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Wortmannin prodrug as well as preparation and application thereof

A wortmannin and prodrug technology, applied in the field of wortmannin prodrug and preparation, can solve the problems of restricting the development and utilization of wortmannin, enhancing toxicity, reducing stability, etc., so as to improve anti-tumor targeting and reduce dosage Effect

Inactive Publication Date: 2018-12-21
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high reactivity of the C20 site of wortmannin, it is easily attacked by nucleophilic groups in water and other biomacromolecules, resulting in a decrease in its stability in aqueous solution and enhanced toxicity, thus limiting the use of wortmannin. Further Development and Utilization of Manpenicillin

Method used

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  • Wortmannin prodrug as well as preparation and application thereof
  • Wortmannin prodrug as well as preparation and application thereof
  • Wortmannin prodrug as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation of embodiment 1 compound (II-1)

[0035] In a 25mL round-bottomed flask, compound I (10mg, 23μmol) and triethylamine (16μL, 100μmol) were dissolved in 10mL of dichloromethane, then compound III (9mg, 28μmol) was added, stirred at room temperature for 10 hours, and vacuum Drain the solvent, use high-efficiency thickening to prepare thin-layer plates for separation, the developing agent is dichloromethane:methanol:triethylamine with a volume ratio of 20:1:0.1, collect samples with an Rf value of 0.6, and obtain the target compound (II-1 ) (7mg, 43%), see Figure 4 .

[0036] 1 H NMR(500MHz,DMSO)δ8.69(s,1H),8.02(s,1H),6.42(s,1H),6.37(s,1H),5.95(dd,J=7.1,4.6Hz,1H) ,4.31(t,J=6.5Hz,2H),4.14(s,1H),3.64-3.73(m,3H),3.04-3.22(m,8H),2.90-3.04(m,3H),2.75-2.84 (ddd,J=19.5,11.7,5.5Hz,3H),2.53-2.63(m,3H),2.20-2.38(m,5H),1.99-2.09(m,4H),1.76(d,J=13.9Hz ,1H),1.42-1.68(m,8H),1.27-1.40(s,2H),0.78(s,3H).HRMS(ESI):m / z[M+Na] + calcd 763.2989, found: 763.3017.

[0037] ...

Embodiment 2

[0038] Preparation of Example 2 Compound (II-2)

[0039] In a 25mL round-bottomed flask, compound I (10mg, 23μmol) and triethylamine (16μL, 100μmol) were dissolved in 10mL of dichloromethane, compound IV (11mg, 28μmol) was added, stirred at room temperature for 10 hours, and vacuum Drain the solvent, use high-efficiency thickening to prepare thin-layer plates for separation, the developing agent is dichloromethane:methanol:triethylamine with a volume ratio of 12:1:0.1, collect samples with an Rf value of 0.5, and obtain the target product (II-2 ) (10mg, 52%), see Figure 5 .

[0040] 1H NMR(500MHz,DMSO)δ8.48(s,1H),7.81(s,1H),6.44(s,1H),6.36(s,1H),5.95(t,J=5.66Hz,1H),5.04 (t,J=8.92Hz,1H),4.37(d,J=5.5Hz,1H),4.27-4.34(m,1H),4.08-4.19(m,1H),3.44-3.66(m,7H), 3.04-3.20(m,7H),2.91-3.09(m,4H),2.74-2.87(m,3H),2.66(s,1H),2.52-2.62(m,2H),2.42-2.46(m,1H ),2.34(s,2H),2.12-2.27(m,4H),1.86-2.08(m,7H),1.70-1.78(m,2H),1.57-1.65(m,2H),1.42-1.54(m ,7H),1.29-1.41(m,3H),0.75(s,4H).HRMS(ESI):...

Embodiment 3

[0042] Preparation of Example 3 Compound (II-3)

[0043] In a 25 mL round bottom flask, compound I (10 mg, 23 μmol) and triethylamine (16 μL, 100 μmol) were dissolved in 10 mL of dichloromethane, compound V (9 mg, 28 μmol) was added, stirred at room temperature for 10 hours, and vacuum Drain the solvent, and use high-efficiency thickening to prepare thin-layer plates for separation. The developing agent is dichloromethane:methanol:triethylamine with a volume ratio of 10:1:0.1, and samples with an Rf value of 0.23 are collected to obtain the target product (II-3 ) (9mg, 46%), see Figure 6 .

[0044] 1 H NMR (500MHz, DMSO) δ7.98(s, 1H), 7.79(s, 1H), 6.32-6.47(m, 3H), 5.95(dd, J=7.3, 4.5Hz, 1H), 4.30(dd, J=15.4,9.6Hz,2H),4.12(s,2H),3.73(s,1H),3.59(s,2H),2.94-3.19(m,11H),2.71-2.89(m,3H),2.53 -2.63(m,5H),1.93-2.18(m,6H),1.87(s,1H),1.76(dd,J=14.3,4.0Hz,1H),1.18-1.58(m,18H),0.78(s ,3H).HRMS(ESI):m / z[M+Na] + calcd 779.3302, found: 779.3310.

[0045]

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Abstract

The invention discloses a wortmannin prodrug as well as preparation and application thereof. Inhibitors with different sustained release effects are constructed by using wortmannin as matrix and adopting a simple chemical synthesis means. The inhibitors provided by the invention are verified to still maintain the impact effect on a PI3K pathway by means of an in-vitro slow release test, a cancer cell proliferation test and AKT phosphorylation detection, and anti-tumor targeting is improved by utilizing drug slow release and a biotin targeting effect, so that dosage for inhibition of cancer cell proliferation is greatly reduced.

Description

(1) Technical field [0001] The invention relates to a wortmannin prodrug, its preparation method and application. (2) Background technology [0002] Wortmannin, produced from the filamentous fungus penicillium funiculosum, has high inhibitory activity on phosphatidylinositol 3-kinase PI3K, and its half-inhibitory concentration (IC 50 ) is about 5nM, nearly 200 times higher than the conventional inhibitor LY294002. Experiments have proved that the inhibition mechanism is that the 20th carbon atom (C20 site) in the wortmannin structure combines with the side chain amino group of lysine (Lys833) in the catalytic active center of PI3K to form an enamine. At the same time, the hydrogen in the enamine forms a hydrogen bond with the adjacent carbonyl, resulting in a stable six-membered ring structure, resulting in irreversible modification of this site (e.g. figure 1 shown), thereby inhibiting the PI3K and PI3K / Akt signaling pathways, and finally promoting the death of tumor cell...

Claims

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Application Information

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IPC IPC(8): C07J73/00A61P35/00
CPCC07J73/003
Inventor 葛璟燕应莎莎董佳赵成艳
Owner ZHEJIANG UNIV OF TECH
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