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Mcl-1 small-molecule fluorescent probe and preparation method and application thereof

A fluorescent probe, mcl-1 technology, applied in the field of medicine, can solve the problems of large fluorescence background interference, poor selectivity, low sensitivity, etc., and achieve the effects of simple post-processing process, fast reaction time and strong specificity

Active Publication Date: 2020-06-05
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the number of current Mcl-1 protein fluorescent probes is very small, and there are problems such as poor selectivity, low sensitivity, and large fluorescence background interference. Therefore, it is very meaningful to develop new small molecule fluorescent probes for Mcl-1 protein

Method used

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  • Mcl-1 small-molecule fluorescent probe and preparation method and application thereof
  • Mcl-1 small-molecule fluorescent probe and preparation method and application thereof
  • Mcl-1 small-molecule fluorescent probe and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Preparation of 5-(dimethylamino)-N-(4-hydroxynaphthalene-1-yl)naphthalene-1-sulfonamide (3)

[0037] After adding 20mL of dichloromethane in the round bottom flask, under ice bath condition, add 4-amino-1-naphthol (0.39g, 2mmol) in the flask, drop triethylamine solution (0.42ml, 3mol) to make it dissolve . Add dansyl chloride (0.59g, 2.2mml) spoon by spoon, remove the ice bath, and react in a water bath at 35°C for 5h. After the reaction was completed, triethylamine was removed by washing with water, dried, filtered and spin-dried to obtain a reddish-brown solid 5-(dimethylamino)-N-(4 -Hydroxynaphthalene-1-yl)naphthalene-1-sulfonamide, the yield is 83%, mp: 216-218°C.

[0038]1H NMR (400MHz, DMSO) 8.48(d, J=8.6Hz, 1H), 8.39(d, J=8.5Hz, 1H), 8.00(d, J=8.3Hz, 1H), 7.86(d, J=7.2 Hz,1H),7.74(d,J=8.4Hz,1H),7.61(t,J=8.1Hz,1H),7.48–7.41(m,1H),7.32(t,J=7.6Hz,1H), 7.26(d, J=7.5Hz, 1H), 7.19(t, J=7.6Hz, 1H), 6.75(d, J=8.1Hz, 1H), 6.61(d, J=8.1Hz, 1H), 2.82( s,6...

Embodiment 2

[0039] Example 2: Preparation of 5-(dimethylamino)-N-(4-oxaphthalene-1(4H)-alkylene)naphthalene-1-sulfonamide (4)

[0040] Add sodium periodate (0.82g, 3.84mmol) into a round bottom flask, add water to dissolve, then add silicon dioxide (4.11g, 19.2mol) and stir for 8h, filter and dry. Add ethyl acetate in the round bottom flask, under the oil bath condition of 50 ℃, add compound 3 (1g, 2.56mmol) thereinto, then add the silicon dioxide dispersed phase (4.93g, 4.93g, 3.84mmol) was stirred for 6h. After the reaction was completed, it was filtered (dichloromethane: methanol = 20:1 to wash the filter cake) and spin-dried, and then column chromatography (petroleum ether: ethyl acetate = 15:1) gave a red solid 5-(dimethylamino)-N -(4-Oxanaphthalene-1(4H)-alkylene)naphthalene-1-sulfonamide, 20% yield, mp: 125-128°C.

[0041] 1H NMR (400MHz, DMSO) δ8.61(d, J=8.5Hz, 1H), 8.39(d, J=7.2Hz, 1H), 8.31(d, J=10.5Hz, 1H), 8.19(d, J =8.6Hz, 1H), 8.03(d, J=7.5Hz, 1H), 7.90(d, J=7.7Hz, 1H), 8...

Embodiment 3

[0042] Example 3: Preparation of 2-((4-((5-(dimethylamino)naphthalene)-1-sulfonamido)-1-hydroxynaphthalene-2-yl)thioglycolic acid (DNSH)

[0043] Compound 4 5-(dimethylamino)-N-(4-oxaphthalene-1(4H)-alkylene)naphthalene-1-sulfonamide (0.12g, 0.33mmol) was added to a round bottom flask, and N , N-dimethylformamide (10 mL) was dissolved, thioglycolic acid (0.07 g, 0.75 mmol) was added dropwise, and stirred at room temperature for 2 h. After the reaction was completed, a large amount of water was added to quench N,N-dimethylformamide, ethyl acetate was extracted and spin-dried, and then the probe DNSH 2-( (4-((5-(Dimethylamino)naphthalene)-1-sulfonamido)-1-hydroxynaphthalene-2-yl)thioglycolic acid was an off-white solid in 90% yield, mp: 151-153°C.

[0044] 1H NMR (400MHz, DMSO) δ10.22(s, 1H), 10.06(s, 1H), 8.48(d, J=8.6Hz, 1H), 8.39(d, J=8.5Hz, 1H), 8.00(d ,J=8.3Hz,1H),7.86(d,J=7.2Hz,1H),7.74(d,J=8.4Hz,1H),7.61(t,J=8.1Hz,1H),7.48–7.41(m ,1H),7.32(t,J=7.6Hz,1H),7.26(d,J=7.5Hz,...

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Abstract

The invention relates to an Mcl-1 small-molecule fluorescent probe and a preparation method and application thereof. The structure of the compound is as shown in a general formula I in the specification. The probe disclosed by the invention is novel in structure, strong in binding affinity to an Mcl-1 protein, good in fluorescence characteristics, short in reaction time and strong in specificity,and can be used for specifically identifying and quantitatively determining the Mcl-1 protein. The probe disclosed by the invention can realize high-throughput screening of the Mcl-1 protein inhibitorand application of the Mcl-1 protein inhibitor in preparation of a reagent for detecting and inhibiting the Mcl-1 protein. The fluorescent probe provided by the invention can be used for marking tumor cells with high Mcl-1 protein expression. Raw materials of the probe are cheap and easy to obtain, reaction steps are simple, and a post-treatment process is simple and convenient.

Description

technical field [0001] The present invention relates to the field of pharmaceutical technology, in particular to Mcl-1 small molecule fluorescent probes and preparation methods thereof, and applications thereof in specific quantitative detection of Mcl-1 protein, activity screening of Mcl-1 inhibitors, cytotoxicity evaluation and cell imaging . Background technique [0002] Apoptosis (programmed cell death) is a conserved evolutionary cellular process that plays a very important role in embryonic development and tissue homeostasis. The abnormality of apoptosis function can lead to the occurrence of various human diseases, including neurodegenerative diseases, autoimmune diseases and cancers, etc. Therefore, regulating apoptosis by regulating key proteins in the apoptotic pathway may be an effective treatment for cancer. [0003] Apoptosis mainly includes two pathways: exogenous pathway and endogenous mitochondrial pathway. In the mitochondria-mediated endogenous apoptosis...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C319/18C09K11/06G01N21/64
CPCC07C303/36C07C303/38C07C319/18C07C323/52C09K11/06C09K2211/1011C09K2211/1014G01N21/6486C07C311/44
Inventor 方浩李佳杨新颖
Owner SHANDONG UNIV
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