ7.52(d, J=7.7Hz, 1H), 6.64(d, J=7.8Hz, 1H), 4.77(d, J=2.5Hz, 2H), 3.49(t ,J=2.5Hz,1H). 13 C NMR (101MHz, DMSO) δ166.55, 155.61, 145.26, 94.61, 79.96, 75.79, 37.84.

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PUM

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Abstract

The invention discloses a nucleoside and base hydroxamic acid compound with DNA transmethylase and / or histone deacetylase inhibition activity, and a preparation method and applications thereof. The structural formula of the nucleoside and base hydroxamic acid compound is shown as the formula I, wherein R is nucleoside and base, nucleoside and base with substituent group or nucleoside and base analogue in DNA and / or RNA; Linker is a connecting chain connecting R with hydroxamic acid function group, the connecting chain comprises but is not limited within alkyl chain, alkyl chain with heteroatom, alkyl chain with aromatic ring, and alkyl chain with heterocycle. In-vitro cell proliferation assay show that the compound shown in the formula I can well inhibit the proliferation of leukemia cell K562 and histocyte lymphoma cell U937. Transmethylase and histone deacetylase inhibition assay shows that the compound shown in the formula I is a compound having inhibition activity on the DNA transmethylase and / or histone deacetylase. The formula I is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to a nucleobase hydroxamic acid derivative with DNMT and HDAC inhibitory activity, a preparation method and application thereof. Background technique [0002] The occurrence and development of tumors are closely related to both genetic abnormalities and epigenetic changes. Gene abnormalities include amplification, translocation, deletion, and point mutation of oncogenes or tumor suppressor genes. Epigenetic modification mainly includes DNA modification and histone modification, such as DNA methylation, histone acetylation, deacetylation, ubiquitination, etc. Epigenetic changes do not involve changes in DNA sequences, and can maintain the genetic information of parents during cell division, but can be reversed under certain conditions, turning malignant cell populations into normal cells. Therefore, enzymes that play a regulatory role in epigenetics are considered to be a new gen...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D401/06C07D403/10C07D473/34A61K31/513A61K31/52A61K31/53A61P35/00A61P35/02
CPCC07D401/06C07D403/06C07D403/10C07D473/34
Inventor 蒋宇扬袁梓高高春梅孙钦升
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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