CN107304197B - Shikonin lipoic acid ester derivatives and synthesis method and application thereof - Google Patents

Shikonin lipoic acid ester derivatives and synthesis method and application thereof Download PDF

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CN107304197B
CN107304197B CN201610268160.3A CN201610268160A CN107304197B CN 107304197 B CN107304197 B CN 107304197B CN 201610268160 A CN201610268160 A CN 201610268160A CN 107304197 B CN107304197 B CN 107304197B
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shikonin
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lipoic acid
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CN107304197A (en
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杨永华
王小明
林红燕
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Nanjing University
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Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid

Abstract

The invention belongs to the technical field of chemical pharmacy, and particularly relates to shikonin derivatives and application thereof in tumor inhibition. The corresponding lipoic acid derivatives are connected with the shikonin by a synthesis method to obtain corresponding ester derivatives, and the research on the in vitro anti-tumor activity shows that the shikonin lipoic acid ester derivatives have strong inhibitory activity on tumor cell strains.

Description

Shikonin lipoic acid ester derivatives and synthesis method and application thereof
One, the technical field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of a lithospermum lipoic acid ester derivative and application of the lithospermum lipoic acid ester derivative in preparation of antitumor drugs.
Second, background Art
Shikonin has multiple pharmacological activities, such as sterilization, anti-inflammation, antioxidation, antivirus, anti-tumor, etc. Recent studies have shown that it has great potential as a lead in the study of functional molecules that inhibit tumor cell proliferation. Such as: the article that Yang Fan is equal to SH-7 published in 2006 at p1184-1193 of International Journal of Cancer 119, A New Synthesized Shikonin derivation, external Its patent Anti-tumor Activities as a topoisomerous enzyme Inhibitor (SH-7), shows that Shikonin derivatives modified by Shikonin skeleton have better inhibiting effect on Topoisomerase than Shikonin, and can inhibit the growth of S-180, SMMC-7721, BEL-7402 and PC-3 Cancer cells, which shows that the Shikonin ester has good activity in tumor inhibition.
In the course of years of research, the subject group obtains a plurality of series of shikonin derivatives, and applies for related patents: shikonin fluorine-containing carboxylic ester derivatives, a synthesis method and application thereof (application number: 201110412497.4), shikonin cinnamate derivatives, a synthesis method and application thereof (application number: 201210002020.3), and a plurality of functional molecules with high tumor cell activity inhibition effect are discovered.
Since shikonin has strong toxic and side effects on normal tissues and cells, the structure modification of shikonin is carried out, the anticancer activity is improved, the defects are overcome, and the acquisition of the derivative with high efficiency and low toxicity is a main research subject.
Third, the invention
The invention takes shikonin as an initial raw material and obtains a novel shikonin carboxylic ester derivative through semi-synthesis. The antitumor activity shows that the derivative has obvious inhibition activity on tumor cell strains HepG2, MCF-7 and HeLa, wherein in the HeLa cell activity result, the activity of the compound 1 is optimal, and the IC is IC50The value reaches 1.54 +/-0.17 mu M; in HepG2 cell activity results, Compound 9 activity was optimal, IC50The value reaches 10.69 +/-0.53 mu M; compound 5 Activity is optimal, IC, in MCF-7 cell Activity results50The value reached 4.02. + -. 0.14. mu.M.
The invention aims to solve the problem of providing shikonin carboxylic ester derivatives with novel structures, and a preparation method and application thereof.
The structural formula of the lithospermum lipoic acid ester derivative is shown as a formula I:
Figure GSB0000190264820000021
Figure GSB0000190264820000031
the shikonin carboxylate derivative with the structure of the formula I is a novel structural active functional compound obtained by semi-synthesizing shikonin and corresponding carboxylic acid.
The shikonin carboxylic acid derivative has obvious inhibition activity on HepG2, MCF-7 and HeLa as proved by in vitro tumor cell inhibition activity, wherein the inhibition activity of the compound 1 on HeLa is strongest, and IC is IC50The value reaches 1.54 +/-0.17 mu M, and the details are shown in attached figures 1, 2 and 3. Proved by toxicity experiments, the novel compound has low toxic and side effects on Vero and IC50The values are all more than 85 μ M, and the toxicity of shikonin is high IC50The value was 6.77. mu.M, as detailed in FIG. 4. In addition, cell adhesion experiments prove that the compound 1 can weaken the adhesion capability of HeLa cells, and the details are shown in figure 5.
