Small-molecule inhibitor of protein kinase A as well as preparation method and application thereof

A small molecule inhibitor, histone technology, applied in the field of biomedicine, can solve the problem of few pancreatic cancer imaging

Active Publication Date: 2020-06-09
PEKING UNION MEDICAL COLLEGE HOSPITAL CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, some small molecule inhibitors of protein kinases have been approved for the treatment of pancreatic cancer, but there are ...

Method used

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  • Small-molecule inhibitor of protein kinase A as well as preparation method and application thereof
  • Small-molecule inhibitor of protein kinase A as well as preparation method and application thereof
  • Small-molecule inhibitor of protein kinase A as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of HF89 by structural modification of H89

[0056] The synthesis process of this example was entrusted (Hua Yi Essotop Co., Ltd.) to carry out according to the routine operation of general chemical synthesis. The reaction process in the experiment was performed routinely and the experimental reagents were purchased commercially.

[0057] (1) H89 reacts with thionyl chloride to generate HF89-1, such as structural formula Ⅰ

[0058]

[0059] (2) HF89-1 and C 2 h 5 N 2 Boc (ethylenediamine under the protection of tert-butoxycarbonyl) reacts to generate HF89-2, such as structural formula II, and the molecular formula of HF89-2 is C 16 h 21 N 3 o 4 S, the molecular mass Exact mass of HF89-2 is 351.13, and the molecular weight Mol.Wt is 351.42;

[0060]

[0061] (3) HF89-2 reacts with trifluoroacetic acid TFA to generate HF89-3, such as structural formula III, and the molecular formula of HF89-3 is C 11 h 13 N 3 o 2 S, the molecular ma...

Embodiment 2

[0069] Example 2: Screening of protein kinase inhibitor HF89 for pancreatic cancer by in vitro cell experiments

[0070] Taking HF89, HFC and HN89 as research objects, the half inhibitory rate (IC50) of pancreatic cancer cell line Panc-1 was determined.

[0071] (1) After digesting the human pancreatic cancer cell line Panc-1 (purchased from the National Experimental Cell Resource Sharing Platform) with 0.25% trypsin, use RPMI-1640 medium (purchased from Hyclone Company of the United States) (plus 10% fetal bovine Serum) was made into a single cell suspension, and the cell number was measured by a cell counter. Cells were seeded in 96-well culture plate, 2*10 per well 4 cells. Set up the experimental group, control group and blank group respectively, with 3 parallel wells in each group.

[0072] (2) Placed at 37°C, 5% CO 2 After culturing in a constant temperature incubator for 2 hours, add HF89, HFC and HN89 dissolved in the culture medium with gradient concentrations. Pl...

Embodiment 3

[0084] Example 3: Efficient Synthesis of Protease A Small Molecule Inhibitors [ 11 C]HF89

[0085] The efficient synthesis provided by this embodiment [ 11 C] the method of HF89, comprises the following steps:

[0086] 1) Adopt HF89 standard substance to determine retention time by high performance liquid chromatography (HPLC) in advance, select 250x 10mm C18 column for use, flow velocity 3ml / min, UV 254nm, the retention time that obtains standard substance is 7.3 minutes, as figure 1 shown;

[0087] 2) The [ 11 C]CO 2 Adopt gas-phase synthesis to synthesize [ 11 C]CH 3 I(0.5-4Ci); specifically, at a suitable flow rate [ 11 C]CO 2 Ni-catalyzed with H 2 At 400°C the reaction converts to [ 11 C]CH 4 ,Then[ 11 C]CH 4 with I 2 The reaction at 700°C produces [ 11 C]CH 3 I(MeI), the main steps are as follows:

[0088]

[0089] 3) The above synthesized [ 11 C]CH 3 I was transferred to the reaction flask at 90°C;

[0090] 4) Dissolve 3mg of HF89 in 0.3ml of anhy...

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Abstract

The invention discloses a small-molecule inhibitor of histone kinase A. The small-molecule inhibitor comprises an H89 isoquinoline precursor structure, the specific molecular formula is CxHyAzNmOnS, and in the molecular formula, x is 20 or 21, y is 20 or 22, A is F, z is 0 or 1, m is 3 or 4, and n is 2 or 4. The invention further provides small-molecule inhibitors HF89, HFC and HN89, and a PET tracer [<11> C] HF<89>. The invention also provides a preparation method and an application of the related small-molecule inhibitor. A new feasible scheme is provided for early diagnosis, treatment, curative effect evaluation and the like of tumors.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a group of small molecule inhibitors of protein kinase A and its preparation method and application. Background technique [0002] Pancreatic cancer is a relatively common malignant tumor of the digestive tract, and its incidence rate accounts for 2.1% of all malignant tumors, which is significantly higher in developed areas, while the incidence rate in underdeveloped areas including China has a clear upward trend with economic development. At present, surgical resection is the only possible cure for pancreatic cancer, but early diagnosis of pancreatic cancer is difficult. Only less than 20% of patients can undergo radical resection when pancreatic cancer is found, and most patients relapse after surgery. The 5-year survival rate is only 6%, seriously affecting human health. Therefore, early diagnosis and accurate staging are effective means to improve the curative effect of...

Claims

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Application Information

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IPC IPC(8): C07D217/02A61P35/00
CPCA61P35/00C07D217/02
Inventor 李方霍力党永红李詝靳晓娜刘宇赵周社李宏利
Owner PEKING UNION MEDICAL COLLEGE HOSPITAL CHINESE ACAD OF MEDICAL SCI
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