CN105153060B - Shikonin carboxylate derivatives, and synthesis method and application thereof - Google Patents

Shikonin carboxylate derivatives, and synthesis method and application thereof Download PDF

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CN105153060B
CN105153060B CN201510416326.7A CN201510416326A CN105153060B CN 105153060 B CN105153060 B CN 105153060B CN 201510416326 A CN201510416326 A CN 201510416326A CN 105153060 B CN105153060 B CN 105153060B
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杨永华
王小明
王子振
邱寒月
罗越琳
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Nanjing University
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    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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Abstract

The invention belongs to the technical field of chemical pharmacy, and particularly relates to phenyl oxadiazole shikonin carboxylate derivatives and application thereof in tumor inhibition. Corresponding carboxylic acid and shikonin are connected through a synthesis means to obtain corresponding ester derivatives, and in-vitro anti-tumor activity research shows that the phenyl oxadiazole shikonin carboxylic ester derivatives have strong inhibition activity on tumor cell strains.

Description

Shikonin carboxylate derivatives, and synthesis method and application thereof
The invention belongs to the technical field of chemical pharmacy, and particularly relates to preparation of a class of phenyl oxadiazole shikonin carboxylic ester derivatives and application of the class of phenyl oxadiazole shikonin carboxylic ester derivatives in tumor inhibition.
II, secondly: background
Shikonin is a naphthoquinone compound, is a natural product extracted from radix Arnebiae, and has broad-spectrum bioactivity, such as antiinflammatory, antitumor, immunoregulatory, antibacterial and antiviral effects. Recent studies show that it has great potential as a lead in the study of functional molecules that inhibit tumor activity.
Shikonin, Shikonin modulators cell proliferation by inhibition of epidermal growth factor receptor in human epidermoid carcinols, issued to Singh et al, was found to inhibit human epidermal cell proliferation in a time and dose dependent manner, to decrease phosphorylation levels of EGFR, ERK1/2 and tyrosine kinases, to further affect cytoplasmic MAPK signaling pathway, and increase phosphorylation level of JNK. Meanwhile, researchers find that alkannin inhibits the survival of a human osteosarcoma cell line in a dose-dependent and time-dependent mode, induces the generation of ROS, increases the phosphorylation of ERK protein, reduces the expression of Bcl-2 and causes apoptosis.