Compared with the prior art, the invention has the following beneficial effects:
compared with shikonin, the obtained shikonin lipoic acid ester derivatives have obvious tumor cell inhibiting activity, and the inhibiting activity of part of novel compounds on tumor cell strains is obviously superior to that of parent shikonin, and the toxic and side effects are low. Meanwhile, the compound 1 has the most obvious inhibition effect on the proliferation of HeLa cells and can weaken the adhesiveness of the HeLa cells. The research aims to deeply explore the action mechanism of the medicine by means of flow, laser confocal and western blot.
Fourthly, the method comprises the following steps: drawings
FIG. 1 shows the inhibition of HepG2 cell proliferation by Compounds 1-18 and shikonin
FIG. 2 shows the inhibition of MCF-7 cell proliferation by compounds 1-18 and shikonin
FIG. 3 shows the inhibition of HeLa cell proliferation by Compounds 1-18 and shikonin
FIG. 4 shows the inhibition of Vero cell proliferation by Compounds 1-18 and shikonin
FIG. 5 shows that Compound 1 can reduce the adhesion of HeLa to tumor cells
Fifthly: Detailed Description
Example one: preparation of shikonin carboxylate derivatives
Alpha-lipoic acid (1mol) was suspended in water (500ml) and sodium bicarbonate (1mol) was added. The mixture was stirred to give a clear solution. The resulting pale yellow solution was cooled with ice and solid sodium borohydride (2mol) was added in small portions with stirring. The solution was stirred in an ice bath for 30 minutes, then at room temperature for 30 minutes. The cloudy solution was cooled with ice and adjusted to pH 1 with 2M hydrochloric acid, and an oil appeared. The solution was extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure at room temperature to give 6, 8-dimercaptooctanoic acid.
To 6, 8-dimercaptooctanoic acid (1mol) in dichloromethane was added aldehyde (1mol) under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, cooled to-25 ℃, boron trifluoride ether was added, and the reaction was warmed to room temperature, after evaporation of the solvent, the target product was obtained by recrystallization from ethyl acetate and petroleum ether.
Ice bath conditionsThen, shikonin, corresponding lipoic acid derivative, refined dichloromethane and catalyst were sequentially added to a 50mL round-bottomed flask, TLC was performed to detect completion of the reaction, and thin-plate chromatography was performed to separate (V)Ethyl acetate∶VPetroleum ether1: 5) to obtain the corresponding shikonin carboxylic ester derivative.
The physicochemical data for the corresponding compounds are as follows:
compound 1:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)，12.43(s，1H，-OH)，7.45(dd，J＝7.9，1.5Hz，2H，Ar-H)，7.38-7.28(m，3H，Ar-H)，7.18(s，2H，Ar-H)，6.97(s，1H，Ar-H)，6.01(dd，J＝6.5，4.6Hz，1H，-O-CH)，5.16(d，J＝3.0Hz，1H，Ar-CH)，5.10(t，J＝7.2Hz，1H，-C＝CH)，3.11-2.92(m，3H，C-CH2-S，C-CH-S)，2.53-2.33(m，3H，O＝C-CH2-C，C-CH2-C＝C)，2.18(d，J＝15.4Hz，1H，C-CH2-C＝C)，1.68(s，3H，C＝C-CH3)，1.57(s，3H，C＝C-CH3)，1.82-1.41(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)，1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 2:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.53(t，J＝20.6Hz，1H，Ar-H)；7.17(d，J＝7.4Hz，5H，Ar-H)；6.97(s，1H，Ar-H)；6.02(t，1H，-O-CH)；5.30(s，1H，Ar-CH)；5.10(s，1H，-C＝CH)；3.16-2.87(m，3H，C-CH2-S，C-CH-S)；2.54-2.25(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.43(s，3H，Ar-CH3)；2.19(d，J＝14.0Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.80-1.39(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.26(s，1H，C-C-C-CH2-C-C-C-C).
compound 3:1H NMR(300MHz，CDCl3)δ：12.60(s，1H，-OH)；12.42(s，1H，-OH)；7.34(d，J＝8.0Hz，2H，Ar-H)；7.17(s，2H，Ar-H)；7.14(d，J＝7.9Hz，2H，Ar-H)；6.97(s，1H，Ar-H)；6.02(dt，J＝14.5，7.2Hz，1H，-O-CH)；5.15-5.05(m，J＝6.8Hz，2H，Ar-CH，-C＝CH)；3.09-2.88(m，3H，C-CH2-S，C-CH-S)；2.53-2.35(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.33(s，3H，Ar-CH3)；2.17(d，J＝13.5Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.75-1.42(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.26(s，1H，C-C-C-CH2-C-C-C-C).
