CN108276370B - 17-alkylthio gibberellin ester compound, preparation method and anti-tumor application thereof - Google Patents
17-alkylthio gibberellin ester compound, preparation method and anti-tumor application thereof Download PDFInfo
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Abstract
The invention discloses a 17-alkylthio gibberellic acid ester compound shown as a general formula (I), a pharmaceutical composition taking the compound as an active ingredient, a preparation method and application of the compound in preparing antitumor drugs. The 17-alkylthio gibberellic acid ester compound is prepared by reacting gibberellic acid derivatives containing double alpha, beta-unsaturated ketone structures with compounds containing sulfydryl under different conditions. The compounds show inhibition effect on proliferation of various human tumor cell strains in vitro anti-tumor activity experiments.
Description
The technical field is as follows:
the invention belongs to the field of chemistry and medicine, and particularly relates to 17-alkylthio gibberellic acid ester compounds, a preparation method and an anti-tumor application thereof.
Background art:
malignant tumor seriously threatens the health and life of human beings, and the incidence rate and the fatality rate of the tumor show a rising trend along with the aging of Chinese population and the influence of environmental factors. The current major tumor treatment methods are surgery, radiation therapy and drug therapy (i.e., chemotherapy). Malignant tumors are systemic rather than local diseases, and the drug therapy acting on the whole body is the most important treatment method at present and occupies an irreplaceable important position in the treatment of tumors. The application of the existing common chemotherapeutic drugs is limited due to serious toxic and side effects, and the search for the chemotherapeutic drugs with new targets, new structures, high activity and low toxicity is still an important and urgent task.
Gibberellin, a natural tetracyclic diterpenoid compound, has the main physiological functions of promoting the growth and development of plants, promoting the germination of seeds, improving the maturing rate, reducing the withering of plant organs, changing the male and female ratio of plants and the like, and is mainly applied to agricultural production. Because of the many and concentrated functional groups in its molecular structure, there are many possibilities in the modification of the chemical structure.
In the study of gibberellin structure modification and bioactivity, we have approved two patents (Zhang hong Bin, Chen Silene, Liu Jian Ping, Qing Chen.3, 15-dicarbonyl gibberellic acid compounds and their esters and salts [ P]ZL 200410021939.2; zhangbin, Chen Silene, Sun bamboo, Cynanchum paniculatum, Liu Jian Ping, Zheng Xiang Hui, Zhang Yan.13-halo-3, 15-dioxo gibberellic acid ester and preparation method thereof [ P]ZL200810058297.1.), with gibberellic acid GA3The derivative is a starting raw material, is structurally modified to obtain a Michael reaction acceptor type gibberellic acid derivative with an A ring having an alpha, beta-unsaturated ketone structure and a D ring having an alpha-methylene cyclopentanone structure, and the compound has good antitumor activity and a multi-target antitumor action mechanism and can obviously reverse the multidrug resistance of tumor cells. GA3The method for preparing the gibberellic acid derivative containing a double alpha, beta-unsaturated ketone structure by structural modification is shown in figure 2:
on the basis of earlier work, the invention continues to take the gibberellic acid derivative containing double alpha, beta-unsaturated ketone structure as a raw material, and through carrying out regioselective Michael addition reaction with a sulfhydryl-containing compound, carboxyl is introduced into a generated multi-sulfur gibberellic acid ester target substance to increase water solubility, so that the bioavailability is improved, and the possibility is provided for developing a water-soluble preparation; in addition, the 17-alkylthio gibberellic acid ester compound is designed and synthesized by taking gibberellic acid derivatives containing double alpha, beta-unsaturated ketone structures as raw materials and carrying out Michael addition reaction with nontoxic cysteine derivatives to prepare the polythiogibberellic acid ester compound so as to increase the stability of a target compound and reduce the toxicity possibly generated in the metabolic process of the target compound as much as possible, and the in vitro anti-tumor activity experiment result shows that: most of the compounds have obvious inhibition effect on the proliferation of various human tumor cell beads.
The invention content is as follows:
the invention aims to provide a 17-alkylthio gibberellic acid ester compound which is not reported in the prior art, a pharmaceutical composition taking the compound as an active ingredient, a preparation method of the compound and application of the compound in preparation of antitumor drugs.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
the invention firstly provides a 17-alkylthio gibberellic acid ester compound shown as a general formula (I) or a medicinal salt thereof,
in the general formula (I), R1Is carboxymethyl, 2-carboxyethyl, (R) -2-methoxycarbonyl-2-acetamidoethyl, (S) -2-methoxycarbonyl-2-acetamidoethyl; r2Is chlorine, hydroxyl, acetoxy; r3Is C1～C8Alkyl, benzyl, p-methoxybenzyl.
