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Bifunctional organic compound and preparation method and application thereof

An organic compound, dual-functional technology, applied in the direction of organic chemistry, drug combination, antineoplastic drugs, etc., to achieve the effect of inhibiting the growth of tumor cells

Active Publication Date: 2020-05-05
XIANGYA HOSPITAL CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, there has been no report of small molecular protein degradation targeting chimera with CD147 protein as the target protein

Method used

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  • Bifunctional organic compound and preparation method and application thereof
  • Bifunctional organic compound and preparation method and application thereof
  • Bifunctional organic compound and preparation method and application thereof

Examples

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preparation example Construction

[0054] Further, one embodiment of the present invention provides a preparation method of the above-mentioned bifunctional organic compound, the preparation method comprising the following steps: dehydrating the compound (I-a) with the carboxyl group and the primary amino group, the compound (I-b) and the vitex acetic acid respectively Condensation reaction, to obtain bifunctional organic compounds.

[0055] Among them, the structures of compound (I-a) and compound (I-b) are as follows, wherein R is at least one selected from alkenyl, alkynyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;

[0056] HOOC-R-NH 2 (I-a);

[0057]

[0058] Compound (I-b) (Protein degrader 1 hydrochloride, protein degrader 1 hydrochloride) is a small molecule ligand of Von-Hippel-Lindau (VHL) protein in the E3 ubiquitin ligase complex, which can bind to E3 ubiquitin Ligase specific binding.

[0059] In one of the embodiments, the structure of the above compound (I-a) is...

Embodiment 1

[0090] The structural formula of the bifunctional organic compound 1 is shown below:

[0091]

[0092] The synthesis steps are as follows:

[0093] 1) Dissolve Boc-glycine (21 mg, 0.12 mmol) in 3 mL of dichloromethane, and add 2-(7-benzotriazole oxide)-N, N, N', N'-tetramethylurea hexa Fluorophosphate (HATU, 64 mg, 0.17 mmol), N, N-diisopropylethylamine (59 μL, 0.36 mmol), compound (I-b) (Protein degrader 1 hydrochloride, 56 mg, 0.12 mmol), reacted for 12 hours, filtered Afterwards, the filtrate was spin-dried, and purified by column chromatography (DCM / MeOH volume ratio=20:1) to obtain 37 mg of intermediate 1b. The structure of intermediate 1b is shown below.

[0094]

[0095] The characterization results of intermediate 1b are as follows:

[0096] 1 HNMR (500MHz, CDCl 3 )δ8.68 (s, 1H), 7.37-7.32 (m, 4H), 4.55-4.45 (m, 3H), 4.41-4.36 (m, 1H), 4.02 (d, J=11.1Hz, 1H), 3.83 -3.63(m, 3H), 2.51(s, 3H), 2.35-2.15(m, 2H), 1.49-1.36(m, 13H), 0.97(s, 9H).

[0097] HRMS(ESI...

Embodiment 2

[0104] The structural formula of the bifunctional organic compound 2 is shown below:

[0105]

[0106] The synthesis steps are the same as in Example 1, except that the Boc-glycine in step 1) of Example 1 is converted into compound 2a to obtain intermediate 2b. The structures of compound 2a and intermediate 2b are shown below.

[0107]

[0108] The characterization results of intermediate 2b are as follows.

[0109] 1 H NMR (500MHz, CDCl 3 )δ: 8.69 (s, 1H), 7.43-7.32 (m, 5H), 6.38-6.28 (m, 1H), 4.78-4.67 (m, 2H), 4.62-4.49 (m, 3H), 4.33 (dd, J=15.0, 5.2Hz, 1H), 4.11(d, J=11.2Hz, 1H), 3.60(d, J=10.1Hz, 1H), 3.12-3.01(m, 2H), 2.51(s, 3H), 2.29-2.12(m, 3H), 1.68-1.56(m, 2H), 1.53-1.33(m, 12H), 0.93(s, 9H).

[0110] HRMS (ESI) m / z: calcd for C 32 h 48 N 5 o 6 8(M+H) + :630.3320, found: 630.3326.

[0111] The characterization results of bifunctional organic compound 2 are as follows:

[0112] 1 HNMR (500MHz, CDCl 3 )δ: 8.70 (s, 1H), 7.43-7.33 (m, 5H), 7.23-7.18 ...

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Abstract

The invention relates to a bifunctional organic compound as well as a preparation method and application thereof. The bifunctional organic compound has a structure as shown in a formula (I), wherein Ris selected from at least one of alkenyl, alkynyl, substituted or unsubstituted alkyl or alkoxy; the golden larch bark acetic acid part can be specifically combined with CD147 protein, and the structure of the hydrochloride part of the protein degradation agent 1 can be combined with E3 ubiquitin ligase. The bifunctional organic compound is a small molecular protein degradation targeting chimericbody. When used for degrading the target CD147 protein, the compound can form a target protein-proteolysis targeting chimerate-E3 ubiquitinase ternary complex, then activated ubiquitin is transferredto the target protein, and finally the ubiquitinated target CD147 protein is recognized and degraded by proteasome, so that tumor cell growth is effectively inhibited.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a bifunctional organic compound and its preparation method and application. Background technique [0002] The protein degradation targeting chimera (PROTACs) technology uses the ubiquitin-proteasome system to specifically degrade unnecessary proteins, thereby achieving the effect of treating various diseases. The protein degradation targeting chimera mainly includes three parts: a ligand part that can bind to a target protein, a ligand part that can bind to E3 ubiquitin ligase, and an intermediate connection structure that combines the two parts. Protein degradation targeting chimeras (PROTACs) chimeras act on the target protein and E3 ubiquitin ligase simultaneously, transfer activated ubiquitin to the target protein, realize its selective ubiquitination, and ultimately ubiquitination The target protein is recognized and degraded by the proteasome. This...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/22A61P35/00
CPCA61P35/00C07D471/22
Inventor 龙菁陈翔彭聪周哲唱祺胡高云李乾斌邓广通王媛李雅芸
Owner XIANGYA HOSPITAL CENT SOUTH UNIV
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