compound 4:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.57(d，J＝7.6Hz，1H，Ar-H)；7.27(t，1H，Ar-H)；7.18(s，2H，Ar-H)；7.00-6.83(m，3H，Ar-H)；6.01(dt，J＝10.0，5.0Hz，1H，-O-CH)；5.70(d，J＝1.6Hz，1H，Ar-CH)；5.10(t，J＝7.3Hz，1H，-C＝CH)；3.86(s，3H，Ar-OCH3)；3.15-2.83(m，3H，C-CH2-S，C-CH-S)，2.54-2.27(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.19(d，J＝13.8Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.84-1.41(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.27(s，1H，C-C-C-CH2-C-C-C-C).
compound 5:1H NMR(300MHz，CDCl3)δ：12.58(s，1H，-OH)；12.41(s，1H，-OH)；7.36(d，J＝8.7Hz，2H，Ar-H)；7.18(s，2H，Ar-H)；6.93(s，1H，Ar-H)；6.84(d，J＝8.7Hz，2H，Ar-H)；5.99(dt，J＝11.3，5.5Hz，1H，-O-CH)；5.15-5.05(m，J＝6.8Hz，2H，Ar-CH，-C＝CH)；3.78(s，3H，-O-CH3)；3.02-2.89(m，3H，C-CH2-S，C-CH-S)；2.51-2.31(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.20-2.08(m，1H，C-CH2-C＝C)；1.69(s，3H，C＝C-CH3)；1.59(s，3H，C＝C-CH3)；1.77～1.39(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.24(s，1H，C-C-C-CH2-C-C-C-C)..
compound 6:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.18(s，2H，Ar-H)；7.04-6.95(m，3H，Ar-H)；6.82(d，J＝8.5Hz，1H，Ar-H)；6.02(dd，J＝7.0，4.6Hz，1H，-O-CH)；5.10(t，J＝6.1Hz，2H，Ar-CH，-C＝CH)；3.90(s，3H，Ar-OCH3)；3.87(s，3H，Ar-OCH3)；3.05-2.91(m，3H，C-CH2-S，C-CH-S)；2.53-2.35(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.17(d，J＝11.4Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.76-1.45(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)，1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 7:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.43(s，1H，-OH)；7.37(d，J＝8.1Hz，2H，Ar-H)；7.18(t，J＝4.0Hz，4H，Ar-H)；6.97(s，1H，Ar-H)；6.02(dt，J＝14.5，7.2Hz，1H，-O-CH)；5.15-5.05(m，2H，Ar-CH，-C＝CH)，3.05-2.92(m，3H，C-CH2-S，C-CH-S)；2.86(dt，J＝13.6，6.8Hz，1H，-CH-(CH3)2)，2.47(dd，J＝15.0，7.5Hz，1H，C-CH2-C＝C)；2.38(t，J＝7.4Hz，2H，O＝C-CH2-C)；2.16(d，J＝14.5Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.78-1.40(m，7H C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.25(s，1H，C-C-C-CH2-C-C-C-C)；1.23(s，3H，Ar-C-CH3)；1.21(s，3H，Ar-C-CH3).
compound 8:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.69-7.63(m，1H，Ar-H)；7.36(dd，J＝7.6，1.7Hz，1H，Ar-H)；7.31-7.21(m，2H，Ar-H)；7.18(s，2H，Ar-H)；6.97(s，1H，Ar-H)；6.02(dd，J＝6.5，4.7Hz，1H，-O-CH)；5.63(d，J＝2.4Hz，1H，Ar-CH)；5.11(t，J＝7.2Hz，1H，-C＝CH)；3.15-2.93(m，3H，C-CH2-S，C-CH-S)；2.53-2.34(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.21(d，J＝14.0Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.72-1.44(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 9:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.38(d，J＝7.3Hz，2H，Ar-H)；7.30(d，J＝8.5Hz，2H，Ar-H)；7.18(s，2H，Ar-H)；6.97(s，1H，Ar-H)；6.01(dt，J＝12.7，6.3Hz，1H，-O-CH)；5.16-5.06(m，2H，Ar-CH，-C＝CH)；3.09-2.88(m，3H，C-CH2-S，C-CH-S)；2.53-2.33(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.18(d，J＝14.5Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.76-1.42(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 10:1H NMR(300MHz，CDCl3)δ：12.60(s，1H，-OH)；12.42(s，1H，-OH)；7.59(dt，J＝7.8，1.4Hz，1H，Ar-H)；7.40(dd，J＝8.0，1.5Hz，1H，Ar-H)；7.22(t，J＝5.8Hz，1H，Ar-H)；7.19(s，2H，Ar-H)；6.97(s，1H，Ar-H)；6.01(dt，J＝11.2，5.6Hz，1H，-O-CH)；5.65(d，J＝2.8Hz，1H，Ar-CH)；5.10(t，J＝7.1Hz，1H，-C＝CH)；3.14-2.92(m，3H，C-CH2-S，C-CH-S)；2.53-2.34(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.21(d，J＝14.2Hz，1H，C-CH2-C＝C)；1.69(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.73-1.43(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.27(s，1H，C-C-C-CH2-C-C-C-C).
