CN103360437B - A kind of Thioctic Acid carbohydrate derivative and preparation method thereof and preparing the application in antitumor drug - Google Patents

A kind of Thioctic Acid carbohydrate derivative and preparation method thereof and preparing the application in antitumor drug Download PDF

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CN103360437B
CN103360437B CN201310152313.4A CN201310152313A CN103360437B CN 103360437 B CN103360437 B CN 103360437B CN 201310152313 A CN201310152313 A CN 201310152313A CN 103360437 B CN103360437 B CN 103360437B
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thioctic acid
carbohydrate derivative
glycosyl
preparation
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CN103360437A (en
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白立飞
徐国华
朱琨
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JIANGSU INSTITUTE OF EDUCATION
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JIANGSU INSTITUTE OF EDUCATION
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Abstract

The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of Thioctic Acid carbohydrate derivative and preparation method thereof and preparing the application in antitumor drug.By chemosynthesis means, saccharide compound is incorporated in thiotic molecules the Thioctic Acid saccharide compound obtaining novel structure, found by anti tumor activity in vitro research, Thioctic Acid carbohydrate derivative has obvious restraining effect to tumour cell A549, SW872-S and NCI-H460.From Activity Results and preparation possibility, Thioctic Acid carbohydrate derivative can be prepared as the antitumor drug of high-efficiency low-toxicity, has wide drug development prospect.

