CN110483284B - 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound and synthetic method and application thereof - Google Patents
1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1-adamantane formic acid-2- (substituted benzoyl oxy) ethyl ester compound and a synthesis method and application thereof, wherein the structural formula of the 1-adamantane formic acid-2- (substituted benzoyl oxy) ethyl ester compound is shown as the formula (I):
Description
Technical Field
The invention relates to a 1-adamantane formic acid-2- (substituted benzoyl oxy) ethyl ester compound and a synthesis method and application thereof.
Background
Adamantane has unique Chemical properties and physical properties, and has been widely applied in a plurality of fields such as medicines (Chemical Reviews,2013,113(5): 3516-. The literature reports that the adamantane derivative has the biological activities of antitumor (Investigational New Drugs,2009,27(6):586-594, applied chemistry, 2018,35(4): 420:. 1989,159(3): 430-. In addition, adamantane is generally considered to have a particular lipophilicity, and introduction of its structure tends to enhance the lipophilicity and stability of the drug, thereby improving the kinetics of its drug metabolism. Thus, adamantane is often used as a known pharmacodynamic agent "additive" for regulating, for example, sulfonylurea hypoglycemic agents (Journal of Medicinal Chemistry,1963,6(6):760), anabolic steroids (Journal of Medicinal Chemistry,1965,8(5):580), nucleosides (Journal of Medicinal Chemistry,1967,10(2): 189: -199), and the like.
Carboxylate is a common chemical structure and is widely applied in the fields of medicines, pesticides and the like. The carboxylic ester compounds are reported to have a broad spectrum of biological activities such as antitumor (pharmaceutical science, 2013,48(06): 874-. Many commercialized pharmaceuticals and agricultural chemicals contain carboxylate structures, such as the antineoplastic drugs capecitabine tablet, kemptol; antiviral drug adefovir dipivoxil tablet, and tenofovir disoproxil fumarate tablet; anti-inflammatory drugs aspirin, salsalate; the insecticides beta-cypermethrin, cyfluthrin; the bactericides such as furalaxyl-m and propamocarb; the herbicides bifenthrin, butafenacil and the like.
In view of the fact that both the adamantane derivatives and the ester compounds have good biological activity, in order to find a novel medicine lead, the invention utilizes an active substructure splicing method to splice adamantane and an ester structure, designs and synthesizes a novel 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound, and is expected to have good biological activity.
The research on the structure and the biological activity of the series of 1-adamantane formic acid-2- (substituted benzoyl oxy) ethyl ester compounds designed and synthesized by the invention is not reported in documents.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention aims to provide a 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound, a synthetic method and an application thereof, wherein the synthetic method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is simple and shows a certain antitumor activity.
The 1-adamantane formic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that: the structural formula is shown as the formula (I):
in the formula (I), H on a benzene ring is mono-substituted, di-substituted or not substituted by a substituent R; n is an integer of 0 to 2, preferably an integer of 1 to 2, and n represents the number of substituents R on the benzene ring; when n is 0, it represents that H on the benzene ring is unsubstituted; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2, H on the benzene ring is disubstituted by a substituent R, and the substituents R at different substitution positions are the same or different; the substituent R is hydrogen, alkoxy of C1-C3, haloalkyl of C1-C2 and halogen, and is preferably hydrogen, methoxy, ethoxy, trifluoromethyl, F, Cl or Br.
The 1-adamantane formic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that: in the formula (I), R (n) is hydrogen, o-fluorine, p-fluorine, o-chlorine, m-bromine, p-methoxy, o-ethoxy, o-trifluoromethyl, 2, 6-difluoro, 2, 3-dichloro or 2, 4-dichloro.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized by comprising the following steps of:
1) dissolving substituted benzoyl chloride shown in a formula (III) in an organic solvent A to prepare a substituted benzoyl chloride solution;
2) mixing an intermediate 2-hydroxyethyl-1-adamantane formate shown in a formula (II), an organic solvent B and an acid-binding agent, stirring for dissolving, dropwise and slowly adding the substituted benzoyl chloride solution prepared in the step 1) under an ice bath condition, reacting at room temperature after the dropwise adding is finished, monitoring by TLC (thin layer chromatography) until the reaction is finished, filtering a reaction solution, removing the solvent from a filtrate through desolventizing, and carrying out column chromatography separation on the obtained desolventizing residue to obtain a 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound shown in the formula (I);
in the formula (III), H on a benzene ring is mono-substituted, di-substituted or not substituted by a substituent R; n is an integer of 0 to 2, preferably an integer of 1 to 2, and n represents the number of substituents R on the benzene ring; when n is 0, it represents that H on the benzene ring is unsubstituted; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2, H on the benzene ring is disubstituted by a substituent R, and the substituents R at different substitution positions are the same or different; the substituent R is hydrogen, alkoxy of C1-C3, haloalkyl of C1-C2 and halogen, and is preferably hydrogen, methoxy, ethoxy, trifluoromethyl, F, Cl or Br.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxygen) ethyl ester compound is characterized in that the molar ratio of the 2-hydroxyethyl-1-adamantane formic ester shown in the formula (II) to the substituted benzoyl chloride shown in the formula (III) is 1: 1-5.0, and preferably 1: 1-1.5.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that an organic solvent A and an organic solvent B are the same, and the organic solvent B is tetrahydrofuran or acetonitrile, preferably tetrahydrofuran; in the step 1), the concentration of the prepared substituted benzoyl chloride solution is 0.25-0.5 mol/L.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that in the step 2), an acid-binding agent is triethylamine or pyridine, preferably triethylamine; the molar ratio of the 2-hydroxyethyl-1-adamantane formate shown in the formula (II) to the acid-binding agent is 1: 1-5, and preferably 1: 1.2-2.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that in the step 2), the molar ratio of the 2-hydroxyethyl-1-adamantane formic ester shown in the formula (II) to the organic solvent B is 1: 30-150, and preferably 1: 70-120.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that in the step 2), the reaction time at room temperature is 1-5 hours, preferably 2-4 hours.