The 17-alkylthiogibberellic acid ester compounds of the general formula (I) include, but are not limited to, the following compounds: 13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid benzyl ester, 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid benzyl ester, N-methyl ester, N-chloro-3, N-15-dioxo-17- (2-carboxyethylthio) gibberellic acid benzyl ester, N-methyl ester, N-N, 13-chloro-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid benzyl ester, 13-chloro-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid benzyl ester, 13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid p-methoxybenzyl ester, 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid p-methoxybenzyl ester, 13-chloro-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid p-methoxybenzyl ester, p-n-ethoxybenzyl ester, p-ethoxycarbonyl-2-acetamidoethylthio ester, n-gibberellic acid, p-ethoxybenzyl ester, p-ethoxycarbonyl-2-benzyl ester, p-ethoxybenzyl ester, p-ethoxycarbonyl-3, p-ethoxybenzyl ester, p-2-ethoxycarbonyl-n-2-n-ethoxybenzyl ester, p-n-ethoxycarbonyl-2-n-ethoxybenzyl ester, p-n-p-n-p-n-p-ethoxybenzyl ester, p-ethoxybenzyl ester, p-n-p-n-p-n-c acid, p-n-p-c acid, p-p, 13-chloro-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester, 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester, 13-hydroxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid methyl ester, 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid methyl ester, N-hydroxy-N-O-N-methyl ester, N-hydroxy-N-methyl ester, N-hydroxy-N-O-N-methyl ester, N-S-N-, 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid benzyl ester, 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid benzyl ester, 13-hydroxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid benzyl ester, 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid benzyl ester, 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid p-methoxybenzyl ester, p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid p-methoxybenzyl ester, 13-acetoxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester, 13-acetoxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester, 13-acetoxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid methyl ester, p-methoxybenzyl ester, 13-acetoxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid methyl ester, p-methoxybenzyl ester, p-ethoxybenzyl ester, p-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid methyl ester, p-methoxybenzyl ester, p-acetoxy-methyl ester, p-methoxy-3, p-methoxy-2-methoxy-methyl ester, p-2-methoxy-methyl ester, p-methoxy-2-methyl ester, p-methoxy-methyl ester, p-2-methoxy-2-methyl ester, and p-methyl ester, p-2-methoxy-2-methoxy-methyl ester, p-methoxy-methyl ester, p-methyl ester, and p-methoxy-2-methoxy-methyl ester, p-methoxy-methyl ester, and a, 13-acetoxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid methyl ester, 13-acetoxy-3, 15-dioxo-17-carboxymethylthio gibberellic acid benzyl ester, 13-acetoxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid benzyl ester, 13-acetoxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid benzyl ester, 13-acetoxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid benzyl ester, and a pharmaceutically acceptable salt thereof, 13-acetoxy-3, 15-dioxo-17-carboxymethylthio gibberellic acid p-methoxybenzyl ester, 13-acetoxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid p-methoxybenzyl ester, 13-acetoxy-3, 15-dioxo-17- ((R) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid p-methoxybenzyl ester, 13-acetoxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid p-methoxybenzyl ester,
the chemical structures corresponding to the compounds are respectively as follows:
in the above structural formula: me is methyl, Bn is benzyl, PMB is p-methoxybenzyl, and Ac is acetyl.
The medicinal salt of the 17-alkylthio gibberellic acid ester compound shown by the general formula (I) refers to a pharmaceutically acceptable salt, and is a carboxylate obtained by reacting a carboxyl-containing 17-alkylthio gibberellic acid ester compound with an alkali metal or alkaline earth metal oxide, hydroxide, methoxide, ethoxylate or carbonate, such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a strontium salt and a bismuth salt.
The invention also provides a pharmaceutical composition containing a therapeutically effective amount of the 17-alkylthio gibberellic acid ester compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention further provides a preparation method of the 17-alkylthio gibberellic acid ester compound shown in the general formula (I), which takes 13-chloro-3, 15-dioxy gibberellic acid ester, or 13-hydroxy-3, 15-dioxy gibberellic acid ester, or 13-acetoxy-3, 15-dioxy gibberellic acid ester compound with the general formula (II) as a raw material, and the 17-alkylthio gibberellic acid ester compound shown in the general formula (I) is prepared by carrying out a regioselective Michael addition reaction with a sulfhydryl-containing compound in a proper solvent under neutral or alkaline conditions.
The preparation method of the 17-alkylthio gibberellic acid ester compound shown in the general formula (I) comprises the synthetic reaction shown in figure 3,
wherein R is1Is carboxymethyl, 2-carboxyethyl, (R) -2-methylOxycarbonyl-2-acetamidoethyl, (S) -2-methoxycarbonyl-2-acetamidoethyl; r2Is chlorine, hydroxyl, acetoxy; r3Is C1～C8Alkyl, benzyl or p-methoxybenzyl;
the raw material (II) is 13-chloro-3, 15-dioxy gibberellic acid ester, or 13-hydroxy-3, 15-dioxy gibberellic acid ester, or 13-acetoxy-3, 15-dioxy gibberellic acid ester compound, and the preparation of the raw material (II) can be carried out according to the methods of patent ZL200410021939.2 and patent ZL 200810058297.1;
in the synthetic route, the raw material (II) and a sulfhydryl-containing compound are subjected to Michael addition reaction in a proper solvent at low temperature, room temperature or under heating and under the condition of no catalyst or basic catalysis to generate a-17-alkylthio gibberellic acid ester compound shown in a general formula (I);
in the synthetic route, the usage of each reactant and the catalyst according to the molar ratio is as follows: the raw material (II)/the mercapto compound/the basic catalyst is 1/0.5-1/0.1-1;
in the above synthetic route, a suitable solvent is any one of N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, chloroform, diethyl ether, cyclopentyl methyl ether, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, methanol, ethanol, propanol or butanol;
in the above synthetic route, the reaction temperature is-78 deg.C to the reflux temperature of the corresponding reaction solvent;
in the synthetic route, the basic catalyst is any one of triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, potassium carbonate and cesium carbonate;
in the synthetic route, the reaction time is 0.5-48 hours.
The invention also provides application of the 17-alkylthio gibberellic acid ester compound or the medicinal salt or the medicinal composition thereof in preparing antitumor medicaments, wherein the tumors are leukemia, liver cancer, lung cancer, breast cancer, colon cancer and melanoma.
The invention also provides the application of the 17-alkylthio gibberellic acid ester compound or the medicinal salt thereof as a prodrug. The prodrug means that the 17-alkylthio gibberellic acid ester compound or the pharmaceutically acceptable salt thereof may have weak activity or even no activity, but is metabolized or otherwise converted into a corresponding bioactive form under physiological conditions after administration.