Description

A kind of Thioctic Acid carbohydrate derivative and preparation method thereof and preparing the application in antitumor drug
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of Thioctic Acid carbohydrate derivative, and preparation method thereof and preparing the application in antitumor drug.
Background technology
Thioctic Acid (Alpha-lipoic acid, LA) be biostearin class active function molecule, nineteen fifty is found in animal livers, it has anti-oxidant, the infringement of anti-cholesterol, minimizing free radical, stabilizing blood sugar, the effect such as hypoglycemic and balance blood sugar concentration, concerned is its oxidisability in early days, be described as " universal antioxidant " together with reduction-state Thioctic acid, dihydro-(DHLA), simultaneously Thioctic Acid in vivo vitamins C and vitamin E deficiency time, also can be used as surrogate and play a role.Research in recent years shows, Thioctic Acid also has antineoplastic effect.
Zhang equal 2010 " Bioorganic & Medicinal Chemistry Letters " the 20th phase 3078-3083 page report be entitled as the synthesis of Synthesis and anticancer evaluation of α-lipoic acid derivatives(lipoic acid derivatives and anti-tumor activity characterizes) article, mainly describe lipozyme series derivates in literary composition to study as antibumor molecules, result shows, derivative has very high anti-tumor activity, in Vitro Tumor process of inhibition, to NCI-460, HO-8910, KB, BEL-7402 and PC-3 cell strain all has remarkable effect.The article being entitled as " synthesis of alpha-lipoic acid and hydrazide derivatives thereof and antitumor activity " that Xu Miao army equals to deliver at " chemistry circular " the 75th phase the 9th volume p837-841 page for 2012 shows, is arrive first thing can obtain the bioactive molecule having and significantly see tumor function with Thioctic Acid.
In addition, the synthesis that Kaskiw etc. delivered to be entitled as Synthesis and cytotoxic activity of diosgenyl saponin analogues(saponin derivative at " Bioorganic & Medicinal Chemistry " the 16th phase 3209-3217 page in 2008 and cytotoxic activity research) article, find in literary composition, Saponin/TSM lipoic acid derivatives has extraordinary anti-tumor activity, reaches 4.81.7.31 and 6.91 μM respectively to the IC50 value of tumor cell line SK-N-SH, Hela cell and MCF-7.
But water-soluble poor due to Thioctic Acid, so limit its application in pharmacy field.
Carbohydrate a kind of extraordinaryly helps effect group, introduces in medicine and can improve its multiple physico-chemical property.Lerchen H G equals 2001 and is published in " Journal of Medicinal Chemistry " the 44th phase 4186 – 4195 pages of Design and Optimization of 20-O-Linked Camptothecin Glycoconjugates as Anticancer Agents(and designs and optimize antitumor drug-camptothecine 20-O-and is connected glycoconjugate) etc. after the carbohydrate introducing taxol of report and camptothecine, obvious improvement and Alaoui A E has been had to equal to its pharmacologically active, 2006 Protecting Groups for Glucuronic Acid:Application to the Synthesis of New Paclitaxel (Taxol) the Derivatives(protecting groups being published in " Journal of Organic Chemistry " the 71st phase 9628 – 9636 pages are glucuronic acid: application and synthesizing new D51-7059).
Summary of the invention
The object of the invention is to effective substance based on Thioctic Acid, by sulfydryl sugar generation, develop a kind of active compound for anti tumor of novelty.The present invention not only obtains serial glycosyl lipoic acid derivatives, and correspondence carries out antitumor activity, shows that Thioctic Acid carbohydrate derivative has significant anti-tumor activity.
In order to reach foregoing invention object, the invention discloses a kind of its general structure of Thioctic Acid carbohydrate derivative such as formula ishown in:
Wherein:
1)formula imiddle R 1and R 2it is 2,3,4,6-tetra-acetylize-β-D-Glucopyranose;
2)formula imiddle R 1and R 2it is the triacetylated-β-D-xylopyranose of 2,3,4-;
3)formula imiddle R 1and R 2it is 2,3,4,6-tetra-acetylize-β-D-galactopyranose;
4)formula imiddle R 1and R 2it is 2,3,4,6-tetra-acetylize-β-D-mannopyranose;
5)formula imiddle R 1and R 2it is the triacetylated-β-D-arabopyranose of 2,3,4-;
6)formula imiddle R 1and R 2it is 2,3,6-tri--O-ethanoyl-4-O-(2,3,4,6-tetra--O-ethanoyl-β-D-galactopyranosyl glycosyl)-β-D-Glucopyranose;
7)formula imiddle R 1and R 2it is 2,3,6-tri--O-ethanoyl-4-O-(2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl)-α-D-Glucopyranose etc.;
8)formula imiddle R 1and R 2for β-D-Glucopyranose;
9)formula imiddle R 1and R 2for β-D-xylopyranose;
10)formula imiddle R 1and R 2for β-D-galactopyranose;
11)formula imiddle R 1and R 2for β-D-mannopyranose;
12)formula imiddle R 1and R 2for β-D-arabopyranose;
13)formula imiddle R 1and R 2for β-D-lactose;
14)formula imiddle R 1and R 2for β-D-Maltose;
15)formula imiddle R 1be 2,3,4,6-tetra-acetylize-β-D-Glucopyranose, R 2for H;
16)formula imiddle R 1be the triacetylated-β-D-xylopyranose of 2,3,4-, R 2for H;
17)formula imiddle R 1be 2,3,4,6-tetra-acetylize-β-D-galactopyranose, R 2for H;
18)formula imiddle R 1be 2,3,4,6-tetra-acetylize-β-D-mannopyranose, R 2for H;
19)formula imiddle R 1be the triacetylated-β-D-arabopyranose of 2,3,4-, R 2for H;
20)formula imiddle R 1be 2,3,6-tri--O-ethanoyl-4-O-(2,3,4,6-tetra--O-ethanoyl-β-D-galactopyranosyl glycosyl)-β-D-Glucopyranose, R 2for H;
