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NQO1 activated 6-diazo-5-oxo-L-n-leucine prodrug as well as preparation method and application thereof

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

Active Publication Date: 2021-10-01
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 severe 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-n-leucine prodrug as well as preparation method and application thereof
  • NQO1 activated 6-diazo-5-oxo-L-n-leucine prodrug as well as preparation method and application thereof
  • NQO1 activated 6-diazo-5-oxo-L-n-leucine prodrug as well as preparation method and application thereof

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 (1.83g, 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 C NMR (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 22 h...

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=193.95,184.70,182.46,171.72,171.68,153.86,143.74,138.09,137.03,136.52,61.66,55.18,51.66,49.01,38.82,36.6,28.90,17.10,146.4MS + ):m / z[M+H] +...

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Abstract

The invention discloses an NQO1 activated type 6-diazo-5-oxo-L-n-leucine prodrug as well as a preparation method and application of thereof. NQO1 is highly expressed in most tumor cells, so a tumor targeting effect can be realized by introducing a quinonyl acid group activated by the NQO1, DON prodrugs can be efficiently and rapidly released in the tumor cells, and the purpose of inhibiting tumor proliferation is achieved. The prodrug shows high affinity to NQO1, and can rapidly, efficiently and directionally release a glutamine metabolism antagonist DON in tumor cells highly expressed by NQO1, so that the toxic and side effects of the drug are reduced, the targeting efficiency of tumor treatment is improved, and a new thought is provided for development of antitumor 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 Applications(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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