CN107304197A - Shikonin lipoate analog derivative and its synthetic method and application - Google Patents

Shikonin lipoate analog derivative and its synthetic method and application Download PDF

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CN107304197A
CN107304197A CN201610268160.3A CN201610268160A CN107304197A CN 107304197 A CN107304197 A CN 107304197A CN 201610268160 A CN201610268160 A CN 201610268160A CN 107304197 A CN107304197 A CN 107304197A
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shikonin
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lipoate
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CN107304197B (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
    • C07—ORGANIC CHEMISTRY
    • 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

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Abstract

The invention belongs to technical field of pharmaceutical chemistry, and in particular to a class Shikonin Derivative Formation and its application in terms of tumor suppression.Corresponding lipoic acid derivatives are connected with shikonin by synthesizing mean, corresponding ester derivative is obtained, the activity research of extracorporeal anti-tumor shows that this kind of shikonin lipoate analog derivative has very strong inhibitory activity to tumor cell line.

Description

Shikonin lipoate analog derivative and its synthetic method and application
First, technical field
The invention belongs to technical field of pharmaceutical chemistry, and in particular to a kind of preparation of shikonin lipoate analog derivative and Its application in terms of tumor suppression.
2nd, background technology
Shikonin has multiple pharmacological activity, such as sterilization, anti-inflammatory, anti-oxidant, antiviral, antitumor.Recent study Show, it there are very big potentiality as primer in terms of the functional molecular research of tumor cell proliferation is suppressed.Such as：Yang Fan Equal to 2006《International Journal of Cancer》The SH-7 that 119th p1184-1193 pages of phase delivered, A New Synthesized Shikonin Derivative, Exerting Its Potent Anti-tumor Activities (a kind of SH-7, the new Shikonin Derivative Formation that synthesis is obtained passes through topoisomerase to as a Topoisomerase Inhibitor Enzyme plays its effective active anticancer) article shows that the Shikonin Derivative Formation modified with shikonin skeleton is to topoisomerase The inhibitory action of enzyme is significantly better than shikonin, while the derivative can suppress S-180, SMMC-7721, BEL-7402 and The growth of tetra- plants of cancer cells of PC-3, this illustrates that the shikonin ester has activity well in terms of tumor suppression.
This seminar obtains multi-series Shikonin Derivative Formation, and applied for Patents during years of researches： Shikonin derivative containing fluorine carboxylic acid ester and its synthetic method and application (application number：201110412497.4) and shikonin meat Cinnamic acid ester derivative and its synthetic method and application (application number：201210002020.3), it was found that it is some that there is efficiently suppression The functional molecular of activity of tumor cells processed.
Because shikonin normal tissue itself, cell have stronger toxic side effect, therefore structure is carried out to shikonin Modification, improves active anticancer, overcomes its shortcoming, obtains the derivative of high-efficiency low-toxicity and turns into main research topic.
3rd, the content of the invention
The present invention passes through the novel shikonin ramification of carboxylic esters of one class of semi-synthetic acquisition using shikonin as initiation material. Antitumor activity shows that the derivative has obvious inhibitory activity to tumor cell line HcpG2, MCF-7, HeLa, wherein In HeLa cytoactive results, optimal, the IC of the activity of compound 150Value reaches 1.54 ± 0.17 μM；In HepG2 cytoactive results In, optimal, the IC of the activity of compound 950Value reaches 10.69 ± 0.53 μM；In MCF-7 cytoactive results, the activity of compound 5 is most It is excellent, IC50Value reaches 4.02 ± 0.14 μM.
The present invention needs to be to provide the novel shikonin ramification of carboxylic esters of a class formation and its preparation the problem of solution Method and the application in tumor suppression.
The shikonin lipoate analog derivative structural formula of the present invention is shown in formula I：
The Formulas I structure shikonin ramification of carboxylic esters of the present invention is to be obtained by shikonin with the semi-synthetic of corresponding carboxylic acid Novel structure-activity functional compounds.