Gibberellin is one of five plant hormones, is put into agricultural production as early as 70 years in the 20 th century, and has the main physiological functions of promoting the growth and development of plants, promoting the germination of seeds, improving the maturing rate, reducing the withering of plant organs, changing the male and female ratio of the plants and the like. Gibberellin belongs to tetracyclic diterpenoid compounds, and because more functional groups exist in the molecular structure, a plurality of possibilities are provided for the modification of the chemical structure. Early studies found that terpenoids having structural units of α, β -unsaturated ketones or α -methylenecyclopentanone mostly have antitumor activity. Gibberellic acid GA3The product is a tetracyclic diterpenoid natural product, commercial fermentation production is realized, the A ring in the molecule can be subjected to oxidation reaction to construct an alpha, beta-unsaturated ketone structure, and the D ring also has the condition of being transformed into alpha-methylene cyclopentanone. We use gibberellic acid GA3Is used as a starting material, and is structurally modified to obtain a batch of Michael reaction acceptor gibberellic acid derivatives shown in the following structural formula,
the compounds are found to have good antitumor activity and a multi-target antitumor action mechanism, and can also obviously reverse the multidrug resistance of tumor cells, and two patent publications (ZL 200410021939.2; ZL 200810058297.1) in China are granted.
On the basis of earlier work, the invention continues to take the gibberellic acid derivative containing double alpha, beta-unsaturated ketone structure as a raw material, and through carrying out regioselective Michael addition reaction with a sulfhydryl-containing compound, carboxyl is introduced into a target substance to increase water solubility, so that the bioavailability is improved, and the possibility is provided for the development of a water-soluble preparation; in addition, the 17-alkylthio gibberellic acid ester compound is designed and synthesized by taking a gibberellic acid derivative containing a double alpha, beta-unsaturated ketone structure as a raw material and carrying out Michael addition reaction with a nontoxic cysteine derivative to increase the stability of a target compound and reduce the toxicity possibly generated in the metabolic process of the target compound as much as possible, and the in vitro anti-tumor activity experiment result shows that: most of the compounds have obvious inhibition effect on the proliferation of various human tumor cell beads.
The 17-alkylthio gibberellic acid ester compound provided by the invention is a compound obtained by structural optimization on the basis of earlier stage work of gibberellic acid derivative antitumor research of the inventor, has good stability, has good antitumor activity as per se or as a prodrug, and provides a new idea and selection for providing an antitumor drug.
The 17-alkylthiogibberellic acid ester compounds of the present invention may be used as they are or in the form of pharmaceutical compositions for use as medicaments. The pharmaceutical composition can also be used in a compound form with other medicines, and contains 0.1-99%, preferably 0.5-90% of the compound, and the balance of pharmaceutically acceptable medicinal carriers and/or excipients which are commonly used in medicinal preparations and are nontoxic and inert to human and animals. The pharmaceutical composition of the present invention is used in the form of a dose per unit body weight. Can be made into solid preparation (tablet, capsule, granule, powder, etc.) with different medicinal adjuvants.
The medicament of the invention can comprise 17-alkylthio gibberellic acid ester compounds or medicinal salts thereof and one or more medicinal diluents or carriers. Pharmaceutically acceptable carriers include, but are not limited to, lecithin, vitamin E, polyethylene glycol, propylene glycol, glycerol, tween or other surfactants for pharmaceutical formulation, aluminum oxide, aluminum stearate, ion exchange materials, buffer substances such as phosphate, sorbic acid, polyvinylpyrrolidone, cellulosic substances, polyvinyl alcohol, sodium carboxymethylcellulose, lanolin, cyclodextrins, and the like, which can be used to facilitate drug delivery of the compounds, pharmaceutically acceptable salts or prodrugs thereof of the present invention.
The medicine of the invention can contain 17-alkylthio gibberellic acid ester compounds or pharmaceutically acceptable salts thereof and other pharmaceutically acceptable auxiliary materials. Pharmaceutically acceptable excipients include, but are not limited to: disintegrating agents such as sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, sodium alginate, etc., binders such as povidone K30, microcrystalline cellulose, sodium alginate, etc., fillers such as anhydrous lactose, starch, glucose, lactose beads, etc., lubricants such as magnesium lauryl sulfate, magnesium stearate, etc., and other excipients, solubilizers, flavoring agents, colorants, etc.
The compound can be prepared into dosage forms including but not limited to granules, capsules, tablets, oral agents, liniments, ointments, injections and the like.
Description of the drawings:
FIG. 1 is a schematic structural diagram of 17-alkylthio gibberellic acid ester compounds according to the present invention.
FIG. 2 is GA3A flow chart of a method for preparing the gibberellic acid derivative containing the double alpha, beta-unsaturated ketone structure by structural modification.
FIG. 3 is a flow chart of a synthetic method of 17-alkylthio gibberellic acid ester compounds shown in general formula (I).
The specific implementation mode is as follows:
the following description will further explain the substance of the present invention by using the embodiments of the present invention with reference to the accompanying drawings, but the present invention is not limited thereto.
Example 1:
preparation and structural data for 13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester (SDG0201)
Methyl 13-chloro-3, 15-dioxogibberellic acid (391mg,1.0mmol) was dissolved in dichloromethane (10mL), followed by the addition of mercaptoacetic acid (0.090mL,1.33g/mL,1.3mmol,1.3eq.) and triethylamine (0.042mL,0.73g/mL,0.3mmol, 0.3eq.) and the reaction stirred at room temperature for 2 hours. After the completion of the reaction by TLC detection, the solvent was evaporated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate: 3:1) gave 430mg of a white solid as a yield: 89 percent.
1H-NMR(300MHz,CDCl3):δ＝7.23(1H,d,J＝6.0Hz),6.10(1H,d,J＝9.3Hz),3.72 (1H,s),3.68(3H,s),3.59(1H,d,J＝10.2Hz),3.17-2.69(5H,m),2.54(1H,dd,J＝12.0Hz), 2.35-2.11(2H,m),2.10-1.81(2H,m),1.35(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝212.89,191.04,175.08.172.63,170.09,145.58, 129.64,89.27,66.22,65.32,62.71,52.58,49.66,46.96,43.15,34.91,30.88,27.56,17.13,11.81；
HRMS(ESI):m/z[m-H]-calcd for C22H23ClO8S:481.0729；found:481.0723.