The synthesis method of the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that in the step 2), an eluant used for column chromatography separation is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3-8.
The 1-adamantane carboxylic acid-2- (substituted benzene acyloxy) ethyl ester compound is applied to preparation of antitumor drugs.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound which is simple to prepare and shows a certain antitumor activity, and in the embodiment of the invention, the inhibition activity tests of tyrosyl-DNA phosphodiesterase 1(TDP1), tyrosyl-DNA phosphodiesterase 2(TDP2) and topoisomerase I (TOP I) are carried out. The results show that most of the synthesized compounds Ia-Il have certain inhibitory activity on tyrosyl DNA phosphodiesterase 1(TDP1) and topoisomerase I (TOP I). The compounds Ib, Id and Ij show moderate inhibitory activity to TDP1, the inhibition rates of the compounds Ib, Id and Ij are all more than 30%, wherein the inhibition rate of the compound Ij to TDP1 can reach 76.9%; the compounds Ib, Id, If, Ig, Ih and Ij all have more than 35 percent of inhibition rate on TOP I, wherein the inhibition rate of the compounds Ib on TOP I can reach 55.7 percent. In addition, the compounds Ie and If also exhibit a certain inhibitory activity on tyrosyl-DNA phosphodiesterase 2(TDP 2).
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1 synthesis of compound Ia (r) (n) ═ H):
a tetrahydrofuran solution (5mL) of benzoyl chloride (1.5mmol) was prepared by dissolving 1.5mmol of benzoyl chloride in 5mL of tetrahydrofuran.
Intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (10mL) and acid-binding agent triethylamine (1.8mmol) were mixed, dissolved with stirring, and a solution of benzoyl chloride (1.5mmol) in tetrahydrofuran (5mL) was slowly added dropwise under ice-bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 2 hours, then, hydrochloride of triethylamine generated in the reaction is removed through filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 5) to obtain light yellow oily liquid, namely 1-adamantanecarboxylic acid-2- (benzoyloxy) ethyl ester, and the calculated yield is 66.5%.
1H NMR(500MHz,CDCl3)δ8.07–8.01(m,2H),7.59–7.54(m,1H),7.47–7.42(m,2H),4.52(t,J＝4.5Hz,2H),4.40(t,J＝5.0Hz,2H),1.99(s,3H),1.89(d,J＝3.0Hz,6H),1.74–1.65(m,6H)；
HRMS(ESI)calcd C20H24O4[M+H]+328.1741,found 328.1697。
Example 2 synthesis of compound Ib (r (n) ═ o fluoro):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (8.5mL) and acid-binding agent triethylamine (2.25mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (4mL) of o-fluorobenzoyl chloride (1.5mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, the hydrochloride of triethylamine generated in the reaction is removed by filtration, the filtrate is subjected to rotary evaporation to remove the solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (the eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3) to obtain a white waxy solid, namely 1-adamantanecarboxylic acid-2- (2-fluorobenzoyloxy) ethyl ester, and the yield is calculated to be 64.9%.