21)formula imiddle R 1be 2,3,6-tri--O-ethanoyl-4-O-(2,3,4,6-tetra--O-ethanoyl-β-D-glucopyranosyl)-α-D-Glucopyranose etc., R 2for H;
22)formula imiddle R 1for β-D-Glucopyranose, R 2for H;
23)formula imiddle R 1for β-D-xylopyranose, R 2for H;
24)formula imiddle R 1for β-D-galactopyranose, R 2for H;
25)formula imiddle R 1for β-D-mannopyranose, R 2for H;
26)formula imiddle R 1for β-D-arabopyranose, R 2for H;
27)formula imiddle R 1for β-D-lactose, R 2for H;
28)formula imiddle R 1for β-D-Maltose, R 2for H;
Wherein, what have industrialization pharmaceutical use especially is:
Formula of the present invention istructural derivative is the functional compounds of the novel structure obtained through chemosynthesis by carbohydrate intermediate and Thioctic Acid.
Thioctic Acid of the present invention is from natural product, and due to the introducing of glycosyl, compound water soluble disclosed by the invention is obviously better than the hydrazide derivatives of Thioctic Acid compound itself and other routines.Significant the development of pharmaceutical field from it.
Meanwhile, anti-tumor activity of the present invention shows, Thioctic Acid carbohydrate derivative has obvious inhibit activities to JEG-3 A549, SW872-S and NCI-H460, and wherein active optimum compound is acetylize xylose derivative, its IC 50value reaches 0.35,0.29 and 0.47 μm of ol/mL respectively, is secondly acetylize galactose derivate, its IC 50value also reaches 0.57,0.36 and 0.68 μm of ol/mL respectively.
Accompanying drawing explanation
Fig. 1 represents the external activity result of Thioctic Acid carbohydrate derivative to tumour cell A549.
Fig. 2 represents the external activity result of Thioctic Acid carbohydrate derivative to tumour cell SW872-S.
Fig. 3 represents the external activity result of Thioctic Acid carbohydrate derivative to tumour cell NCI-H460.
Embodiment
embodiment one:thioctic acid, dihydro-preparation method
Get 50g Thioctic Acid and be placed in 1L water, add sodium borohydride 9.5g in batches, to reacting completely, adding chloroform and stirring standing 2h in a moment, separating chloroform layer, be spin-dried for and obtain 6,8-Thioctic acid, dihydro-.
embodiment two:the synthetic method of formula I class lipoic acid derivatives
The full acetylated bromo sugar of the Thioctic acid, dihydro-and 1.04mmol of getting 0.5 mmol is dissolved in 20 mL chloroformic solutions, and in 0 DEG C ~ 50 DEG C, stirring reaction detects Thioctic Acid raw material point to TLC and disappears.
Then concentrating under reduced pressure is carried out to it, observe the change of solution, if there is the reaction system of solid, so just obtain product by recrystallization.If there is the system of viscous fluid after rotary evaporation, so just first add the diluted ethyl acetate viscous fluid of 20 mL, then proper silica gel is added again after, continue decompression concentrated solution, to forming pressed powder, with ethyl acetate: sherwood oil=1:2 column chromatography, obtains Thioctic Acid glycosyl derivatives, yield about 85%.
Reaction is for glucose:
Compound 2 ~ 7 can be obtained with method:
。
embodiment three:the synthesis of formula I class deprotection glycosyl lipoic acid derivatives
The compound obtained in embodiment two is got 0.1 mmol to be dissolved in 5 mL ethanol; be that-4 DEG C ~ 5 DEG C scopes drip sodium methoxide solutions in temperature; reaction disappears to full acetylated glycosyl Thioctic Acid raw material point; neutralize with dilute hydrochloric acid; product adds 0.05g silica gel and naturally volatilizes; with ethanol: chloroform=1:4 column chromatography, obtains product, and yield is about 85%.
After the same method, the compound 2 ~ 7 obtained in embodiment 2 is carried out deacetylation operation respectively, obtains compound 8 ~ 14;
。
embodiment four.formula I class Thioctic Acid carbohydrate derivative is applied
We have carried out antitumor activity to formula I class Thioctic Acid carbohydrate derivative, choose tumour cell A549, and SW872-S, NCI-H46 are for detecting cell, and with mtt assay, microplate reader measures its absorbancy and calculates OD value under 570 nm conditions.
IC50 value calculating method is such as formula shown:
Cell inhibitory rate (%)=(control group OD value-experimental group OD value)/control group OD value × 100%
Result shows; Thioctic Acid carbohydrate derivative has obvious inhibit activities to JEG-3 A549, SW872-S and NCI-H460; experimental result is shown in Fig. 1 ~ Fig. 3, and wherein active optimum compound is acetylize xylose derivative, and it is for the IC of A549, SW872-S and NCI-H460 50value reaches 0.35,0.29 and 0.47 μm of ol/mL respectively, and be secondly acetylize galactose derivate, it is for the IC of A549, SW872-S and NCI-H460 50value also reaches 0.57,0.36 and 0.68 μm of ol/mL respectively.
The water-soluble test of embodiment five formula I class Thioctic Acid carbohydrate derivative
We carry out class simultaneous test to carbohydrate lipoic acid derivatives of the present invention and traditional hydrazide derivatives, find that in the present invention, 1-7 can be dissolved in the water on a small quantity, and 8-14 solvability is fabulous, and traditional hydrazide derivatives are without obvious dissolution phenomena.
Specific implementation method: get 1 mL water, be added to the water by 0.5g sample, sees concrete dissolving situation, and compound 1-7 small part is dissolved, and 8-14 can dissolve well, and hydrazides class is without obvious dissolution phenomena.

