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Thiazole derivative and application thereof in restraining dihydroorate dehydrogenase

A technology of drugs and compounds, applied in the application of diseases, the field of synthesis of thiazole derivatives, can solve the problems of toxic side effects, narrow therapeutic window of Brequinar, etc.

Active Publication Date: 2017-06-27
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Brequinar is mainly used for anti-tumor and host rejection caused by organ transplantation, but the therapeutic window of Brequinar is narrow, and when combined with cisplatin or cyclosporine A, there will be more serious side effects, such as leukocytes, thrombocytopenia and mucous membrane Inflammation etc.

Method used

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  • Thiazole derivative and application thereof in restraining dihydroorate dehydrogenase
  • Thiazole derivative and application thereof in restraining dihydroorate dehydrogenase
  • Thiazole derivative and application thereof in restraining dihydroorate dehydrogenase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] 2-Methylthiosemicarbazide(1)

[0080]

[0081] Weigh 2.5g (17.3mmol) of methylhydrazine sulfate in a 250ml single-necked bottle, add 100ml of ethanol, add 1.6g (20.8mmol) of ammonium thiocyanate under stirring, heat to reflux, and react for 72 hours, then cool the reaction solution to After suction filtration at room temperature, the filtrate was spin-dried by silica gel column chromatography (DCM / MeOH=40:1), and the second by-product was separated to obtain 0.63 g of a white powdery solid, with a yield of 34.2%. 1 H NMR (400MHz, DMSO-d 6 ,ppm)δ 7.36(s,2H),4.89(s,2H),3.41(s,3H).GC-MS(EI)calcd for C 2 h 7 N 3 S[M] + 105.0, found 105.0.

[0082] 2-Methyl-1-(2-carboxybenzyl)thiosemicarbazide (2)

[0083]

[0084] Weigh 80mg (0.76mmol) of compound (1) in a 50ml single-necked bottle, add 20ml of ethanol, add o-carboxybenzaldehyde 114mg (0.76mmol) under stirring, heat to reflux, monitor the reaction by TLC until the conversion of raw materials is complete, and coo...

Embodiment 2

[0153] Cultivation and purification of hsDHODH protein

[0154] Cultivation of protein: hsDHODH protein was obtained according to the hsDHODH gene sequence in GenBank according to conventional methods, such as conditions described in Sambrook et al., Molecular Cloning: A Laboratory Guide (NewYork: Cold Spring Harbor Laboratory Press, 1989).

[0155] Transform the recombinant plasmid pET-19b-DHODH with correct sequencing into E.coli BL21(DE3) competent, smear it on the LB plate containing ampicillin and culture it, and randomly pick the strains and inoculate it in the LB medium containing 100μM ampicillin Cultivate overnight at 37°C, 230rpm on a shaker. Inoculate at a ratio of 1:200 in 500 mL of LB medium containing 100 μL of ampicillin for expansion at 37 °C and 230 rpm. When the OD value of the bacteria reached 0.8-1, IPTG was added to the medium to make the final concentration of IPDG 0.5 mM, and the expression was induced overnight at 25°C. The induced bacteria were colle...

Embodiment 3

[0158]Enzyme level activity test of the compound represented by formula Ⅰ

[0159] The principle of enzyme level activity test is: firstly, dihydroorotate (DHO) is oxidatively dehydrogenated under the catalysis of DHODH to generate orotate (Orotate, OA), and at the same time, it is accompanied by the acceptance of flavin mononucleotide (FMN) 2H + and 2e - reduced to reduced flavin mononucleotide (FMNH 2 ); followed by coenzyme Q (C O Q) accept FMNH as hydrogen acceptor 2 electrons and protons are reduced to reduced coenzyme Q (C O QH 2 ), the reduced coenzyme Q transfers electrons to the chromogenic substrate dichloroindophenol sodium salt (DCIP), and finally DCIP is reduced. DCIP has a maximum absorption at 600nm, while the reduced DCIP has no absorption at 600nm. The degree of oxidation of the substrate DHO can be judged according to the weakening degree of absorbance. The degree of oxidation of the substrate DHO per unit time is the initial rate of the enzymatic rea...

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Abstract

The invention relates to a thiazole derivative used as a DHODH restrainer and an application thereof. Specifically, the invention relates to a compound shown as formula I, a drug compound containing the compound shown as formula I and the application of the compound in preparing the drug for treating DHODH mediated diseases or restraining DHODH.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; Specifically, the present invention relates to a novel thiazole derivative and its synthetic method and its use as a dihydroorotate dehydrogenase (Dihydroorotate dehydrogenase, DHODH) inhibitor in the treatment of DHODH-mediated diseases Applications. Background technique [0002] Dihydroorotate dehydrogenase (Dihydroorotate dehydrogenase, DHODH) is an iron-containing flavin-dependent mitochondrial enzyme that catalyzes the fourth step of pyrimidine de novo synthesis, that is, the dehydrogenation of dihydroorotate into orotate , which is the rate-limiting step in the de novo synthesis of pyrimidines. Thus, inhibition of DHODH blocks de novo pyrimidine synthesis. For most organisms, pyrimidine bases can be obtained by de novo synthesis and salvage synthesis. For resting lymphocytes in the human body, the pyrimidine obtained by the salvage synthesis pathway is sufficient to meet their ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/50A61K31/426A61P37/06A61P31/04A61P33/00A61P31/12A61P35/00A61P19/02A61P17/06A61P29/00
CPCC07D277/50
Inventor 李洪林徐玉芳赵振江宋文琳李诗良王佳炜全丽娜徐刘昕王蕊朱丽丽
Owner EAST CHINA UNIV OF SCI & TECH
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