Example 2:
preparation and structural data for 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester (SDG0202)
Methyl 13-chloro-3, 15-dioxogibberellic acid (391mg,1.0mmol) was dissolved in dichloromethane (10mL), followed by addition of mercaptopropionic acid (0.104mL,1.22g/mL,1.2mmol,1.2eq.) and triethylamine (0.042mL,0.73g/mL,0.3mmol, 0.3eq.), and reaction stirred at 50 ℃ for 2 hours. After the completion of the reaction by TLC detection, the solvent was evaporated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate 3:1) gave 408mg of a white solid as a yield: 82 percent.
1H-NMR(300MHz,CDCl3):δ＝7.22(1H,d,J＝9.6Hz),6.10(1H,d,J＝9.3Hz),3.66 (3H,s),3.58(1H,d,J＝10.2Hz),2.95-2.68(9H,m),2.49(1H,d,J＝11.7Hz),2.34-2.01(4H, m),1.84(1H,m),1.33(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝212.85,191.07,177.47,172.64,170.09,145.64,129.61, 89.28,66.42,65.31,62.83,61.05,52.54,49.60,46.86,43.12,34.32,30.90,29.66,28.25,26.86, 17.12,11.80；
HRMS(ESI):m/z[m-H]-calcd for C22H25ClO8S:495.0886；found:495.0880.
Example 3:
preparation and structural data of 13-chloro-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid methyl ester (SDG0203)
Methyl 13-chloro-3, 15-dioxogibberellic acid (391mg,1.0mmol) was dissolved in dichloromethane (10mL), and then N-acetyl-L-cysteine methyl ester (195mg,1.1mmol,1.1eq.) and triethylamine (0.042mL,0.73g/mL,0.3mmol, 0.3eq.) were added and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction by TLC detection, the solvent was evaporated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate 1:5) gave 500mg of a white solid, yield: 88 percent.
1H-NMR(300MHz,CDCl3):δ＝6.89(1H,d,J＝7.7Hz),4.78(2H,d,J＝5.8Hz),4.67 (1H,d,J＝4.5Hz),3.56(3H,s),3.24(3H,s),3.49(1H,d,J＝6.9Hz),3.18-3.04(2H,m), 3.04-2.88(1H,m),2.94-2.80(2H,m),2.74(1H,dd,J＝4.9Hz),2.64(1H,d,J＝9.1Hz),2.47- 2.35(2H,m),2.10(1H,d,J＝11.8Hz),1.95(3H,s),1.73(1H,d,J＝10.5Hz),1.11(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝213.86,197.50,173.21 171.34,170.35,170.18,145.58, 129.63,94.55,64.18,60.36,60.21,58.85,52.90,52.41,49.93,48.76,43.66,35.93,34.67, 30.26,27.61,27.34,23.01,17.31,10.25；
HRMS(ESI):m/z[m+Na]+calcd for C26H30ClNO9S:590.1229；found:590.1227.
Example 4:
preparation and structural data for 13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid benzyl ester (SDG0204)
Methyl 13-chloro-3, 15-dioxogibberellic acid (497mg,1.0mmol) was dissolved in dichloromethane (10mL), followed by the addition of thioglycolic acid (0.083mL,1.33g/mL,1.2mmol,1.2eq.) and triethylamine (0.042mL,0.73g/mL,0.3mmol, 0.3eq.), and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction by TLC detection, the solvent was evaporated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate 3:1) gave 471mg of a white solid, yield: 80 percent.
1H-NMR(300MHz,CDCl3):δ＝7.21(2H,d,J＝8.4Hz),7.18(1H,d,J＝9.3Hz),6.89 (2H,d,J＝8.7Hz),6.08(1H,d,J＝9.3Hz),5.05(1H,d,J＝11.7Hz),4.93(1H,d,J＝11.7 Hz),3.82(3H,s),3.66(1H,s),3.58(1H,d,J＝10.2Hz),3.34(2H,q),2.97(1H,dd,J＝6.3, 6.3Hz),2.86-2.77(3H,m),2.62(1H,t),2.43(1H,d,J＝11.7Hz),2.27-2.11(3H,m),1.80(1H, t),1.32(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝212.84,191.00,175.51,172.59,169.41,159.96,145.50, 130.70,129.66,126.74,114.15,89.19,67.51,66.14,65.33,62.89,61.06,55.33,49.73,47.18, 43.10,34.80,30.86,27.40,17.11,11.87；
HRMS(ESI):m/z[m-H]-calcd for C29H29ClO9S:587.1148；found:587.1142.
Example 5:
preparation and structural data for 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid benzyl ester (SDG0205)
Methyl 13-chloro-3, 15-dioxogibberellic acid (497mg,1.0mmol) was dissolved in dichloromethane (10mL), followed by addition of mercaptopropionic acid (0.095mL,1.22g/mL,1.1mmol,1.1eq.) and triethylamine (0.042mL,0.73g/mL,0.3mmol, 0.3eq.), and reaction stirred at room temperature for 2 hours. After the completion of the reaction by TLC detection, the solvent was evaporated to dryness under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate 1:1) gave 491mg of white solid, yield: 83 percent.
1H-NMR(300MHz,CDCl3):δ＝7.23(2H,d,J＝8.7Hz),7.18(1H,d,J＝9.3Hz),6.89 (2H,d,J＝8.7Hz),6.08(1H,d,J＝9.6Hz),4.99(2H,q),3.82(3H,s),3.58(1H,d,J＝10.2 Hz),2.88-2.71(8H,m),2.67(1H,dd,J＝6.3,6.9Hz),2.43(1H,d,J＝11.7Hz),2.30-2.01(4H, m),1.81(1H,t),1.32(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝212.69,190.95,176.85,172.55,169.39,159.96,145.47, 130.64,129.69,126.76,114.13,89.15,67.49,66.31,65.34,62.87,61.08,55.31,49.74,47.10, 43.13,34.18,30.91,28.26,26.84,17.12,11.87；
HRMS(ESI):m/z[m-H]-calcd for C30H31ClO9S:589.1305；found:589.1299.
