Antineoplastic compounds and pharmaceutical compositions thereof

一种化合物、底物的技术，应用在抗肿瘤药、药物组合、周期表第5/15族元素的化合物等方向，能够解决降低体内稳定性、不能渗透、不容易转运等问题

Inactive Publication Date: 2008-06-18
CENT DE ING GENETICA & BIOTECNOLOGIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the peptides described in such reports have the limitation of being impermeable into cells by themselves, thus requiring membrane-permeable peptides fused to them
In general, when compared with small molecules, the use of peptides has the disadvantages of reduced in vivo stability during circulation, degradation, difficult formulation into oral dosage forms and they are not easily transported intracellularly (Ludger Wess, Isogenica : Improving peptides, Biocentury October 25, 2004)
Other problems with peptides widely described in this literature are rapid clearance, their immunogenic potential, and their known cost per therapeutic dose is generally superior to that of non-peptide drugs

Method used

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  • Antineoplastic compounds and pharmaceutical compositions thereof
  • Antineoplastic compounds and pharmaceutical compositions thereof
  • Antineoplastic compounds and pharmaceutical compositions thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0194] Example 1: Compound selection by in silico molecular modeling

[0195] Several compounds were selected based on the higher values ​​of the calculated binding energies of the receptor-ligand complexes (Table 1 ) by using a computational model developed from an extensive and substantial screen. This approximate energy value was estimated taking into account a comprehensive analysis of the conformation and several high-energy components using a computational program developed in our laboratory.

[0196] Table 1: Calculated interaction energies for receptor-ligand complexes

[0197] compound

Embodiment 2

[0198] Example 2: Effect of the Compounds on Phosphorylation of Typical CK2 Substrates

[0199]The assay involves performing an in vitro phosphorylation reaction using oncoprotein E7 derived from human papillomavirus type 16 (VHP-16), which acts as a glutathione S-transferase (GST) in Escherichia coli, as a substrate. Fusion protein expression. The resulting E7-GST was then purified by glutathione-agarose (Pharmacia) affinity chromatography. Before the enzymatic reaction, E7-GST was pre-incubated for 1 hour at 37°C, where different concentrations of compounds were used. The reaction was prepared by 50μl Tris: HCL 25mM pH 7.5 buffer, 1μCi 32 P-γATP, 100 μM ATP, 40 μl of resin containing E7-GST, 0.2M NaCl, 10 mM MgCl and 1 unit of CK2 enzyme (Promega) were carried out at 37°C for 40 minutes. After the reaction, the resin was washed 3 times with 0.5 ml of reaction buffer and finally the phosphorylation level of E7-GST was analyzed in 10% polyacrylamide gel electrophoresis (PAG...

Embodiment 3

[0203] Example 3: Effects of the Compounds on Phosphorylation of the CK2 Consensus Site

[0204] This assay involves performing an in vitro phosphorylation reaction using as a substrate the sequence RRREEETEEE, which is generally recognized as the optimal consensus phosphorylation domain for CK2 substrates.

[0205] The substrate peptides were pre-incubated for 1 hour at 37°C prior to the enzymatic reaction, using different concentrations of compounds. The reaction was prepared by 50μl Tris: HCL 25mM pH7.5 buffer, 1μCi 32 P-γATP, 100 μM ATP, 40 μl of E7-GST-containing resin, 0.2 M NaCl, 10 mM MgCl and 1 unit of CK2 enzyme (Promega) were incubated at 37°C for 10 minutes. After the reaction, 5 μl of the reaction mixture was spread on Whatmann PE-81 filter paper and washed with 10 mM H 3 PO 4 After washing four times, the filter-associated radioactivity was finally measured and the cpm values ​​of each sample were directly related to CK2 enzymatic activity.

[0206] IC50 valu...

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PUM

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Abstract

The invention relates to chemical compounds which are obtained by means of in silico molecular modelling and which have a structure that can be used to block phosphorylation by interacting said compounds with the phosphorylation domain or the environment thereof in the substrates of the Casein Kinase II enzyme. The invention also relates to pharmaceutical compositions that contain said compounds and to the use thereof in the preparation of medicaments for the treatment of diseases associated with neoplastic processes.

Description

field of invention [0001] The present invention can be described in the field of molecular pharmacology, in particular in relation to oncology, and more specifically in relation to compounds obtained by in silico molecular modeling based on the fact that they, through direct or indirect interactions, block casein The ability of the phosphate acceptance site on the Kinase 2 substrate has obvious cytotoxic and antitumor effects. Background technique [0002] Casein kinase 2 (CK2) is a serine / threoninase involved in the increase of cell proliferation, and its main intracellular location is the nucleus during malignant transformation (Tawfic S., Yu S., Wang H. et al. (2001) Protein kinase CK2 signal in neoplasia. Histol. Histopathol. 16:573-582). In addition, some viral proteins critical to HIV and HCV have been reported as CK2 substrates (Meggio F., Marin O. et al. (2001) Mol Cell Biochem 227:145-151; Franck N., Le Seyec J. et al. (2005) Hepatitis C virus NS2 proteinis phosph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/22C07D487/04C07D239/42C07D239/36C07D233/54C07D235/14C07D215/18C07D213/82C07D207/36C07C237/30C07C327/44C07C313/06C07C275/36C07C275/22C07C275/18
CPCC07C257/14C07C211/14C07C275/24C07D239/46C07C237/06C07D233/88C07C271/64C07C237/22C07D213/81C07D235/14C07C327/42C07C275/08C07C243/28C07D251/22C07D213/82C07D207/34C07C255/42C07D215/46C07D307/52C07D233/91C07C317/28C07F9/224C07C271/22C07C281/12C07C275/16C07D487/04C07D209/14C07D239/54C07D239/36C07C337/08A61P35/00A61P43/00A61K31/132A61K31/13C07D237/30
Inventor R·E·罗德里格斯费尔南德斯R·薇拉阿尔瓦雷斯A·德拉努埃斯弗乌莱斯Y·马佐洛雷耶斯S·E·佩莱亚罗德里格斯B·E·阿塞韦多卡斯特罗A·穆萨基奥拉萨R·乌维塔戈麦斯
Owner CENT DE ING GENETICA & BIOTECNOLOGIA
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