Kumar, A. et al, investigated the antiproliferative activity of substituted 1, 3, 4-oxadiazole derivatives by inhibiting HIF-1 transduction in EAT cells. The results show good inhibition of EAT activity. Substituted 1, 3, 4-oxadiazole derivatives have potent antiproliferative activity by FACS analysis and a method of decreasing ALP activity. In addition, oxadiazole ring-containing derivatives reduce HIF-1 expression due to nuclear transport.
The shikonin has the disadvantages of potential toxic and side effects, poor solubility and the like, so that the shikonin is difficult to serve as a clinical candidate drug. Based on the above-mentioned disadvantages of shikonin and the 1, 3, 4-oxadiazole derivative, both have strong antiproliferative activity. The subject group carries out structural modification on shikonin, and a lead compound shikonin and oxadiazole ring are connected through an intermediate bridge, so as to obtain the shikonin derivative with high efficiency and low toxicity.
Thirdly, the method comprises the following steps: disclosure of Invention
The invention aims to solve the problem of providing a phenyl oxadiazole shikonin carboxylic ester derivative with a novel structure, a preparation method thereof and application thereof in tumor inhibition.
The structural formula of the phenyloxadiazole shikonin carboxylate derivative is shown as the formula I:
Figure BSA0000119110260000021
Figure BSA0000119110260000031
fourthly, the method comprises the following steps: drawings
FIG. 1 shows the inhibitory activity of shikonin carboxylate derivatives on tumor cells MCF-7
FIG. 2 shows the inhibitory activity of shikonin carboxylate derivatives on tumor cells A549
FIG. 3 shows the inhibitory activity of shikonin carboxylate derivatives on HeLa of tumor cells
Fifthly: Detailed Description
Example one: preparation of shikonin carboxylate derivatives
Under the ice bath condition, shikonin, corresponding carboxylic acid, refined dichloromethane and a catalyst are sequentially added into a 50mL round-bottom flask, TLC detection reaction is completed, and the corresponding shikonin carboxylic ester derivative is obtained through thin-plate chromatography separation.
The physicochemical data for the corresponding compounds are as follows:
compound 1:1H NMR(300MHz，CDCl3)δ12.55(s，1H，-OH)，12.38(s，1H，-OH)，7.87(t，J＝8.2Hz，4H，Ar-H)，7.31(s，1H，Ar-H)，7.29(s，1H，Ar-H)，7.16(s，1H，Ar-H)，5.98(d，J＝1.6Hz，1H，-CH＝C)，5.30(s，1H，-CH)，3.81(s，2H，-CH2)，2.42(d，J＝2.6Hz，3H，-CH3)，2.35(t，J＝7.5Hz，2H，-CH2)，1.65(d，J＝6.1Hz，3H，-CH3)，1.56(s，3H，-CH3).
compound 2:1H NMR(300MHz，CDCl3)δ12.54(d，J＝7.7Hz，1H，-OH)，12.38(s，1H，-OH)，7.92(d，J＝7.9Hz，2H，Ar-H)，7.16(s，3H，Ar-H)，7.07(s，1H，Ar-H)，6.91(s，1H，Ar-H)，6.12(s，1H，-CH＝C)，5.14-5.07(m，1H，-CH)，4.18(s，2H，-CH2)，2.36(t，J＝7.5Hz，2H，-CH2)，1.67(s，3H，-CH3)，1.57(s，3H，-CH3).