1H NMR(500MHz,CDCl3)δ7.97–7.90(m,1H),7.57–7.51(m,1H),7.25–7.18(m,1H),7.12–7.18(m,1H),4.54(t,J＝4.5Hz,2H),4.39(t,J＝4.5Hz,2H),2.01(s,3H),1.90(d,J＝3.0Hz,6H),1.75–1.64(m,6H)；
HRMS(ESI)calcd C20H23FO4[M+H]+346.1627,found 346.1668。
Example 3 synthesis of compound Ic (r (n) ═ p-fluoro):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (8.5mL) and acid-binding agent triethylamine (2.0mmol) were mixed, dissolved with stirring, and a solution of p-fluorobenzoyl chloride (1.5mmol) in tetrahydrofuran (4mL) was slowly added dropwise under ice-bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, hydrochloride of triethylamine generated in the reaction is removed by filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3) to obtain a white waxy solid, namely 1-adamantanecarboxylic acid-2- (4-fluorobenzoyloxy) ethyl ester, and the calculated yield is 55.7%.
1H NMR(500MHz,CDCl3)δ8.09–8.04(m,2H),7.16–7.10(m,2H),4.52(t,J＝4.5Hz,2H),4.40(t,J＝5.0Hz,2H),2.00(s,3H),1.89(d,J＝3.0Hz,6H),1.74–1.66(m,6H)；
HRMS(ESI)calcd C20H23FO4[M+H]+346.1688,found 346.1598。
Example 4 synthesis of compound Id (r (n) ═ o-chloro):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (12mL) and acid-binding agent triethylamine (2.7mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (6mL) of o-chlorobenzoyl chloride (2.0mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 4 hours, then, hydrochloride of triethylamine generated in the reaction is removed by filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (2-chlorobenzoyloxy) ethyl ester, and the calculated yield is 57.6%.
1H NMR(500MHz,CDCl3)δ7.86–7.80(m,1H),7.48–7.42(m,2H),7.36–7.30(m,1H),4.55(t,J＝3.5Hz,2H),4.39(t,J＝4.0Hz,2H),2.00(s,3H),1.89(d,J＝3.0Hz,6H),1.75–1.64(m,6H)；
HRMS(ESI)calcd C20H23ClO4[M+H]+362.1385,found 362.1388。
Example 5 synthesis of compound Ie (r (n) ═ m-chloro):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (12mL) and acid-binding agent triethylamine (2.7mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (6mL) of m-chlorobenzoyl chloride (2.0mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 4 hours, then, hydrochloride of triethylamine generated in the reaction is removed through filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 4) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (3-chlorobenzoyloxy) ethyl ester, and the calculated yield is 54.5%.
1H NMR(500MHz,CDCl3)δ8.05–7.99(m,1H),7.96–7.91(m,1H),7.58–7.52(m,1H),7.43–7.37(m,1H),4.53(t,J＝4.5Hz,2H),4.40(t,J＝5.0Hz,2H),2.01(s,3H),1.90(d,J＝2.5Hz,6H),1.76–1.66(m,6H)；
HRMS(ESI)calcd C20H23ClO4[M+H]+362.1398,found 362.1309。
Example 6 synthesis of compound If (r (n) ═ m bromine):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (10mL) and acid-binding agent triethylamine (2.4mmol) were mixed, dissolved with stirring, and a solution of m-bromobenzoyl chloride (1.5mmol) in tetrahydrofuran (5mL) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, hydrochloride of triethylamine generated in the reaction is filtered out, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 4) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (3-bromobenzoyloxy) ethyl ester, and the calculated yield is 59.2%.
1H NMR(500MHz,CDCl3)δ8.22–8.15(m,1H),8.01–7.94(m,1H),7.74–7.66(m,1H),7.37–7.31(m,1H),4.53(t,J＝4.5Hz,2H),4.40(t,J＝5.0Hz,2H),2.01(s,3H),1.90(d,J＝2.6Hz,6H),1.76–1.66(m,6H)；
HRMS(ESI)calcd C20H23BrO4[M+H]+406.0834,found 406.1255。
Example 7 synthesis of the compound Ig (r (n) ═ p-methoxy):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (12mL) and acid-binding agent triethylamine (3.0mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (6mL) of p-methoxybenzoyl chloride (1.5mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, hydrochloride of triethylamine generated in the reaction is removed by filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 8) to obtain a white waxy solid, namely 1-adamantanecarboxylic acid-2- (4-methoxybenzoyloxy) ethyl ester, and the calculated yield is 59.8%.
1H NMR(500MHz,CDCl3)δ8.02–7.98(m,2H),6.95–6.92(m,2H),4.49(t,J＝4.5H,2H),4.39(t,J＝5.0Hz,2H),3.87(s,3H),2.01(s,3H),1.89(d,J＝3.0Hz,6H),1.75–1.66(m,6H)；
HRMS(ESI)calcd C21H26O5[M+H]+358.1843,found 358.1888。
Example 8 synthesis of compound Ih (r (n) ═ o-ethoxy):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (12mL) and acid-binding agent triethylamine (3.0mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (6mL) of o-ethoxybenzoyl chloride (1.5mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, hydrochloride of triethylamine generated in the reaction is removed through filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 6) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (2-ethoxybenzoyloxy) ethyl ester, and the calculated yield is 67.4%.
