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Indirubin-derived degradation agent as well as preparation and application thereof

A degrading agent, indirubin technology, applied in the preparation method of peptides, medical preparations containing active ingredients, anti-inflammatory agents, etc., can solve the problems of staying, poor effect, inactivation and so on

Active Publication Date: 2021-07-06
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Indirubin has been proven to have biological activities, such as anti-leukemia, anti-tumor, anti-virus, anti-inflammatory, antibacterial effects, such as: "Synthesis and Research Progress of Indirubin and Its Derivatives" reported: There are studies in 5 , The introduction of an ester group at the 5′ position significantly improved the inhibitory activity of indirubin derivatives on GSK-3 kinase; some studies also found that the inhibitory activity of 5-substituted indirubin derivatives on CDK1, CDK5, GSK-3, etc., the inhibitory effect Significant, but the effect of introducing a methyl group at the N1 position is relatively poor; in other studies, it was found that when the 7-position of indirubin is substituted with bromine and the 5'-position is a carboxylic acid group, indirubin has no effect on DRYK ( Dual-specificity tyrosine phosphorylation-regulated kinases, involved in neuropathology such as AD and Down's syndrome) Kinases exhibit effective selective inhibition, etc., but the article also clearly records that "only 5, 3', 4' , The 5' position is easy to replace, and the substitution at the 1, 6, 7, 6', 7' position will lead to inactivation... Because of the difficulty of synthesis, the modification of indirubin mostly stays at the 3' position, 5 position, etc. The substituting group is also relatively simple”, therefore, most reports in the prior art are that indirubin or its related derivatives inhibit or improve the enzyme activity, but no indirubin or its related derivatives degrade HDAC6 to report

Method used

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  • Indirubin-derived degradation agent as well as preparation and application thereof
  • Indirubin-derived degradation agent as well as preparation and application thereof
  • Indirubin-derived degradation agent as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The degradation agent IP1-5 derived from indirubin has a structural formula of:

[0054]

[0055] The synthetic method of the degradation agent derived from indirubin comprises the steps:

[0056] Step a: Add indirubin and hydroxylamine hydrochloride into a flask, add pyridine to dissolve, heat to reflux for 4 hours, wash with 2N hydrochloric acid, and filter to obtain product 1.

[0057] Step b: Add indirubin-3'-oxime to the flask, dissolve in ethanol, add methyl bromobutyrate, add tetramethylguanidine, heat to reflux for 2 hours, dilute with water and 1N hydrochloric acid, filter to take the filter residue, and wash with water Filter residue is dried to obtain product 2;

[0058] Step c: Dissolve the product 2 of step b with propyne bromide, cesium carbonate, and potassium iodide in DMF, stir at room temperature, and react for 0.5-1h. After the reaction is completed, add 2-3 times of water to quench the reaction, extract with DCM, and saturated saline After washi...

Embodiment 2

[0073] The degradation agent V1 derived from indirubin has a structural formula of:

[0074]

[0075] The preparation method of the above-mentioned indirubin-derived degradation agent is based on Example 1, replacing the thalidomide E3 ligase ligand (4-position substitution) with the VHL E3 ligase ligand in step g (as shown in route 6, containing azide compounds); while limiting the length n of azide-PEG-carboxylic acid to be 1.

[0076] Compound V1 13 C-NMR, 1 H-NMR and HR-MS data

[0077] Compound V1: 1 H NMR (400MHz, DMSO-d 6 )δppm: 11.66(s, 1H), 10.37(s, 1H), 9.07(s, 1H), 8.87(d, J=7.7Hz, 1H), 8.74(s, 1H), 8.13(d, J=7.7 Hz,1H),7.97(s,1H),7.80-7.55(m,5H),7.47–6.96(m,5H),6.88(s,1H),6.48(t,J=5.5Hz,1H),5.52 (s,1H),5.11(s,2H),5.04(dd,J=12.4,5.3Hz,1H),4.61(t,J=6.0Hz,2H),4.49(t,J=5.1Hz,2H) ,4.40(m,3H),3.82(t,J=5.1Hz,2H),3.55(t,J=5.3Hz,2H),3.51-3.41(m,2H),3.35(d,J=5.5Hz, 2H), 3.27(s, 1H), 2.34-2.32(m, 2H), 2.20(d, J=14.2Hz, 2H), 2.22(s, 3H), 2.18–2.12(m, 2H), 0.94(s ,9...

Embodiment 3

[0079] Indirubin-derived degradation agent P1, whose structure is

[0080]

[0081] The preparation method of the above-mentioned indirubin-derived degradation agent is based on Example 1, and the thalidomide E3 ligase ligand (4-position substitution) is replaced by the thalidomide E3 ligase ligand in step g. Enzyme ligand (5-position substitution) (as shown in Scheme 5, containing azide compound); at the same time, the length n of azide-PEG-carboxylic acid is limited to 1.

[0082] Compound P1 13 C-NMR, 1 H-NMR and HR-MS data

[0083] Compound P1: 1 H NMR (400MHz, DMSO-d 6 )δppm: 11.71(s, 1H), 11.09(s, 1H), 10.46(s, 1H), 8.73(s, 1H), 8.63(d, J=7.6Hz, 1H), 8.12(d, J=7.4 Hz,1H),8.00(s,1H),7.56–7.49(m,1H),7.42(dd,J=13.4,7.5Hz,2H),7.21–7.10(m,3H),7.07–6.99(m, 3H),6.52(s,1H),5.11(s,2H),5.06(d,J=7.3Hz,1H),4.59(s,2H),4.49(s,2H),3.79(s,2H), 3.51(s, 4H), 2.87(s, 1H), 2.57(d, J=15.2Hz, 2H), 2.23–2.09(m, 4H), 2.03(s, 1H).13C NMR (100MHz, DMSO-d6 )δppm:172.57,170.84,169.84,168...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an indirubin-derived degradation agent and preparation and application thereof. The indirubin-derived degradation agent prepared through the method can degrade HDAC6 in a targeted mode, so that application in preparation of HDAC6 degradation agents or anti-inflammatory drugs is achieved. The indirubin-derived degradation agent has low toxicity and excellent anti-inflammatory activity, and the quality and the safety of products are ensured.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an indirubin-derived degradation agent and its preparation and application. Background technique [0002] Histone deacetylase 6 (HDAC6) belongs to a type IIb histone deacetylase (HDAC) with zinc-dependent deacetylase activity and mainly functions in the cytoplasm. Due to the unique structure of two catalytic domains (CD1 and CD2) and a ubiquitin-binding zinc finger domain (BUZ), HDAC6, as an important regulator, plays an important role in various biological functions and It is closely related to various human diseases such as cancer, neurodegenerative diseases, autoimmune diseases, and inflammatory diseases. Studies have shown that HDAC6 can regulate many substrates such as α-tubulin, Hsp90, cortactin, peroxiredoxin, HSF-1, Ku70, etc. through sirtuin activity. On the other hand, the BUZ of HDAC6 can not only directly bind to DNA to participate in the reg...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07K5/062C07K1/02A61K38/05A61K31/454A61P29/00C12P17/16
CPCC07D401/14A61K31/454A61P29/00C07K5/06034C12P17/16A61K38/00Y02P20/55
Inventor 何彬曹灼贤赵永龙李燕刘亭李勇军
Owner GUIZHOU MEDICAL UNIV