Small molecule inhibitor SLD9059 and application thereof in pharmacy

A technology of small molecule inhibitors and drugs, applied in drug combinations, antineoplastic drugs, respiratory diseases, etc., can solve the problems of little effect, low toxicity effect, and insignificant effect of advanced breast cancer

Active Publication Date: 2018-06-15
CHINA THREE GORGES UNIV
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Problems solved by technology

However, in the phase II clinical study, it was found that BENSpm as a single drug has no significant effect on the treatment of advanced breast cancer, and the extended experiment for this study shows that BENSpm has a synergistic effect when used in combination with other conventional chemotherapy drugs
The second-generation spermine analog CPENSpm has

Method used

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  • Small molecule inhibitor SLD9059 and application thereof in pharmacy
  • Small molecule inhibitor SLD9059 and application thereof in pharmacy
  • Small molecule inhibitor SLD9059 and application thereof in pharmacy

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Experimental program
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Effect test

Embodiment Construction

[0034] A small molecule inhibitor SLD4650, the specific structural formula is:

[0035]

[0036] Pharmacophore results

[0037] In the complex structure, a lot of hydrogen bond interactions are formed between Spd and SMO. In order to ensure the rationality of the pharmacophore model, we only kept two pairs of key hydrogen bond characteristic elements. In addition, in order to ensure the diversity of the structure, after analyzing the characteristics of the active pocket, we added a set of hydrogen bond characteristic elements based on acceptor amino acids P1-Ser O. details as follows( figure 1 ): two donor centers - P1-Ser O and P3-Glu O.

[0038] Molecular docking results

[0039] Molecular docking was carried out on the compounds obtained through the above pharmacophore model, and the compounds were combined in the active pocket defined by docking according to the docking energy scoring. figure 2 Map defined as binding mode of SLD9059.

[0040] Effects of small mol...

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Abstract

The invention provides a small molecule inhibitor SLD9059, which has a structural formula shown as the specification. The small molecule inhibitor SLD9059 provided by the invention is applied to preparation of drugs inhibiting spermine oxidase, and the result shows that the SLD9059 can change the growth cycle of human small cell lung cancer A549 cell and change A549 cell cycle protein expression content, and at the same time can induce autophagy of A549 cell.

Description

technical field [0001] The invention provides a small-molecule inhibitor for inhibiting spermine oxidase, and the application of the small-molecule inhibitor in the preparation of drugs for treating tumor diseases. Background technique [0002] Polyamines (putrescine, spermidine, and spermine) are small molecular organic compounds widely present in eukaryotic cells, and participate in important physiological functions such as cell differentiation, proliferation, and gene regulation. Studies have found that high intracellular polyamine content is necessary for the rapid growth of tumor cells, so the polyamine metabolic pathway has gradually become a new target for anti-tumor therapy and drug design. Spermine oxidase (Spermine oxidase, SMO) is a key enzyme involved in the degradation and metabolism of polyamines. This enzyme is a FAD (flavin adenine dinucleotide)-dependent oxidase. Spm) oxidation as its preferred substrate decomposition pathway. The products of this enzyme a...

Claims

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Application Information

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IPC IPC(8): C07D471/08A61P35/00A61P35/04A61P11/00
CPCC07D471/08
Inventor 王艳林杨建林曹春雨孙丽丹
Owner CHINA THREE GORGES UNIV
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