The present invention proves shikonin carboxylic acid derivates to HepG2, MCF-7, HeLa by tumor cell in vitro inhibitory activity With obvious inhibitory activity, wherein compound 1 is most strong to HeLa inhibitory activity, IC50Value is referred to attached up to 1.54 ± 0.17 μM Fig. 1,2,3.The compound for demonstrating this class novelty by toxicity test is low to African green monkey kidney cell (Vero) toxic side effect, IC50Both greater than 85 μM of value, and the larger IC of the toxicity of shikonin50It is worth for 6.77 μM, refers to accompanying drawing 4.In addition, cell adhesion is tested Prove, compound 1 can weaken the Adhering capacity of HeLa cells, refer to accompanying drawing 5.
Its advantage compared with prior art of the invention：
In the present invention, shikonin lipoate analog derivative is obtained compared with shikonin, is respectively provided with obvious tumour thin Born of the same parents' inhibitory activity, part compounds are substantially better than its parent molecule shikonin to the inhibitory activity of tumor cell line, and Toxic side effect is low.The suppression that compound 1 is bred to HeLa cells simultaneously is the most obvious, and can weaken its adhesion.This research is intended Mechanism of drug action is deeply probed into by streaming, laser co-focusing and western blot means.
Four：Brief description of the drawings
Fig. 1 represents the suppression that compound 1-18 and shikonin are bred to HepG2 cells
Fig. 2 represents the suppression that compound 1-18 and shikonin are bred to MCF-7 cells
Fig. 3 represents the suppression that compound 1-18 and shikonin are bred to HeLa cells
Fig. 4 represents the suppression that compound 1-18 and shikonin are bred to Vero cells
Fig. 5 represents that compound 1 can weaken tumour cell HeLa Adhering capacity
Five：Embodiment
Example one：The preparation of shikonin ramification of carboxylic esters
Alpha-lipoic acid (1mol) is suspended in water (500ml), adds sodium acid carbonate (1mol).The mixture is stirred, is produced Settled solution.By gained pale yellow solution refrigerated with ice, solid sodium borohydride (2mol) is added portionwise on a small quantity under agitation. Solution is stirred 30 minutes in ice bath, is then stirred at room temperature 30 minutes.Turbid solution refrigerated with ice, pH is adjusted extremely with 2M hydrochloric acid 1, it may appear that grease.The solution is extracted with chloroform, is dried with anhydrous magnesium sulfate, filters, solvent is evaporated under reduced pressure at room temperature, 6,8- dimercapto octanoic acids.
Under nitrogen atmosphere, into dichloromethane aldehyde (1mol) is added in 6,8- dimercapto octanoic acids (1mol).By mixture It is stirred at room temperature 1 hour, is cooled to -25 DEG C, add BFEE, and warms to room temperature reaction, evaporation solvent Afterwards, target product is recrystallized to give by ethyl acetate and petroleum ether.
Under condition of ice bath, shikonin, corresponding lipoic acid derivatives, refined dichloromethane are sequentially added in 50mL round-bottomed flasks Alkane and catalyst, TLC detection reactions are complete, and (V is separated through thin plate chromatographyEthyl acetate∶VNot oily ether=1: 5) obtain corresponding shikonin carboxylic acid Ester derivative.
The physicochemical data of respective compound is 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=8.0) Hz, 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) δ 12.58 (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) δ：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-CH2-S)；2.54-2.35 (m, 4H, O=C-CH2-C, C-C- C-C-C-C-CH2-C)；1.69 (s, 3H, C=C-CH3)；1.59 (s, 3H, C=C-CH3)；1.77-1.60 (m, 5H, C-C- CH2-CH2-CH2-C-C-C)；(1.55-1.38 m, 2H, C-CH2-C)；1.25 (s, 1H, C-C-C-CH2-C-C-C-C)
Example two：The application of Formulas I class shikonin lipoate analog derivative
Using HepG2, HeLa, MCF-7, Vero cell line as detection strain, MTT colorimetric methods are detection method, by Formulas I Class shikonin acid esters of gallic acid derivatives inhibiting tumour cells activity research finds that such novel structure derivative has obvious Tumor cell in vitro inhibitory activity, it is and relatively low to normal cytotoxicity.As a result accompanying drawing 1,2,3,4 is seen.
Example three：Compound 1 weakens the adhesion of HeLa cells
HeLa cells are acted on various concentrations (0,0.7,1.4,2.8,5.6 μM) compound 1,24h is handled, collect thin Born of the same parents, count；Adding 50 μ L fibronectins or layer into 96 orifice plates, even 4 DEG C of connection albumen (10 μ g/mL) is stayed overnight.96 orifice plates are taken out, are used 0.2%BSA (50 μ L) room temperature closes 2h.Washed with PBS twice, add the cell of the collection of equivalent, 37 DEG C, 5%CO2It is incubated 30- 40min.Washed with PBS twice, add MTT and be incubated after 4h the survey OD values under 570nm optical wavelength.As a result accompanying drawing 5 (A, B) is seen.
Shikonin lipoate analog derivative of the present invention can be prepared into antineoplastic.

Claims (2)

1. a class shikonin lipoate analog derivative, its structural formula is as follows：
2. application of the shikonin lipoate analog derivative in oncotherapy described in claim 1.
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