Example 6:
preparation and structural data of p-methoxybenzyl 3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid (SDG0206)
P-methoxybenzyl 13-chloro-3, 15-dioxogibberellic acid (497mg,1.0mmol), N-acetyl-L-cysteine methyl ester (195mg,1.1mmol,1.1eq.), amounts of other reactants, catalyst, solvent and procedures were the same as in example 5, and 580mg of a white solid was obtained by silica gel column chromatography (petroleum ether/ethyl acetate 1:2) with yield: 86 percent.
1H-NMR(300MHz,CDCl3):δ＝7.19(2H,d,J＝8.5Hz),6.88(2H,d,J＝8.5Hz),6.78 (1H,d,J＝7.9Hz),5.02-4.86(2H,m),4.77-4.60(1H,m),3.80(3H,s),3.74(3H,s),3.52(1H, t,J＝10.5Hz),3.50(1H,d,J＝6.9Hz),3.02-2.97(2H,m),2.97-2.91(1H,m),2.92-2.83(2H, m),2.82-2.74(2H,m),2.75-2.57(4H,m),2.28(1H,t,J＝10.8Hz),2.11(1H,dd,J＝11.9,6.4 Hz),2.00(3H,s),1.86-1.55(1H,m),1.14(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝213.56,197.44,173.27,171.40,170.62,170.35,159.94, 145.78,130.75,130.75,129.63,126.92,114.20,114.20,90.52,67.40,64.29,60.36,57.94, 55.41,53.07,51.73,49.84,48.69,43.81,42.54,39.47,34.80,29.99,27.84,23.08,17.34,10.43；
HRMS(ESI):m/z[m+Na]+calcd for C33H36ClNO10S:696.1646；found:696.1644.
Example 7:
preparation and structural data for 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester (SDG0207)
Methyl 13-hydroxy-3, 15-dioxogibberellic acid (372mg,1.0mmol) was dissolved in chloroform (10mL), followed by addition of thioglycolic acid (0.076mL,1.33g/mL,1.1mmol,1.1eq.) and diisopropylethylamine (0.050mL,0.78g/mL,0.3mmol,0.3eq.) using a microsyringe, and heating at 70 ℃ under reflux overnight. After the completion of the reaction by TLC detection, the solvent was evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate/acetic acid ═ 2:3:0.005) to give 395mg of a white solid compound, yield: 85 percent.
1H-NMR(300MHz,CDCl3):δ＝7.39(1H,d,J＝9.3Hz),5.95(1H,d,J＝9.6Hz),3.54 (3H,s),3.49(1H,d,J＝10.5Hz),3.29(2H,s),2.99(1H,d,J＝10.5Hz),2.87-2.70(2H,m), 2.38(1H,d,J＝11.4Hz),2.24-2.19(1H,m),2.09(1H,d,J＝11.4Hz),2.03-1.72(5H,m), 1.19(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝217.14,193.41,174.67,174.18,172.55,148.41,129.82, 91.20,76.57,66.58,62.69,61.67,52.58,50.62,42.00,35.50,29.49,28.58,17.77,12.17；
HRMS(ESI):m/z[m-H]+calcd for C22H24O9S:463.1068；found:463.1062.
Example 8:
preparation and structural data for 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester (SDG0208)
The preparation method is the same as example 7, the using amount of mercaptopropionic acid is (0.1mL,1.22g/mL,1.1mmol,1.1eq.), the using amounts of other reactants, catalysts and solvents and the operation process are the same as example 7, and 426mg of white solid compound is obtained by silica gel column chromatography (petroleum ether/ethyl acetate/acetic acid 2:3:0.01), the yield is: 89 percent.
1H-NMR(300MHz,CDCl3):δ＝7.22(1H,d,J＝9.3Hz),6.09(1H,d,J＝9.6Hz),3.65 (3H,s),3.58(1H,d,J＝10.2Hz),3.04(1H,dd,J＝3.9,3.9Hz),2.87(2H,d,J＝9.9Hz), 2.77-2.59(4H,m),2.51(1H,d,J＝11.7Hz),2.23(1H,d,J＝11.7Hz),2.18-1.94(4H,m), 1.83(1H,t),1.32(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝215.18,191.28,176.38,172.90,170.49,145.92,129.50, 89.39,76.28,65.40,61.34,61.15,58.61,52.46,49.61,47.90,40.29,34.02,28.95,27.55,27.12, 16.83,11.80；
HRMS(ESI):m/z[m-H]-calcd for C23H25O9S:476.1147；found:476.1149.
Example 9:
preparation and structural data of 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid methyl ester (SDG0209)
The preparation method is the same as that of example 7, 13-hydroxy-3, 15-dioxygibberellic acid methyl ester (372mg,1.0mmol), N-acetyl-L-cysteine methyl ester (194mg,1.1mmol,1.1eq.), the amounts of other reactants, catalysts and solvents and the operation process are the same as that of example 7, and silica gel column chromatography conditions are (petroleum ether/ethyl acetate 1:2), so that 495 mg of white solid is obtained with the yield of 90%.
1H-NMR(300MHz,CDCl3):δ＝6.89(1H,d,J＝7.7Hz),4.76(2H,d,J＝5.8Hz),4.67 (1H,d,J＝4.5Hz),3.56(3H,s),3.24(3H,s),3.48(1H,d,J＝6.9Hz),3.19-3.03(2H,m), 3.04-2.87(1H,m),2.93-2.80(2H,m),2.75(1H,dd,J＝4.9Hz),2.63(1H,d,J＝9.1Hz),2.47- 2.35(2H,m),2.11(1H,d,J＝11.8Hz),1.96(3H,s),1.72(1H,d,J＝10.5Hz),1.10(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝213.84,197.51,173.20,171.34,170.35,170.17,145.57, 129.63,94.56,76.18,62.36,61.21,58.85,52.90,52.44,49.92,48.76,43.67,35.93,34.69, 30.27,27.61,27.35,23.02,17.27,10.21；
HRMS(ESI):m/z[m+Na]+calcd for C29H31NO10S:572.1560；found:572.1566.
