A kind of nucleoside base hydroxamic acid derivative compound and its preparation method and application
What is Al technical title?
Al technical title is built by PatSnap Al team. It summarizes the technical point description of the patent document.
A nucleoside base hydroxime, hydroxamic acid functional technology, applied in the field of medicine, can solve the problems of complex pharmacokinetics, reduced therapeutic effect, drug resistance of tumor cells, etc.
Active Publication Date: 2020-05-22
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
View PDF2 Cites 0 Cited by
Summary
Abstract
Description
Claims
Application Information
AI Technical Summary
This helps you quickly interpret patents by identifying the three key elements:
Problems solved by technology
Method used
Benefits of technology
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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more
Image
Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
Click on the blue label to locate the original text in one second.
Reading with bidirectional positioning of images and text.
[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.
[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.
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
PUM
Login to view more
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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
Application Information
Patent Timeline
Application Date:The date an application was filed.
Publication Date:The date a patent or application was officially published.
First Publication Date:The earliest publication date of a patent with the same application number.
Issue Date:Publication date of the patent grant document.
PCT Entry Date:The Entry date of PCT National Phase.
Estimated Expiry Date:The statutory expiry date of a patent right according to the Patent Law, and it is the longest term of protection that the patent right can achieve without the termination of the patent right due to other reasons(Term extension factor has been taken into account ).
Invalid Date:Actual expiry date is based on effective date or publication date of legal transaction data of invalid patent.