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Synthesis and application of an anti-melanoma prodrug activated by a dual bioactive factor cascade

A bioactive factor, anti-melanin technology, applied in the field of organic synthesis, can solve problems such as side effects of melanocytes, and achieve the effect of reducing toxic and side effects

Active Publication Date: 2022-08-09
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although tyrosinase-activating prodrugs have been shown to be selective for melanoma cells, given that certain levels of tyrosinase are also expressed in normal melanocytes, melanoma prodrugs may be activated in normal melanocytes. tyrosinase activation, which has certain side effects on normal melanocytes

Method used

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  • Synthesis and application of an anti-melanoma prodrug activated by a dual bioactive factor cascade
  • Synthesis and application of an anti-melanoma prodrug activated by a dual bioactive factor cascade
  • Synthesis and application of an anti-melanoma prodrug activated by a dual bioactive factor cascade

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]

[0041] Compound 1a (4 mmol) and 7-diethylaminocoumarin aldehyde (4 mmol) were dissolved in DMSO (15 mL), and the mixture was reacted at 120°C. After monitoring the completion of the reaction by TLC chromatography, after the reaction mixture was cooled, the system was poured into an appropriate amount of ice water, then the resulting precipitate was filtered off with suction and washed with water three times, recrystallized with ethanol, and the filtered precipitate was vacuum-dried to obtain the compound 2a as an orange-yellow solid (1.31 g, 62.1% yield). 1H NMR (400MHz, Chloroform-d) δ8.37 (dt, J=8.1, 1.1 Hz, 1H), 7.86–7.78 (m, 2H), 7.60–7.54 (m, 2H), 7.33–7.29 (m, 2H) ),7.23(d,J=8.9Hz,1H),7.00–6.94(m,2H),6.63(dd,J=8.9,2.5Hz,1H),6.55(d,J=2.5Hz,1H),5.95 (s, 1H), 5.17(s, 1H), 4.80(s, 1H), 3.49(q, J=7.1Hz, 4H), 1.29(d, J=11.6Hz, 6H).

[0042]

[0043] In a 100mL double neck bottle, in N 2 Under the atmosphere, bis(pinacol)diboron (9 mmol), KOAc (18 mmol) and co...

Embodiment 2

[0045]

[0046] Compound 1a (4 mmol) and 4-pyridinecarbaldehyde (4 mmol) were dissolved in DMSO (15 mL), and the mixture was reacted at 120 °C to obtain compound 2b as a white solid (1.01 g, yield 64.3%). 1 H NMR (400MHz, DMSO-d 6 )δ8.71–8.61(m,2H),8.24(dd,J=8.0,1.5Hz,1H),7.92(ddd,J=8.5,7.2,1.6Hz,1H),7.75(dd,J=8.3, 1.2Hz, 1H), 7.64 (ddd, J=8.1, 7.2, 1.2Hz, 1H), 7.52–7.38 (m, 4H), 6.98–6.87 (m, 2H), 5.12 (s, 2H). 13 C NMR (101MHz, DMSO-d 6 )δ161.63,154.29,150.32,147.26,142.63,136.32,135.40,131.83,129.11,128.16,127.92,126.96,122.90,121.03,120.76,48.04.ESI-MSm / z, calc for C 20 H 14b rN 3 O + [M+H] + :393.25; found, 393.3.

[0047]

[0048] In a 100mL double neck bottle, in N 2 Under the atmosphere, bis(pinacol)diboron (9 mmol), KOAc (18 mmol) and compound 2b (6 mmol) were dissolved in 35 mL of 1,4-dioxane, the system was evacuated 3 times, and then Pd ( dppf)Cl 2 (0.3 mmol) was added to the system, and the vacuum was evacuated twice, and the mixture was refluxed a...

Embodiment 3

[0052]

[0053] In a 100mL single-neck flask, add 15mL THF and isatoic anhydride (12mmol), stir and dissolve at room temperature, then add 3-bromophenethylamino (12mmol) and triethylamine (12mmol), and react the mixture at room temperature for about 3 hours . Column chromatography (CH 2 Cl 2 ) after purification of the crude product gave compound 1c as a yellow solid (1.766 g, 46.1% yield). 1 H NMR (400MHz, DMSO-d 6 )δ8.26(s,1H),7.46(s,1H),7.40(d,J=7.3Hz,2H),7.26(d,J=5.2Hz,2H),7.12(t,J=7.7Hz, 1H), 6.68(d, J=8.2Hz, 1H), 6.49(t, J=7.5Hz, 1H), 6.33(s, 2H), 3.44(q, J=6.8Hz, 2H), 2.84(t, J=7.2Hz, 2H). 13 C NMR (101MHz, DMSO-d 6 )δ169.36,150.01,143.07,132.03,131.93,130.87,129.41,128.41,128.32,122.07,116.76,115.35,115.01,40.56,35.02.ESI-MS m / z,calcd for C 15 H 15b rN 2 O + [M+Na] + :343.2; found, 343.02

[0054]

[0055] Compound 1c (4 mmol) and 7-diethylaminocoumarin aldehyde (4 mmol) were dissolved in DMSO (15 mL), and the mixture was reacted at 120°C to give comp...

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Abstract

The invention discloses an anti-melanoma prodrug activated by a cascade of dual biological active factors and a synthesis method and application thereof. The structural formula of the anti-melanoma prodrug is wherein R 1 is or n is 1-6, and R is a coumarin substituent or a triphenylphosphine substituent. The anti-melanoma prodrug activated by the cascade of dual bioactive factors of the present invention can be activated by hydrogen peroxide and tyrosinase cascade to generate a product with an o-quinone structure, wherein the prodrug can only be activated in melanoma cells to generate The active center of the drug causes damage to mitochondria, induces mitochondrial dysfunction, and exerts anti-cancer effects, while it has little toxicity to other cells, which minimizes the toxic and side effects of traditional anti-cancer drugs.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to an anti-melanoma prodrug activated by a cascade of dual biological active factors, a synthesis method and application thereof, and has significant tumor suppressing effect on melanoma cells. Background technique [0002] Cancer treatment has always been a major problem in today's society, but traditional anti-cancer chemotherapeutics bring non-negligible side effects to patients due to their non-selectivity to cancer cells, so the development of prodrugs is particularly important. In the design process of prodrug molecules, the most basic of which is the design of small molecule prodrugs, which are favored by scientists due to their simple structure and easy absorption. Therefore, they can be designed to be activated by active molecules that are highly expressed only in the tumor environment. the prodrug. In general, there are two types of prodrug activatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02A61P35/00C07D405/04
CPCC07F5/025A61P35/00C07D405/04
Inventor 黄静李国瑞黄佩玲杨轶
Owner HUNAN UNIV
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