Example 10:
preparation and structural data of p-methoxybenzyl 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid (SDG0210)
The preparation method is the same as that of example 7, 13-hydroxy-3, 15-dioxogibberellic acid p-methoxybenzyl ester (479mg,1.0 mmol), mercaptoacetic acid (36 μ L,1.33g/mL,0.5mmol,1.2eq.), other catalysts, solvents and procedures are the same as example 7, silica gel column chromatography (petroleum ether/ethyl acetate/acetic acid ═ 1:2:0.01) is performed to obtain 464mg of white solid compound, yield: 81 percent.
1H-NMR(300MHz,CDCl3):δ＝7.21(2H,d,J＝8.4Hz),7.19(1H,d,J＝9.3Hz),6.88 (2H,d,J＝8.7Hz),6.07(1H,d,J＝9.3Hz),5.04(1H,d,J＝11.7Hz),4.89(1H,d,J＝11.4 Hz),3.81(3H,s),3.57(1H,d,J＝10.2Hz),3.31(2H,d,J＝7.2Hz),3.03(1H,dd,J＝4.8,5.1 Hz),2.86(1H,d,J＝10.5Hz),2.69(1H,q),2.49-2.40(2H,m),2.20-2.09(4H,m),1.91-1.76 (3H,m),1.31(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝215.06,191.26,174.31,172.95,169.86,159.83,145.83, 130.76,129.55,126.85,114.12,89.40,76.20,67.38,65.42,61.36,61.13,59.20,55.35,49.73, 48.24,40.46,33.89,29.04,27.78,16.84,11.87；
HRMS(ESI):m/z[m-H]-calcd for C29H30O10S:569.1487；found:569.1452.
Example 11:
preparation and structural data of p-methoxybenzyl 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid (SDG0211)
The preparation method is the same as that of example 7, 13-hydroxy-3, 15-dioxogibberellic acid p-methoxybenzyl ester (479mg,1.0 mmol), mercaptopropionic acid (0.1mL,1.22g/mL,1.1mmol,1.1eq.), the other reactants, catalysts and solvents are used and the operation process is the same as that of example 7, silica gel column chromatography (petroleum ether/ethyl acetate/acetic acid 2:3:0.04) is carried out to obtain 471mg of white solid compound, yield: 80.5 percent.
1H-NMR(300MHz,CDCl3):δ＝7.20(2H,d,J＝8.7Hz),7.17(1H,d,J＝9.3Hz),6.87 (2H,d,J＝8.7Hz),6.05(1H,d,J＝9.6Hz),5.04(1H,d,J＝11.7Hz),4.89(1H,d,J＝11.4 Hz),3.79(3H,s),3.56(1H,d,J＝10.2Hz),2.93(1H,dd,J＝4.5,4.8Hz),2.84-1.74(15H,m), 1.30(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝215.47,191.35,175.65,172.96,169.90,159.96,145.91, 130.83,129.66,126.98,114.14,89.41,76.31,67.35,65.50,61.46,61.05,58.49,55.41,49.82, 48.35,40.32,34.06,29.13,27.62,27.14,16.94,11.98；
HRMS(ESI):m/z[m-H]-calcd for C30H32O10S:483.1643；found:483.1637.
Example 12:
preparation and structural data of p-methoxybenzyl 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylamino) ethylsulfanylgibberellic acid (SDG0212)
The preparation method is the same as that of 7, 13-hydroxy-3, 15-dioxogibberellic acid p-methoxybenzyl ester (479mg,1.0 mmol), N-acetyl-L-cysteine methyl ester (213mg,2.2mmol,1.2eq.), and other reactants, catalysts, solvents and procedures are the same as those of example 7, and the white solid 610mg and yield are obtained by silica gel column chromatography (petroleum ether/ethyl acetate ═ 1: 2): 93 percent.
1H-NMR(300MHz,CDCl3):δ＝7.11(2H,d,J＝8.5Hz),6.87(2H,d,J＝8.5Hz),6.78 (1H,d,J＝7.9Hz),5.02-4.86(2H,m),4.77-4.60(1H,m),3.81(3H,s),3.75(3H,s),3.52(1H, t,J＝10.5Hz),3.50(1H,d,J＝6.9Hz),3.02-2.97(2H,m),2.97-2.91(1H,m),2.92-2.83(2H, m),2.81-2.74(2H,m),2.76-2.56(4H,m),2.28(1H,t,J＝10.8Hz),2.11(1H,dd,J＝11.9,6.4 Hz),2.01(3H,s),1.86-1.56(1H,m),1.16(3H,s)；
13C-NMR(75MHz,CDCl3):δ＝213.53,197.45,173.28,171.43,170.61,170.37,159.93, 145.76,130.76,130.75,129.63,126.92,114.20,114.20,90.52,76.45,64.30,61.23,57.98, 55.43,53.17,51.78,49.89,48.73,43.81,42.55,39.43,34.80,29.95,27.76,23.18,17.34,10.43；
HRMS(ESI):m/z[m+Na]+calcd for C33H37NO11S:678.1979；found:678.1985.
Pharmacodynamics experimental part
First, cell proliferation inhibition experiment
1. Experimental reagent
MTS (3- (4, 5-dimethylthiozol-2-yl) -5- (3-carboxymethyloxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium), DMSO was purchased from Sigma, USA; DMEM, RPMI-1640, penicillin/streptomycin from Hyclone; trypsin was purchased from Bioind; CellTiter
AQueousOne Solution Cell Prolification Assay kit was purchased from Promega corporation. The compounds related to the invention are all prepared by self-synthesis in the laboratory.