compound 11:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.60(d，J＝8.0Hz，1H，Ar-H)；7.38(d，J＝2.1Hz，1H，Ar-H)；7.22-7.15(m，3H，Ar-H)；6.97(s，1H，Ar-H)；6.01(dt，J＝10.3，5.3Hz，1H，-O-CH)；5.56(d，J＝2.3Hz，1H，Ar-CH)；5.10(t，J＝7.6Hz，1H，-C＝CH)；3.13-2.93(m，3H，C-CH2-S，C-CH-S)；2.53-2.34(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.20(d，J＝11.9Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.73-1.43(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)，1.24(s，1H，C-C-C-CH2-C-C-C-C).
compound 12:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.35～7.28(m，2H，Ar-H)；7.18(s，2H，Ar-H)；7.14(t，J＝8.0Hz，1H，Ar-H)；6.97(s，1H，Ar-H)；6.01(m，2H，-O-CH，Ar-CH)；5.12(t，J＝7.2Hz，1H，-C＝CH)；3.05-2.92(m，3H，C-CH2-S，C-CH-S)；2.52-2.34(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.20(d，J＝14.1Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.71-1.53(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)，1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 13:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.61(s，1H，Ar-H)；7.41(dd，J＝13.3，7.9Hz，2H，Ar-H)；7.21(t，J＝5.4Hz，1H，Ar-H)；7.18(s，2H，Ar-H)；6.97(s，1H，Ar-H)；6.01(dt，J＝10.7，5.4Hz，1H，-O-CH)；5.11(t，J＝5.6Hz，2H，Ar-CH，-C＝CH)；3.05-2.92(m，3H，C-CH2-S，C-CH-S)，2.53-2.32(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.18(d，J＝13.2Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.80-1.39(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 14:1H NMR(300MHz，CDCl3)δ12.58(s，1H，-OH)，12.42(s，1H，-OH)，7.72(s，1H，Ar-H)，7.65(d，J＝7.7Hz，1H，Ar-H)，7.56(d，J＝7.9Hz，1H，Ar-H)，7.45(dd，J＝13.4，5.6Hz，1H，Ar-H)，7.18(s，2H，Ar-H)，6.97(t，J＝1.0Hz，1H，Ar-H)，6.02(dd，J＝6.5，4.7Hz，1H，-O-CH)，5.20(d，J＝3.5Hz，1H，Ar-CH)，5.10(t，J＝7.3Hz，1H，-C＝CH)，3.07-2.94(m，3H，C-CH2-S，C-CH-S)，2.53-2.42(m，3H，O＝C-CH2-C，C-CH2-C＝C)，2.39(t，J＝7.3Hz，1H，C-CH2-C＝C)，2.26-2.13(m，1H，C-CH2-C＝C)，1.68(s，3H，C＝C-CH3)，1.79-1.53(m，5H，C-C-CH2-CH2-CH2-C-C-C)，1.57(s，3H，C＝C-CH3)，1.54-1.40(m，2H，C-CH2-C)，1.26(s，1H，C-C-C-CH2-C-C-C-C).
compound 15:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；7.63-7.51(m，4H，Ar-H)；7.19(s，2H，Ar-H)；6.97(s，1H，Ar-H)；6.01(dt，J＝12.7，6.3Hz，1H，-O-CH)；5.20(t，J＝4.5Hz，1H，Ar-CH)；5.10(t，J＝7.3Hz，1H，-C＝CH)；3.07-2.93(m，3H，C-CH2-S，C-CH-S)；2.53-2.31(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.18(t，J＝11.9Hz，1H，C-CH2-C＝C)；1.69(s，3H，C＝C-CH3)；1.59(s，3H，C＝C-CH3)；1.79-1.60(m，5H，C-C-CH2-CH2-CH2-C-C-C)；1.59-1.41(m，2H，C-CH2-C)；1.24(s，1H，C-C-C-CH2-C-C-C-C).