compound 3:1H NMR(300MHz，CDCl3)δ12.58(s，1H，-OH)，12.40(s，1H，-OH)，8.00(dd，J＝7.9，1.7Hz，2H，Ar-H)，7.58-7.46(m，3H，Ar-H)，7.18(s，2H，Ar-H)，7.10(d，J＝0.9Hz，1H，Ar-H)，6.14(dd，J＝6.5，5.2Hz，1H，-CH＝C)，5.11(t，J＝7.3Hz，1H，-CH)，4.20(s，2H，-CH2)，2.61(ddd，J＝22.2，14.8，7.9Hz，2H，-CH2)，1.68(s，3H，-CH3)，1.58(s，3H，-CH3).
compound 4:1H NMR(300MHz，CDCl3)δ12.55(d，J＝2.3Hz，1H，-OH)，12.37(d，J＝2.4Hz，1H，-OH)，7.89-7.79(m，2H，Ar-H)，7.67-7.58(m，2H，Ar-H)，7.16(s，2H，Ar-H)，7.06(d，J＝0.9Hz，1H，Ar-H)，6.18-6.05(m，1H，-CH＝C)，5.09(t，J＝7.3Hz，1H，-CH)，4.15(d，J＝12.6Hz，2H，-CH2)，2.74-2.41(m，2H，-CH2)，1.64(d，J＝14.2Hz，3H，-CH3)，1.57(s，3H，-CH3).
compound 5:1H NMR(300MHz，CDCl3)δ12.55(d，J＝3.3Hz，1H，-OH)，12.39(s，1H，-OH)，7.92(dd，J＝11.6，6.1Hz，6H，Ar-H)，7.06(d，J＝9.0Hz，1H，Ar-H)，6.16＝6.06(m，1H，-CH＝C)，5.09(s，1H，-CH)，4.26(q，J＝7.1Hz，2H，-CH2)，2.71-2.45(m，3H，-CH3)，2.40-2.26(m，2H，-CH2)，1.66(s，3H，-CH3)，1.56(s，3H，-CH3).
compound 6:1H NMR(300MHz，CDCl3)δ12.56(s，1H，-OH)，12.39(d，J＝2.3Hz，1H，-OH)，7.88(dd，J＝7.7，1.8Hz，1H，Ar-H)，7.73(dd，J＝7.9，1.2Hz，1H，Ar-H)，7.48-7.36(m，2H，Ar-H)，7.17(s，2H，Ar-H)，7.08(d，J＝0.8Hz，1H，Ar-H)，6.13(dd，J＝6.5，5.3Hz，1H，-CH＝C)，5.10(t，J＝7.3Hz，1H，-CH)，4.19(d，J＝0.6Hz，2H，-CH2)，2.60(ddd，J＝22.7，15.0，8.3Hz，2H，-CH2)，1.68(s，3H，-CH3)，1.57(s，3H，-CH3).
compound 7:1H NMR(300MHz，CDCl3)δ12.56(s，1H，-OH)，12.38(s，1H，-OH)，7.56(d，J＝1.0Hz，1H，Ar-H)，7.53(s，1H，Ar-H)，7.51-7.48(m，1H，Ar-H)，7.44-7.39(m，1H，Ar-H)，7.37(d，J＝7.8Hz，1H，Ar-H)，7.16(s，2H，Ar-H)，6.16-6.06(m，1H，-CH＝C)，5.09(t，J＝7.3Hz，1H，-CH)，4.17(s，2H，-CH2)，3.87(d，J＝2.7Hz，3H，-CH3)，2.74-2.50(m，2H，-CH2)，1.67(s，3H，-CH3)，1.57(s，3H，-CH3).
compound 8:1H NMR(300MHz，CDCl3)δ12.56(s，1H，-OH)，12.39(s，1H，-OH)，7.94(ddd，J＝7.8，3.9，1.9Hz，1H，Ar-H)，7.57-7.34(m，4H，Ar-H)，7.16(s，2H，Ar-H)，6.12(dd，J＝6.6，5.3Hz，1H，-CH＝C)，5.10(t，J＝7.2Hz，1H，-CH)，4.19(s，2H，-CH2)，2.73-2.54(m，2H，-CH2)，1.67(s，3H，-CH3)，1.57(s，3H，-CH3).
compound 9:1H NMR(300MHz，CDCl3)δ12.56(s，1H，-OH)，12.39(s，1H，-OH)，8.00(ddd，J＝9.0，6.4，2.6Hz，1H，Ar-H)，7.53(tdd，J＝8.4，5.0，1.8Hz，1H，Ar-H)，7.32＝7.27(m，1H，Ar-H)，7.24-7.18(m，1H，Ar-H)，7.16(s，2H，Ar-H)，7.07(d，J＝0.8Hz，1H，Ar-H)，6.12(dd，J＝6.4，5.0Hz，1H，-CH＝C)，5.09(t，J＝7.3Hz，1H，-CH)，4.18(s，2H，-CH2)，2.71-2.50(m，2H，-CH2)，1.67(s，3H，-CH3)，1.57(s，3H，-CH3).
compound 10:1H NMR(300MHz，CDCl3)δ12.55(s，1H，-OH)，12.36(s，1H，-OH)，7.17-7.11(m，3H，Ar-H)，7.09(d，J＝2.3Hz，2H，Ar-H)，7.06(d，J＝0.9Hz，1H，Ar-H)，6.17-6.06(m，1H，-CH＝C)，5.15-5.02(m，1H，-CH)，4.16(s，2H，-CH2)，3.84(s，6H，-CH3)，2.72-2.50(m，2H，-CH2)，1.67(s，3H，-CH3)，1.56(s，3H，-CH3).
compound 11:1H NMR(300MHz，CDCl3)δ12.58(d，J＝15.1Hz，1H，-OH)，12.38(s，1H，-OH)，7.91(d，J＝8.6Hz，2H，Ar-H)，7.51-7.40(m，2H，Ar-H)，7.16(s，2H，Ar-H)，7.05(d，J＝9.9Hz，1H，Ar-H)，6.11(dd，J＝6.5，5.1Hz，1H，-CH＝C)，5.09(t，J＝7.2Hz，1H，-CH)，4.17(s，2H，-CH2)，2.71-2.50(m，2H，-CH2)，1.67(s，3H，-CH3)，1.58(d，J＝8.3Hz，3H，-CH3).
compound 12:1H NMR(300MHz，CDCl3)δ12.55(s，1H，-OH)，12.37(d，J＝2.3Hz，1H，-OH)，7.98(ddd，J＝9.7，5.1，2.5Hz，2H，Ar-H)，7.20(td，J＝4.3，1.6Hz，1H，Ar-H)，7.17(q，J＝1.6Hz，1H，Ar-H)，7.15(d，J＝3.2Hz，2H，Ar-H)，7.07(d，J＝0.9Hz，1H，Ar-H)，6.16-6.05(m，1H，-CH＝C)，5.16-5.03(m，1H，-CH)，4.17(s，2H，-CH2)，2.74-2.50(m，2H，-CH2)，1.66(s，3H，-CH3)，1.56(s，3H，-CH3).