The cells used in the experiment, A549, SMMC-7721, HL-60, MCF-7, SW480 and A-375, were purchased from Shanghai cell bank of Chinese academy of sciences.
PBS buffer (pH 7.4, 10 × stock solution) preparation: 80g of NaCl and KH2PO4 2.4g， Na2HPO4·12H235.8g of O and 2g of KCl, adjusting the pH value to 7.4, diluting to 1L, and diluting to 1 Xbuffer solution when in use.
2. Experimental methods
Cell survival rate detection by MTS method: CellTiter
AQueousThe One Solution cell proliferation detection kit detects the number of living cells in experiments such as cell proliferation and cytotoxicity by a colorimetric method. The reagent comprises a novel tetrazole compound (3- (4, 5-dimethylthiozol-2-yl) -5- (3-carboxymethyloxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium, inner salt, MTS) and an electron coupling agent (PES). PES enhances chemical stability, which allows it to be mixed with MTS to form a stable solution. MTS is reduced into colored formazan products by various dehydrogenases in cells, the colored formazan products can be directly dissolved in a culture solution, and the light absorption value of the formazan products detected at 490nm is in direct proportion to the number of living cells in the culture.
The method comprises the following specific steps:
(1) the cell suspension concentration was adjusted to 5X 10 with a culture medium containing 10% fetal bovine serum4And each cell/mL, 100 mu L of cell suspension is added into a 96-well plate, namely 5000 cells are inoculated into each well, and 200 mu L of sterilized water is added into the side holes of the micro-well plate to balance the humidity of the micro-well plate and reduce the edge effect.
(2) The plates were incubated at 37 ℃ in 5% CO2Culturing in incubator for 16-24 hr, and adding compound when cell reaches logarithmic growth phase after adherence.
(3) The highest concentration of the test compound 80. mu.M was prepared from the culture medium, and the concentration was 5-fold diluted in a gradient manner to obtain 5 concentrations, i.e., 80. mu.M, 16. mu.M, 3.2. mu.M, 0.64. mu.M and 0.128. mu.M, respectively.
(4) 100 μ L of the diluted compounds of different concentrations were added to a 96-well plate, and 3 duplicate wells were provided for each assay concentration.
(5) The cells were incubated at 37 ℃ with 5% CO2After incubation for 48 hours in the incubator, the incubation was stopped, the culture medium in the 96-well plate was removed, and 120. mu.L of MTS diluent (MTS diluent, i.e., culture medium: CellTiter) was added
AQueousOne Solution reagent 5: 1).
(6) Blank control setup: due to CellTiter
AQueousThere was a slight amount of spontaneously generated light absorption at 490nm after incubation of One Solution Reagent with cell culture medium, so 3 duplicate blank wells (no cells) were required. The control well contained equal volumes of cell culture medium and CellTiter to the experimental well
AQueousAnd subtracting the light absorption value of the blank control hole without the cell from the light absorption value of the experimental hole to obtain a corrected light absorption value.
(7) The plates were incubated at 37 ℃ in 5% CO2After the incubator is incubated for 1-4h, the culture plate is placed on an oscillator for low-speed oscillation for 5min, and the light absorption value of each hole is detected at 490nm of an enzyme-linked immunosorbent assay detector. Recording OD values and calculating cell viability for different concentrations of compound and IC for each test compound50The value is obtained.
3. Results of the experiment
TABLE 117-alkylthio gibberellic acid ester compounds with antitumor and proliferating effects
The 17-alkylthio gibberellic acid ester compound disclosed by the invention is used for carrying out in-vitro cell proliferation inhibition experiments on six human tumor cell lines including leukemia HL-60, liver cancer SMMC-7721, lung cancer A-549, breast cancer MCF-7, colon cancer SW480 and melanoma A-375, and cisplatin is used as a positive control drug, so that the results show that most of the 17-alkylthio gibberellic acid ester compounds shown in the general formula (I) have obvious inhibition effects on the proliferation of the tumor cells, and part of data are shown in the table 1.
Example 13:
preparation of tablets:
the compounds according to the invention are prepared as described in examples 1 to 12, one or a mixture of several compounds is/are taken, and excipients are added in a weight ratio of 1:5 to 1:10 to the excipients, and the mixture is granulated and tabletted.
Example 14:
preparation of oral liquid preparation:
the compounds of the invention are prepared as described in examples 1-5, and one or a mixture of several compounds is used to prepare oral liquid according to conventional oral liquid preparation methods.
Example 15:
preparation of capsules, granules or medicinal granules:
the compound of the invention is prepared by the method of the embodiment 1-5, one compound or the mixture of several compounds is taken, and the excipient is added according to the weight ratio of 5:1 of the compound and the excipient, and the compound is prepared into capsules, granules or granules.
Claims (8)
1. 17-alkylthio gibberellin ester compounds shown in general formula (I) or medicinal salts thereof,
the 17-alkylthio gibberellic acid ester compound shown in formula (I) is not 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetamidoethylthio) gibberellic acid methyl ester.
2. The 17-alkylthiogibberellin-based compound of claim 1, wherein the 17-alkylthiogibberellin-based compound is the following compound:
13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid methyl ester, 13-chloro-3, 15-dioxo-17-carboxymethylthiogibberellic acid p-methoxybenzyl ester, 13-chloro-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid p-methoxybenzyl ester, 13-chloro-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid methyl ester, 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid methyl ester, 13-hydroxy-3, 15-dioxo-17-carboxymethylthiogibberellic acid p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17- (2-carboxyethylthio) gibberellic acid p-methoxybenzyl ester, 13-hydroxy-3, 15-dioxo-17- ((S) -2-methoxycarbonyl-2-acetylaminoethylthio) gibberellic acid p-methoxybenzyl ester,
the chemical structures corresponding to the compounds are respectively as follows:
in the above structural formula: me is methyl, PMB is p-methoxybenzyl and Ac is acetyl.
