nqo1 activated 6-diazo-5-oxo-l-norleucine prodrug and its preparation method and application

A norleucine, diazo group technology, applied in the field of medicinal chemistry, can solve the problems of limited application, gastrointestinal side effects, uneven biological distribution, etc.

Active Publication Date: 2022-05-10
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

6-diazo-5-oxo-L-norleucine (DON), as a substrate-competitive inhibitor of GLS1, exhibits excellent antitumor activity clinically, but there are serious gastrointestinal side effects due to DON , limiting its further clinical application
Clinical data show that the biodistribution of DON in the body is not uniform, which will cause serious gastrointestinal side effects, thus limiting clinical use

Method used

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  • nqo1 activated 6-diazo-5-oxo-l-norleucine prodrug and its preparation method and application
  • nqo1 activated 6-diazo-5-oxo-l-norleucine prodrug and its preparation method and application
  • nqo1 activated 6-diazo-5-oxo-l-norleucine prodrug and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Compound (S)-6-diazo-2-(3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-diene-1- Synthesis of ethyl)butanylamino)-5-oxohexanoate (LJR-201)

[0084] Dissolve compound 3e (1g, 3.99mmol) in DCM, add HATU (1.78g, 4.69mmol), DIPEA (1.83 g, 14.08mmol), stir at room temperature (26°C) for 0.5 hours, then slowly add compound 5a (0.80g , 4.0 mmol), after stirring at room temperature for 4 hours, the solvent was evaporated under reduced pressure, separated and purified by column chromatography (PE:EA=3:1) to obtain a light yellow solid LRJ-201 (1.07g). Yield 62%. mp=107-109°C. 1 H NMR (300MHz, CDCl 3 ):δ=6.28(d,1H,J=6.0Hz), 5.30-5.26(m,1H),4.47-4.40(m,1H),4.18-4.11(m,2H),2.83(s,2H), 2.36-2.33(m,2H),2.11(s,3H),1.95(d,6H,J=6.0Hz),1.42(s,6H),1.26(t,3H,J=6.0Hz)ppm. 13 CNMR (75MHz, CDCl 3 ):δ=193.74,191.11,187.56,171.90,171.68,153.05,143.42,137.99,137.88,125.23,69.2, 66.2,61.62,51.59,48.96,38.28,36.49,28.92,28.80,14.11,12.70,12.13ppm.HRMS (ESI + ): m / z [M+H] + calcd for C ...

Embodiment 2

[0086] Compound (S)-6-diazo-2-(3-(4,5-dimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)-3-methyl Synthesis of ethyl butyramide-5-oxohexanoate (LJR-202)

[0087] Dissolve compound 3f (0.94g, 3.99mmol) in DCM, add HATU (1.78g, 4.69mmol), DIPEA (1.83g, 14.08mmol), stir at room temperature (26°C) for 0.5 hours, then slowly add compound 5a (0.80 g, 4.0mmol), stirred at room temperature (26°C) for 4 hours, evaporated the solvent under reduced pressure, separated and purified by column chromatography (PE:EA=1:1) to obtain a yellow solid LJR-202 (0.85g), yield 51 %. 1 H NMR (300MHz, CDCl 3 )δ=6.48(s,1H),6.23(d,1H,J=9.0Hz),5.24(s,1H),4.44-4.37(m,1H),4.17-4.10(m,2H),2.86-2.73 (m,2H),2.36-2.31(m,2H),2.13(s,1H),2.04-1.98(m,7H),1.61(s,6H),1.32-1.24(m,3H)ppm.HRMS( ESI + ):m / z[M+H] + calcd for C 21 h 28 N 3 o 6 + , 418.1973; found. 418.1965.

Embodiment 3

[0089] Compound (S)-2-(3-(5-bromo-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)-3-methylbutane Synthesis of ethyl amido)-6-diazo-5-oxohexanoate (LJR-203)

[0090] Dissolve compound 3g (1.25g, 3.99mmol) in DCM, add EDCI (0.89g, 4.69mmol), HOBT (0.62g, 4.69mmol), stir at room temperature (26°C) for 0.5 hours, then slowly add compound 5a (0.80 g, 4.0mmol), stirred at room temperature (26°C) for 3 hours, evaporated the solvent under reduced pressure, separated and purified by column chromatography (PE:EA=3:1) to obtain a brown solid LJR-203 (0.66g), and the yield was 33%. mp=115-117°C. 1 H NMR (300MHz, CDCl 3 ):δ=6.27(d,1H,J=9.0Hz),5.31(d,1H,J=6.0Hz),4.49-4.42(m,1H),4.19-4.12(m,2H),3.14-3.09( m,1H),2.80 (s,1H),2.70-2.65(m,1H),2.37-2.34(m,2H),2.16(s,6H),2.04-1.94(m,2H),1.44(d, 6H,J=9.0Hz),1.27-1.25(m,3H)ppm. 13 C NMR (75MHz, CDCl 3 ):δ=193.95,184.70,182.46,171.72, 171.68,153.86,143.74,138.09,137.03,136.52,61.66,55.18,51.66,49.01,38.82,36.6,28.90, 27.10,16.68,14.44,14.11ppm....

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Abstract

The invention discloses an NQO1 activated 6-diazo-5-oxo-L-norleucine prodrug, a preparation method and application thereof. Since NQO1 is highly expressed in most tumor cells, the introduction of NQO1-activated quinonic acid groups can achieve tumor targeting, and can efficiently and quickly release DON prodrugs in tumor cells to achieve the purpose of inhibiting tumor growth. The prodrug shows a high affinity for NQO1, and can rapidly and efficiently release the glutamine metabolism antagonist DON in tumor cells with high NQO1 expression, thereby reducing the toxic and side effects of the drug and improving the target for tumor therapy. It provides a new idea for the development of anticancer drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an NQO1-activated 6-diazo-5-oxo-L-norleucine prodrug and its preparation method and application. Background technique [0002] The prodrug approach is a well-established strategy for improving the physicochemical, biopharmaceutical, and pharmacokinetic properties of potential drug molecules. About 5-7% of globally approved drugs are prodrugs. In recent years, NAD(P)H: quinone oxidoreductase 1 (NAD(P)H: Quinone Oxido reductase, NQO1) activating prodrug with benzoquinone and indole quinone as the carrier is known for its good selectivity and high efficiency. The anticancer activity has aroused widespread concern and shows broad application prospects in the field of tumor therapy. The NQO1-activating prodrug consists of a trigger group, an intermediate connecting chain and a pharmacophore. The trigger group determines the affinity between the drug and the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C245/00C07D207/28C07C269/06C07C271/22A61P35/00A61P35/02A61P37/02A61P3/00
CPCC07C245/00C07D207/28C07C269/06A61P35/00A61P35/02A61P37/02A61P3/00C07C2601/14C07C2601/16C07C271/22
Inventor 卞金磊李志裕沈晨任洁李勉陈甜吴红茜邱志霞
Owner CHINA PHARM UNIV
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