compound 13:1H NMR(300MHz，CDCl3)δ12.55(s，1H，-OH)，12.37(d，J＝2.3Hz，1H，-OH)，7.80-7.74(m，1H，Ar-H)，7.71-7.64(m，1H，Ar-H)，7.52-7.42(m，1H，Ar-H)，7.24-7.18(m，1H，Ar-H)，7.18-7.14(m，2H，Ar-H)，7.07(d，J＝0.9Hz，1H，Ar-H)，6.17-6.07(m，1H，-CH＝C)，5.14-5.03(m，1H，-CH)，4.18(s，2H，-CH2)，2.72-2.51(m，2H，-CH2)，1.66(d，J＝4.0Hz，3H，-CH3)，1.57(s，3H，-CH3).
compound 14:1H NMR(300MHz，CDCl3)δ12.55(s，1H，-OH)，12.37(s，1H，-OH)，7.97(dt，J＝7.3，1.6Hz，1H，Ar-H)，7.90-7.83(m，1H，Ar-H)，7.53-7.36(m，2H，Ar-H)，7.15(s，2H，Ar-H)，7.06(d，J＝0.8Hz，1H，Ar-H)，6.16-6.06(m，1H，-CH＝C)，5.14-5.03(m，1H，-CH)，4.18(s，2H，-CH2)，2.71-2.45(m，2H，-CH2)，1.65(d，J＝8.7Hz，3H，-CH3)，1.57(s，3H，-CH3).
compound 15:1H NMR(300MHz，CDCl3)δ12.54(s，1H，-OH)，12.37(s，1H，-OH)，7.54-7.49(m，1H，Ar-H)，7.47(d，J＝1.9Hz，1H，Ar-H)，7.14(s，2H，Ar-H)，7.05(d，J＝0.6Hz，1H，Ar-H)，6.91(d，J＝8.4Hz，1H，Ar-H)，6.12(dd，J＝6.4，5.2Hz，1H，-CH＝C)，5.09(t，J＝7.3Hz，1H，-CH)，4.15(s，2H，-CH2)，3.95(t，J＝2.8Hz，6H，-CH3)，2.72-2.42(m，2H，-CH2)，1.66(s，3H，-CH3)，1.56(s，3H，-CH3).
compound 16:1H NMR(300MHz，CDCl3)δ12.55(s，1H，-OH)，12.38(s，1H，-OH)，7.85(dd，J＝7.6，1.7Hz，1H，Ar-H)，7.48(ddd，J＝9.1，6.4，1.7Hz，1H，Ar-H)，7.16(s，2H，Ar-H)，7.06(s，1H，Ar-H)，7.03(d，J＝0.8Hz，1H，Ar-H)，7.01(d，J＝1.8Hz，1H，Ar-H)，6.12(dd，J＝6.2，5.0Hz，1H，-CH＝C)，5.09(t，J＝7.3Hz，1H，-CH)，4.21-4.12(m，2H，-CH2)，3.94(d，J＝4.7Hz，3H，-CH3)，2.61(ddd，J＝25.1，14.9，6.7Hz，2H，-CH2)，1.66(s，3H，-CH3)，1.56(s，3H，-CH3).
compound 17:1H NMR(300MHz，CDCl3)δ12.56(s，1H，-OH)，12.41(d，J＝2.4Hz，1H，-OH)，7.33(s，1H，Ar-H)，7.31(s，1H，Ar-H)，7.29(s，2H，Ar-H)，7.27(d，J＝3.1Hz，1H，Ar-H)，7.18(s，2H，Ar-H)，7.03(d，J＝0.9Hz，1H，Ar-H)，6.08(dd，J＝7.1，4.8Hz，1H，-CH＝C)，5.06(dd，J＝18.8，11.5Hz，1H，-CH)，4.17(s，2H，-CH2)， 4.09(d，J＝1.1Hz，2H，-CH2)，2.69-2.41(m，2H，-CH2)，1.67(s，3H，-CH3)，1.56(s，3H，-CH3).
example two: application of phenyloxadiazole shikonin carboxylate derivatives in formula I
MCF-7, A549 and Hela cell strains are taken as detection strains, an MTT colorimetric method is taken as a detection method, and the in vitro tumor cell inhibition activity research on the phenyloxadiazole shikonin carboxylic ester derivatives in the formula I shows that the novel structural derivatives have obvious in vitro tumor cell inhibition activity. And compound 15 had the best antitumor activity. The results are shown in figures 1, 2 and 3.
The phenyl oxadiazole shikonin carboxylate derivative can be prepared into antitumor drugs.

Claims (2)

1. A shikonin carboxylic ester derivative has the following structural formula:
Figure FSB0000190514110000011
2. the use of the shikonin carboxylate derivatives as claimed in claim 1 in the preparation of antitumor drugs.
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CN107304193B (en) * 2016-04-22 2022-07-29 南京大学 Shikonin piperazinate derivative and synthesis method and application thereof
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