Claims (5)

1. a Thioctic Acid carbohydrate derivative, its structural formula is as follows:
。
2. prepare a method for Thioctic Acid carbohydrate derivative according to claim 1, it is characterized in that:
Step one: the acquisition of full acetylated glycosyl Thioctic Acid:
Be dissolved in chloroformic solution with the full acetylated bromo sugar of the Thioctic acid, dihydro-of 0.5 mmol and 1.04 mmol, detect Thioctic acid, dihydro-raw material point in 0 DEG C ~ 50 DEG C stirring reactions to TLC and disappear;
Step 2: the purifying of full acetylated glycosyl Thioctic Acid:
The solution that concentrating under reduced pressure step one obtains, observes solution change, and operates accordingly respectively according to following two kinds of situations;
Situation one: occur solid, then obtain full acetylated glycosyl Thioctic Acid by recrystallization;
Situation two: solution forms the state of viscous fluid; First add diluted ethyl acetate viscous fluid, and then add silica gel continuation decompression concentrated solution to forming pressed powder, with ethyl acetate: sherwood oil=1:2 column chromatography, obtain full acetylated glycosyl Thioctic Acid;
Step 3: the synthesis of de-acetyl glycosyl Thioctic Acid:
The full acetylated glycosyl Thioctic Acid of 0.1 mmol is dissolved in 5 mL ethanol; be that-4 DEG C ~ 5 DEG C scopes drip sodium methoxide solutions in temperature; reaction disappears to full acetylated glycosyl Thioctic Acid raw material point; neutralize with dilute hydrochloric acid; product adds 0.05g silica gel and naturally volatilizes; with ethanol: chloroform=1:4 column chromatography, obtains target product and take off acetyl glycosyl Thioctic Acid.
3. preparation method according to claim 2, it is characterized in that the preparation method of described Thioctic acid, dihydro-is: be fully dissolved in the water by Thioctic Acid, add sodium borohydride in batches, total add-on of sodium borohydride and Thioctic Acid add-on etc. mole, after reacting completely, add chloroform and stir, leave standstill, get chloroform layer, concentrating under reduced pressure obtains Thioctic acid, dihydro-.
4. Thioctic Acid carbohydrate derivative described in claim 1 is preparing anticancer strain A549, the application in SW872-S, NCI-H46 medicine.
5. application according to claim 4 is the application in the anti-lung cancer of preparation, lipotropism fat cancer drug.
CN201310152313.4A 2013-04-27 2013-04-27 A kind of Thioctic Acid carbohydrate derivative and preparation method thereof and preparing the application in antitumor drug Active CN103360437B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1328566A (en) * 1998-11-24 2001-12-26 美国家用产品公司 Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
CN1338932A (en) * 1999-02-16 2002-03-06 人机能改善中心国际有限公司 Use of lipoic acid combination with ascorbic acid in the treatment of cancer
CN101765370A (en) * 2007-04-18 2010-06-30 基石制药公司 Lipoic acid derivatives
CN101820875A (en) * 2007-04-18 2010-09-01 基石医药公司 Contain the pharmaceutical preparation of lipoic acid derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100184711A1 (en) * 2008-12-22 2010-07-22 University College Dublin, National University Of Ireland, Dublin Alpha-GLYCOSYL THIOLS AND alpha-S-LINKED GLYCOLIPIDS

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1328566A (en) * 1998-11-24 2001-12-26 美国家用产品公司 Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
CN1338932A (en) * 1999-02-16 2002-03-06 人机能改善中心国际有限公司 Use of lipoic acid combination with ascorbic acid in the treatment of cancer
CN101765370A (en) * 2007-04-18 2010-06-30 基石制药公司 Lipoic acid derivatives
CN101820875A (en) * 2007-04-18 2010-09-01 基石医药公司 Contain the pharmaceutical preparation of lipoic acid derivatives

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