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Synthesis method of novel urushiol hydroxamic acid derivatives with HDAC inhibition and antitumor activity

A technology of urushiol-based hydroxamic acid and anti-tumor activity, which is applied in the field of pharmaceutical synthetic chemistry and can solve the problem of lack of zinc ion binding region, a key structural unit of HDAC inhibition.

Inactive Publication Date: 2020-07-24
INST OF CHEM IND OF FOREST PROD CHINESE ACAD OF FORESTRY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Studies have shown that unsaturated urushiol has certain HDAC inhibitory activity, and its structure is similar to that of FDA-approved HDAC inhibitor SAHA, but it still lacks the zinc ion binding region, a key structural unit of HDAC inhibition

Method used

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  • Synthesis method of novel urushiol hydroxamic acid derivatives with HDAC inhibition and antitumor activity
  • Synthesis method of novel urushiol hydroxamic acid derivatives with HDAC inhibition and antitumor activity
  • Synthesis method of novel urushiol hydroxamic acid derivatives with HDAC inhibition and antitumor activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Synthesis of target compound 4

[0061] Dissolve 5.5g of compound S1 in 50mL of acetic acid, cool down to 0°C, add 20mL of concentrated nitric acid under vigorous stirring, add 100mL of water after 6 hours, extract 4 times with ethyl acetate, each time 100mL, combine the organic layers with saturated carbonic acid Wash twice with sodium hydrogen solution, 200 mL each time, and dry with anhydrous magnesium sulfate; evaporate the solvent to dryness under reduced pressure to obtain a light yellow oil, take 2.3 g of it and dissolve it in 100 mL of methanol, put it in an ice-water bath, and add 6.0 g of anhydrous ammonium chloride , slowly add 8.0g of zinc powder, add 100mL of EA and 600mL of PE after reacting for 20min, filter, evaporate the filtrate to dryness, and quickly carry out silica gel column chromatography, elute with PE-EA, PE:EA=5:1, wash Remove the liquid and evaporate the solvent to dryness under reduced pressure to obtain 0.6g of brown oil, dissolve all of it...

Embodiment 2

[0077] Structural identification of target compound 4-11

[0078] use 1 H-NMR, 13 The chemical structures of the synthesized target compounds 4-11 were identified and confirmed by means of C-NMR, ESI-MS, and IR. The physical and chemical properties and spectral data of the eight compounds are shown in Table 1.

[0079] Table 1 Physicochemical constants and spectral data of compounds 4-11

[0080]

[0081]

Embodiment 3

[0083] Molecular docking of target compounds 4-11 with HDAC 2 and HDAC 8

[0084] The present invention uses the GLIDE program to dock the molecules of compound 4-11 with the crystal structure of HDAC 2 (PDB ID: 4LXZ) and the crystal structure of HDAC 8 (PDB ID: 3SFF); The docking effect, the Glide score results show that the docking scores of compound 4-11 and HDAC 2 are -7.627, -8.474, -8.079, -7.035, -7.999, -7.994, -7.655 and -7.788, and the docking scores with HDAC 8 They were -8.218, -9.022, -8.278, -8.269, -8.022, -8.177, -8.524 and -9.635; all 8 compounds could well bind to the active pockets of HDAC 2 and HDAC 8, and the lipids of 8 compounds The chain part occupies the long and narrow channel in the pocket, and the hydroxamic acid group is located at the bottom of the channel, and the hydroxamic acid group can be combined with the Zn at the bottom of the pocket. 2+ Form stable chelation; 8 compounds can form stable hydrogen bond interactions with amino acid residues...

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Abstract

The invention relates to a synthesis method of novel urushiol hydroxamic acid derivatives with HDAC inhibition and antitumor activity. Triene alkyl urushiol is used as a raw material; through etherification reaction, urushiol oxidative polymerization is blocked; diels-Alder reaction, hydrolysis reaction, condensation reaction and the like are carried out, a hydroxamic acid group is introduced intothe tail part of a urushiol alkyl side chain; carbonyl is introduced into the urushiol alkyl chain through reactions such as acylation, Schiman, oxidation, reduction and the like; different pharmacodynamic groups such as F, Cl, amino, sulfanilamide, triazole, benzamido and hydroxyl are introduced into a benzene ring, eight novel urushiol hydroxamic acid derivatives are synthesized, the eight compounds can be well combined with an active pocket of HDAC, and the IC50 value for inhibiting HDAC 2 / 8 and the IC50 value for inhibiting four tumor cells are both lower than or equal to the IC50 value of HDAC inhibitor SAHA approved by FDA. The novel urushiol hydroxamic acid derivatives have good HDAC2 / 8 inhibitory activity and antitumor activity, can be developed into novel urushiol-based HDAC inhibitors used in antitumor drugs, and have extremely high added value.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry, and relates to a synthesis method of a series of novel urushiol-based hydroxamic acid derivatives and their HDAC inhibitory and antitumor activities. Background technique [0002] Urushiol is a natural active ingredient in the secretion of lacquer (Toxicodendron verniciflum (Stokes) F.A.Barkl.), and it is an important forest special product in China. 85% of the lacquer in the world is produced in China. Urushiol is an alkylphenol compound with a catechol structure, and its side chains are C with different degrees of saturation. 15 of alkanes. Urushiol has good anti-tumor biological activity, and it has inhibitory effects on 29 types of tumor cells in 9 organs of the human body. The mechanism of action includes inducing tumor cell apoptosis, inhibiting tumor cell proliferation, inhibiting tumor angiogenesis, inhibiting nuclear transcription factors, Toxicize tumor cell...

Claims

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Application Information

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IPC IPC(8): C07D317/66C07D317/62C07D405/04C07D317/64A61P35/00
CPCC07D317/66C07D317/62C07D405/04C07D317/64A61P35/00
Inventor 王成章周昊
Owner INST OF CHEM IND OF FOREST PROD CHINESE ACAD OF FORESTRY
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