compound 16:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.42(s，1H，-OH)；8.20(d，J＝8.8Hz，2H，Ar-H)；7.63(d，J＝8.8Hz，2H，Ar-H)；7.18(s，2H，Ar-H)；6.94(s，1H，Ar-H)；6.02(dt，J＝14.5，7.2Hz，1H，-O-CH)；5.22(d，J＝2.9Hz，1H，Ar-CH)；5.10(t，J＝7.2Hz，1H，-C＝CH)；3.09-2.92(m，3H，C-CH2-S，C-CH-S)；2.53-2.32(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.21(d，J＝14.8Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.79-1.37(m，7H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C)；1.25(s，1H，C-C-C-CH2-C-C-C-C).
compound 17:1H NMR(300MHz，CDCl3)δ：12.59(s，1H，-OH)；12.43(s，1H，-OH)；7.18(s，2H，Ar-H)；6.97(s，1H，Ar-H)；6.02(dd，J＝7.2，4.6Hz，1H，-O-CH)；5.11(t，J＝7.2Hz，1H，-C＝CH)；4.06(dd，J＝4.9，2.4Hz，1H，Ch-CH)；2.97-2.72(m，3H，C-CH2-S，C-CH-S)；2.54-2.31(m，3H，O＝C-CH2-C，C-CH2-C＝C)；2.12(d，J＝10.8Hz，1H，C-CH2-C＝C)；1.68(s，3H，C＝C-CH3)；1.57(s，3H，C＝C-CH3)；1.94-1.40(m，16H，C-C-CH2-CH2-CH2-C-C-C，C-CH2-C，Ch-H)；1.26(td，J＝22.1，10.9Hz，3H，C-C-C-CH2-C-C-C-C，Ch-H).
compound 18: 1H NMR (300MHz, CDCl3) delta: 12.59(s, 1H, -OH); 12.42(s, 1H, -OH); 7.18(s, 2H); 6.98(s, 1H); 6.02(dt, J ═ 14.5, 7.2Hz, 1H, -O-CH); 5.11(t, J ═ 7.2Hz, 1H, -C ═ CH); 3.67-3.48(m, 1H, C-CH-S); 3.28-3.03(m, 2H, C-CH 2-S); 2.54-2.35(m, 4H, O ═ C-CH2-C, C-CH 2-C); 1.69(s, 3H, C ═ C-CH 3); 1.59(s, 3H, C ═ C-CH 3); 1.77-1.60(m, 5H, C-C-CH2-CH2-CH 2-C-C-C); 1.55-1.38(m, 2H, C-CH 2-C); 1.25(s, 1H, C-C-C-CH2-C-C-C-C).
Example two: application of lithospermum thioctic acid ester derivatives of formula I
HepG2, HeLa, MCF-7 and Vero cell strains are taken as detection strains, an MTT colorimetric method is taken as a detection method, and the research on the in-vitro tumor cell inhibition activity of the shikonin carboxylate derivatives of the formula I shows that the derivatives with the novel structure have obvious in-vitro tumor cell inhibition activity and lower toxicity to normal cells. The results are shown in figures 1, 2, 3 and 4.
Example three: compound 1 reduces adhesion of HeLa cells
Treating HeLa cells with compound 1 at different concentrations (0, 0.7, 1.4, 2.8, 5.6 μ M), treating for 24h, collecting cells, and counting; add 50. mu.L fibronectin or laminin (10. mu.g/mL) to 96-well plates overnight at 4 ℃. The 96-well plate was removed and blocked with 0.2% BSA (50. mu.L) for 2h at room temperature. Washed twice with PBS, and equal amounts of collected cells were added, 5% CO at 37 deg.C2And incubating for 30-40 min. The cells were washed twice with PBS and the OD was measured at 570nm after incubation for 4h with MTT. The results are shown in FIG. 5(A, B).
The lithospermum lipoic acid ester derivatives can be prepared into antitumor drugs.

Claims (2)

1. A lithospermum lipoic acid ester derivative has the following structural formula:
Figure FSB0000188584340000011
Figure FSB0000188584340000021
2. the use of the lipoic acid ester derivatives of shikonin as set forth in claim 1 for preparing antitumor drugs.
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