Isoquinoline compounds capable of inhibiting inhibitor-of-apoptosis proteins and preparation method and application of isoquinoline compounds

A technology of apoptosis-inhibiting proteins and compounds, applied in the field of isoquinoline compounds and their preparation, can solve the problems of inability to inhibit IAP proteins, low bioavailability, and short action time, and achieve broad action objects and pathways and anti-tumor activity The effect of high and small molecular mass

Inactive Publication Date: 2014-08-06
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current protein inhibitors are still easily degraded by proteases, have low bioavailability, short action time and rapid excretion; and most of them can only bind to the BIR3 domain of XIAP, but cannot inhibit other IAPs including cIAPs and survivin protein, limited promotion in the clinic (5)

Method used

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  • Isoquinoline compounds capable of inhibiting inhibitor-of-apoptosis proteins and preparation method and application of isoquinoline compounds
  • Isoquinoline compounds capable of inhibiting inhibitor-of-apoptosis proteins and preparation method and application of isoquinoline compounds
  • Isoquinoline compounds capable of inhibiting inhibitor-of-apoptosis proteins and preparation method and application of isoquinoline compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 CCK-8 method detects cell viability and confirms the compound 1 For ovarian cancer A2780, A2780cisR has an anti-tumor effect, see figure 1 shown. By CCK-8 method, we tested the cell viability of A2780 and A2780cisR cells treated with compound 1. It was found that compound 1 can inhibit the proliferation of ovarian cancer cells, and this inhibitory effect is concentration-dependent. Among them, at a concentration of 10 μg / mL, the tumor inhibition rate of the cells was 69.8%. At the same time, according to the tumor cell growth inhibition curve, the IC50 of compound 1 against A2780 and A2780cisR were 5.9 and 64.4 μg / mL, respectively.

Embodiment 2

[0052] Example 2 Detection of cell apoptosis rate by Ho chest staining to confirm compound 1 It can promote the apoptosis of ovarian cancer SKOV3. See figure 2 shown. The apoptotic ability of ovarian cancer SKOV3 treated with Compound 1 was analyzed by Hochest staining. Among them, compared with the blank control group, the number of apoptotic cells in the ovarian cancer A2780 and A2780cisR cells treated with compound 1 increased, and the number was B01002 (246.3±35.6) and (125.7±34.9) in turn, compared with the blank control group There were statistical differences (P figure 2 It can be seen that many obvious nuclear fragmentation and nuclear pyknosis can be seen in the ovarian cancer cells treated with compound 1.

Embodiment 3

[0053] Example 3 The expression of PARP, Caspase-3, and PCNA was detected by Western Blot, and it was confirmed that compound 1 has the effect of promoting apoptosis and inhibiting proliferation of ovarian cancer SKOV3 cells, see image 3 , Figure 4 shown. Caspase-3 is a key protein in the IAP protein inhibiting apoptosis signaling pathway, so we used Western Blot method to detect the expression of Caspase-3 in each group of tumor tissues, and we also performed the activation of the Caspase cleavage substrate PARP Protein—determination of the expression of cleaved PARP protein. The results showed that the expressions of cleaved PARP and cleaved Caspase-3 were different in each group, and the expression of cleaved PARP and cleaved Caspase-3 in the tumor tissue of the nude mice in the compound 1 group was the highest. In addition, the inhibition of tumor growth by compound 1 was reflected by detecting the expression of PCNA in tumor tissue. The results showed that the express...

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Abstract

The invention belongs to the field of biomedical technology and particularly relates to isoquinoline compounds capable of inhibiting inhibitor-of-apoptosis proteins and a preparation method and an application of the isoquinoline compounds. According to the invention, a series of isoquinoline compounds capable of being interacted with a BIR2 structural domain of an IAP family are designed and synthesized, so that the activities of various IAPs are decreased; on one hand, an inhibition effect of XIAP on Caspase-3 is antagonized, and on the other hand, the ubiquitination of cIAP and degradation of proteasome are promoted and thus the isoquinoline compounds have biological activity against the growth of ovarian cancer. The isoquinoline compounds disclosed by the invention play roles in resisting ovarian cancer and reversing the drug resistance to ovarian cancer by inhibiting IAPs, and the roles can be confirmed by CCK-8 and a large number of experiments, such as in vivo nude mice subcutaneously transplanted tumors experiment. The compounds disclosed by the invention have the advantages of small molecular mass, high oral bioavailability, flexibility in clinical medication and relatively high anti-tumor activity; combined with the BIR2 structural domains of various IAPs, the compounds have broader action objects and action routes, and have more advantages in clinical application.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to an isoquinoline compound for inhibiting apoptosis inhibitory protein, a preparation method and application thereof. Background technique [0002] The apoptotic signaling pathway of tumor cells usually has different degrees of distortion, and they rely on this to maintain their own vitality. One of the ways to escape apoptosis is through the upregulation of inhibitor of apoptosis proteins (IAPs) (1). IAPs are a group of protein families with similar structures and functions, and are endogenous inhibitors of apoptosis (2), mainly including XIAP (X-linked IAP), cIAP1 (cellular inhibitor of apoptosis proteins 1), cIAP2 (cellular inhibitor of apoptosis proteins 2), ML-IAP, survivin, etc. All IAP families have at least one baculovirus IAP repeat (BIR) domain. cIAP1, cIAP2, and XIAP all contain three BIR structures, and their N-terminal BIR1 domains are relatively cons...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P35/00
CPCC07D401/12
Inventor 尧良清陈晨郑旦庆吴劼
Owner FUDAN UNIV
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