Matrix metal protease inhibitor and medicinal use thereof

A kind of use, amino technology, applied in the field of new matrix metalloproteinase inhibitors, can solve the problems of low bioavailability, poor selectivity of hydroxamic acids, etc.

Active Publication Date: 2017-04-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to overcome the defective of prior art, provide novel matrix metalloproteinase inhibitor and its medicinal use; Especially rela

Method used

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  • Matrix metal protease inhibitor and medicinal use thereof
  • Matrix metal protease inhibitor and medicinal use thereof
  • Matrix metal protease inhibitor and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: Synthesis of benzamide ilomastat derivatives

[0019]

[0020] Using the method explored by Liu Keliang et al., using isocaproyl chloride as the starting material to synthesize compound 2 through multiple non-reactions;

[0021] Compound 1: Take a two-necked bottle, N 2 Protect, vacuumize, first add compound 2, stir and dissolve with anhydrous DCM, add EDCI·HCl and DMAP, react for 1 hour, add phenylenediamine substitute, stir overnight, TLC detection (DCM:MeOH=10:1) raw material Whether the reaction is complete. After the reaction was completed, it was concentrated under reduced pressure, extracted with DCM, saturated NaHCO 3 , water, saturated NaCl solution, and the organic layer was anhydrous NaSO 4 Dry, concentrate, and purify on a silica gel column (DCM:MeOH=30:1-15:1) to obtain the target compound (1a-1h) in powder form.

[0022] N-Deshydroxy-N-(2-aminophenyl)ilomastat (1a)

[0023] White powder, yield 36.23%. 1 H NMR (400MHz, CD 3 OD) δppm: 7....

Embodiment 2

[0038] Example 2: Inhibition of benzamide ilomastat derivatives on MMP-2 and MMP-9

[0039] A fluorescent drug detection kit was used to screen the inhibitory activity of the synthesized compounds on MMP-2 and MMP-9. In this method, a quenched fluorescent peptide is used to screen the corresponding inhibitors. MMP-2 Fluorescent Drug Kit (BML-AK409-0001) and MMP-9 Fluorescent Drug Kit (BML-AK411-0001) (purchased from Enzo Life Sciences company), the screening principle of the kit: quenched fluorescent polypeptide substrate OmniMMP TM fluorgenic substrate Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2 [Mca=(7-methoxycoumarin-4-yl)-acetyl; Dpa=N-3-(2,4-dinitrophenyl)-L-α-β-diaminopropionyl]; the fluorescence properties of Mca can be inhibited by the Dpa group, but MMPs can break the quenched fluorescent polypeptide into two chains at Gly-Leu, so that the fluorescence of Mca can be visualized, and then the screening of MMPI inhibitors can be carried out;

[0040] Pretreatment: first tha...

Embodiment 3

[0047] Embodiment 3: the mensuration of the fat-water partition coefficient logP of compound 1a

[0048] Take 20ml of water and 20ml of n-octanol in Erlenmeyer flasks with stoppers (3 copies for each group), vortex for 5min, shake at room temperature for 24h, place in a separating funnel, let stand for 24h, separate the liquid, and take Add about 1.15mg E-1 (1.83mg Ilomastat) to 1ml of the upper layer (saturated n-octanol layer) (so that the concentration of the drug in both n-octanol and aqueous phases is less than 0.01mol / l), and vortex for 5min. Mix with 1ml of n-octanol-saturated aqueous phase, vortex for 5min, shake at room temperature for 24h, centrifuge at 3500rpm for 15min, take 100μL respectively in the sample tube, in 30% acetonitrile + 1% TFA (Ilomastat: 25% acetonitrile + 1% TFA ) under HPLC analysis. Measured: 1a: logP=1.912±0.006; and Ilomastat: logP=1.036±0.005, the results show that benzamide analogue 1a has certain druggability.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a novel matrix metal protease inhibitor and medicinal use thereof. The inhibitor is benzamide ilomastat derivative as shown in a formula (1) defined in the description, wherein R1 includes but is not limited to 2-NH2, an amino group is substituted with an acetyl amino group, R2 includes but is not limited to aromatic groups such as hydrogen atoms, fluorine, chlorine, bromine, a methyl group, an ethyl group, NH2, substituted amino, a methoxyl group, an ethoxy group, a trifluoromethyl group, a cyclohexyl group, a phenyl group, substituted phenyl, thiophene, pyrrole, furan, thiazole and pyridine, and the substituted phenyl of R2 includes but is not limited to radical groups such as a methyl group, an ethyl group, a methoxyl group, an ethoxy group, a trifluoromethyl group, a hydroxyl group, fluorine, chlorine, bromine, an acetyl group and benzophenone connected with 4' position of a benzene ring. Experiments show that the benzamide ilomastat derivative can be used for preparing drugs for resisting invasion and diffusion of tumors such as a liver cancer, a lung cancer, a breast cancer and an ovarian cancer.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and medicine, and in particular relates to a novel matrix metalloproteinase inhibitor and its medicinal use. Background technique [0002] Malignant tumors are currently one of the main causes of threats to human health and death. According to the 2014 World Cancer Report, the number of cancer cases in China in 2012 was 3.065 million, accounting for about one-fifth of the global incidence; the number of cancer deaths was 2.205 million, accounting for about one-quarter of the global cancer deaths. According to statistics, tumor cell metastasis is currently the main cause of death of patients, accounting for more than 95% of cancer deaths. Studies have shown that tumor metastasis is a complex and multi-stage process, one of which is the ability of tumor cells to infiltrate and migrate, and this process requires the participation of extracellular matrix metalloproteinases MMPs. Matrix m...

Claims

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Application Information

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IPC IPC(8): C07D209/20A61K31/405A61P35/00A61P9/10A61P29/00A61P11/06A61P11/00
Inventor 孙逊宋姣彭鹏昌军
Owner FUDAN UNIV
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