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Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies

A disease, hydrogen atom technique, applied in the field of indole-derived compounds

Active Publication Date: 2014-11-05
CENT NAT DE LA RECHERCHE SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] However, said compound has a flat structure containing 4 loops, which has the disadvantage of being intercalated between DNA bases and thus can cause cytotoxicity

Method used

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  • Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies
  • Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies
  • Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0354] Example 1: Development of IDC16-derived compounds

[0355] The present inventors have demonstrated that the compound IDC16 (BAKKOUR et al., supra, 2007) functionally interacts with the SF2 / ASF complex, thereby helping to block alternative splicing during HIV replication, leading to a reduction in Tat protein production. termination.

[0356] Therefore, it is known that the family of polycyclic indoles to which the compound IDC16 belongs exhibits the properties of DNA intercalators. Such compounds thus present a risk of unwanted side effects.

[0357] The inventors thus attempted to develop new molecules that exhibit activity comparable to IDC16 in inhibiting HIV splicing, but at the same time do not exhibit the characteristics of a DNA intercalator.

[0358] In their original hypothesis, the inventors believed that the 2 polar heterocycles at the 2 ends of compound IDC16 were related to its activity, while the 2 middle rings were less important.

[0359] Based on t...

Embodiment 2

[0363] Embodiment 2: the method for synthesizing the compound of the present invention

[0364] [A1.] A list of compounds used in this study is provided in Table I below.

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413] The synthesis of the compounds described in Table I is illustrated below.

[0414] Synthesis of stilbene (alkene) compounds

[0415]

[0416] 4-Chloropyridine 1 was obtained by neutralizing 4-chloropyridine hydrochloride with 10...

Embodiment 3

[0441] Embodiment 3: according to the selective inhibition of compound of the present invention to HIV-1mRNA ex vivo splicing

[0442] Using the pΔPSP plasmid (JACQUENET et al., J.Biol.Chem., vol.276, p.40464-40475, 2001) of the HIV-1 genome of the provirus containing the deletion of nucleotides 1511-4550, the test was performed in Example 2 Efficacy of the compounds described in . The pΔPSP plasmid contains all HIV-1 splice sites, and the relative use of these different sites is similar to that of the wild-type virus.

[0443] HeLa cells were cultured to 70-80% confluence in RPMI1640 medium (GIBCO) supplemented with fetal bovine serum on 3 cm diameter plates (NUNC). These cells were then transfected with the pΔPSP plasmid as described by JACQUENET et al. (2001).

[0444] HeLa cells transfected with pΔPSP were then treated with different concentrations (1.5 μM or 3 μM) of the compound described in Example 2 or IDC16 as a positive control. Cells transfected with pΔPSP but ...

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Abstract

The present invention relates to a compound of one of the formulas I to XXI; a pharmaceutical composition comprising at least one such compound; and the use of at least one such compound in preparing a drug to treat, in a subject, a genetic disease resulting from at least one splicing anomaly.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of January 12, 2009, an application number of 200980106361.1, and an invention title of "Chemical Molecules Inhibiting the Splicing Mechanism for Treating Diseases Caused by Abnormal Splicing". technical field [0002] This patent application claims priority from French patent application FR08 / 50144 filed January 10, 2008, which is hereby incorporated by reference. [0003] The present invention relates to novel indole-derived compounds for the preparation of compositions useful in the treatment of diseases caused by alterations in the splicing process. Background technique [0004] Certain indole-derived compounds such as ellipticine derivatives and aza-ellipticine derivatives are known as intercalating molecules for correcting dysfunctions in gene expression, especially DNA replication. They have been more specifically described for the treatment of diseas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D213/82C07D213/74C07C237/30A61K31/44A61K31/4439A61K31/165A61P35/00A61P25/28A61P9/10A61P3/10A61P19/10A61P27/02A61P25/24A61P25/16A61P21/00
CPCC07C237/30C07D213/38C07D249/06C07D401/12C07D213/75C07D233/64C07D213/74C07D213/56C07D213/82C07D233/61C07D401/14C07C233/75C07C233/80C07C237/34C07C237/40C07C237/42A61P1/04A61P1/16A61P1/18A61P13/12A61P15/00A61P17/00A61P19/00A61P19/10A61P21/00A61P21/06A61P25/00A61P25/16A61P25/24A61P25/28A61P27/02A61P3/10A61P31/12A61P31/14A61P31/18A61P35/00A61P35/02A61P35/04A61P43/00A61P7/12A61P9/10A61K31/166A61K31/417A61K31/4409A61K31/4406A61K31/4439A61K31/4725A61K31/4192
Inventor J·塔泽D·格里尔森F·马于托-贝茨尔P·鲁
Owner CENT NAT DE LA RECHERCHE SCI
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