3. The 17-alkylthiogibberellic acid ester compound of the general formula (i) or its pharmaceutically acceptable salt of claim 1, wherein the pharmaceutically acceptable salt is a carboxylate obtained by reacting the carboxyl-containing 17-alkylthiogibberellic acid ester compound of claim 1 with an alkali metal or alkaline earth metal oxide, hydroxide, methoxide, ethoxylate or carbonate, and the carboxylate is a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a strontium salt or a bismuth salt.
4. A pharmaceutical composition comprising a therapeutically effective amount of any one or a mixture of two or more of the 17-alkylthiazyl gibberellic acid ester compounds of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. The use of the pharmaceutical composition of claim 4 in the preparation of an anti-tumor medicament, wherein the tumor is leukemia, liver cancer, lung cancer, breast cancer, colon cancer, melanoma.
6. The use of 17-alkylthiogibberellic acid ester compounds or their pharmaceutically acceptable salts as claimed in claim 1 in the preparation of anti-tumor drugs.
7. The use of the 17-alkylthiogibberellic acid ester compound or its pharmaceutically acceptable salt in preparing an anti-tumor medicament according to claim 6, wherein the tumor is leukemia, liver cancer, lung cancer, breast cancer, colon cancer, or melanoma.
8. A process for producing 17-alkylthiogibberellic acid ester compounds as claimed in claim 1, wherein: the method uses 13-chloro-3, 15-dioxy gibberellic acid ester, or 13-hydroxy-3, 15-dioxy gibberellic acid ester, or 13-acetoxy-3, 15-dioxy gibberellic acid ester compound as raw material, in a suitable solvent, under neutral or alkaline condition, to produce the 17-alkylthio gibberellic acid ester compound of claim 1 through Michael addition reaction with sulfhydryl-containing compound,
the method comprises a synthetic reaction shown as the following formula:
wherein R is1Is carboxymethyl, 2-carboxyEthyl, (R) -2-methoxycarbonyl-2-acetylaminoethyl, (S) -2-methoxycarbonyl-2-acetylaminoethyl; r2Is chlorine, hydroxyl, acetoxy; r3Is C1～C8Alkyl, benzyl or p-methoxybenzyl;
in the synthetic route, the raw material (II) and a sulfhydryl-containing compound are subjected to Michael addition reaction in a proper solvent at low temperature, room temperature or under heating and under the condition of no catalyst or basic catalysis to generate a 17-alkylthio gibberellic acid ester compound shown in a general formula (I);
in the synthetic route, the usage of each reactant and the catalyst according to the molar ratio is as follows: the raw material (II)/the mercapto compound/the basic catalyst is 1/0.5-1/0.1-1;
in the above synthetic route, a suitable solvent is any one of N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, chloroform, diethyl ether, cyclopentyl methyl ether, ethyl acetate, propyl acetate, butyl acetate, tetrahydrofuran, 1, 4-dioxane, benzene, toluene, methanol, ethanol, propanol or butanol;
in the above synthetic route, the reaction temperature is-78 deg.C to the reflux temperature of the corresponding reaction solvent;
in the synthetic route, the basic catalyst is any one of triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, potassium carbonate and cesium carbonate;
in the synthetic route, the reaction time is 0.5-48 hours.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1775769A (en) * | 2005-06-22 | 2006-05-24 | 云南大学 | Method for synthesizing gibberellin GA4 |
| CN101260095A (en) * | 2008-04-18 | 2008-09-10 | 云南大学 | 13-halo-3,15-dioxygibberellic acid ester and preparation method thereof |
| CN101497590A (en) * | 2009-03-11 | 2009-08-05 | 云南大学 | 13-alkoxy-3,15-dioxo-gibberellic acid ester and preparation thereof |
| WO2010062372A2 (en) * | 2008-11-03 | 2010-06-03 | President And Fellows Of Harvard College | Methods for modulating nf-kb using gibberellins |
| CN101830873A (en) * | 2010-02-02 | 2010-09-15 | 云南大学 | Preparation method of 13-chloro-3,15-dicarbonyl gibberellic acid and salt thereof |
| CN102108075A (en) * | 2009-12-28 | 2011-06-29 | 中国药科大学 | Method for synthesizing novel derivatives from gibberellane GA3 and use thereof |
| WO2013142873A2 (en) * | 2012-03-23 | 2013-09-26 | The Board Of Trustees Of The University Of Illinois | Complex and structurally diverse compounds |
-
2018
- 2018-02-09 CN CN201810131676.2A patent/CN108276370B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1775769A (en) * | 2005-06-22 | 2006-05-24 | 云南大学 | Method for synthesizing gibberellin GA4 |
| CN101260095A (en) * | 2008-04-18 | 2008-09-10 | 云南大学 | 13-halo-3,15-dioxygibberellic acid ester and preparation method thereof |
| WO2010062372A2 (en) * | 2008-11-03 | 2010-06-03 | President And Fellows Of Harvard College | Methods for modulating nf-kb using gibberellins |
| CN101497590A (en) * | 2009-03-11 | 2009-08-05 | 云南大学 | 13-alkoxy-3,15-dioxo-gibberellic acid ester and preparation thereof |
| CN102108075A (en) * | 2009-12-28 | 2011-06-29 | 中国药科大学 | Method for synthesizing novel derivatives from gibberellane GA3 and use thereof |
| CN101830873A (en) * | 2010-02-02 | 2010-09-15 | 云南大学 | Preparation method of 13-chloro-3,15-dicarbonyl gibberellic acid and salt thereof |
| WO2013142873A2 (en) * | 2012-03-23 | 2013-09-26 | The Board Of Trustees Of The University Of Illinois | Complex and structurally diverse compounds |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of gibberellin derivatives with anti-tumor bioactivities;Jingbo Chen,et al.;《Bioorganic & Medicinal Chemistry Letters》;20090722;第19卷;第5496-5499页 * |
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