1H NMR(500MHz,CDCl3)δ7.80(dd,J＝8.0,2.0Hz,1H),7.48–7.42(m,1H),7.01–6.94(m,2H),4.50(t,J＝4.5Hz,2H),4.38(t,J＝5.0Hz,2H),4.12(q,J＝7.0Hz,2H),2.00(s,3H),1.90(d,J＝3.0Hz,6H),1.75–1.66(m,6H),1.46(t,J＝7.0Hz,3H；
HRMS(ESI)calcd C22H28O5[M+H]+372.1946,found 372.1973。
Example 9 synthesis of compound Ii (r (n) ═ o-trifluoromethyl):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (9mL) and acid-binding agent triethylamine (2.7mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (4.5mL) of o-trifluoromethylbenzoyl chloride (1.5mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 4 hours, then, hydrochloride of triethylamine generated in the reaction is removed through filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (2-trifluoromethyl benzoyloxy) ethyl ester, and the calculated yield is 69.4%.
1H NMR(500MHz,CDCl3)δ7.85–7.77(m,1H),7.79–7.73(m,1H),7.67–7.61(m,2H),4.55(t,J＝4.5Hz,2H),4.38(t,J＝5.0Hz,2H),2.01(s,3H),1.90(d,J＝2.5Hz,6H),1.75–1.65(m,6H)；
HRMS(ESI)calcd C21H23F3O4[M+H]+396.1577,found 196.1795。
Example 10 synthesis of compound Ij (r (n) ═ 2, 6-difluoro):
intermediate 2-hydroxyethyl-1-adamantanecarboxylate (0.336g, 1.5mmol), tetrahydrofuran (10mL) and acid-binding agent triethylamine (2.5mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (5mL) of 2, 6-difluorobenzoyl chloride (1.5mmol) was slowly added dropwise under ice-bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 2 hours, then, hydrochloride of triethylamine generated in the reaction is removed through filtration, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 5) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (2, 6-difluorobenzoyloxy) ethyl ester, and the calculated yield is 54.8%.
1H NMR(500MHz,CDCl3)δ7.47–7.41(m,1H),7.01–6.94(m,2H),4.58(t,J＝5.0Hz,2H),4.37(t,J＝5.0Hz,2H),2.02(s,3H),1.91(d,J＝3.0Hz,6H),1.75–1.66(m,6H)；
HRMS(ESI)calcd C20H22F2O4[M+H]+364.1577,found 364.0917。
Example 11 synthesis of compound Ik (r (n) ═ 2, 3-dichloro):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (14.6mL) and acid-binding agent triethylamine (3.0mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (7.5mL) of 2, 3-dichlorobenzoyl chloride (2.0mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, hydrochloride of triethylamine generated in the reaction is filtered out, the filtrate is subjected to rotary evaporation to remove a solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 4) to obtain a white waxy solid, namely 1-adamantanecarboxylic acid-2- (2, 3-dichlorobenzoyl oxy) ethyl ester, wherein the yield is calculated to be 66.6%.
1H NMR(500MHz,CDCl3)δ7.68(dd,J＝8.0,2.0Hz,1H),7.62(dd,J＝8.0,2.0Hz,1H),7.29(t,J＝8.0Hz,1H),4.57(t,J＝5.0Hz,2H),4.40(t,J＝
5.0Hz,2H),2.02(s,3H),1.90(d,J＝3.0Hz,6H),1.74–1.66(m,6H)；
HRMS(ESI)calcd C20H22Cl2O4[M+H]+396.0929,found 396.0900。
Example 12 synthesis of compound Il (r (n) ═ 2, 4-dichloro):
intermediate 2-hydroxyethyl-1-adamantane formate (0.336g, 1.5mmol), tetrahydrofuran (14.6mL) and acid-binding agent triethylamine (3.0mmol) were mixed, dissolved with stirring, and a tetrahydrofuran solution (7.5mL) of 2, 4-dichlorobenzoyl chloride (2.0mmol) was slowly added dropwise under ice bath conditions. After the dropwise addition, the reaction is carried out at room temperature for 3 hours, then, hydrochloride of triethylamine generated in the reaction is filtered out, the filtrate is subjected to rotary evaporation to remove solvent tetrahydrofuran, and the obtained rotary evaporation residue is subjected to column chromatography separation (eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3) to obtain colorless oily liquid, namely 1-adamantanecarboxylic acid-2- (2, 4-dichlorobenzoyl oxy) ethyl ester, and the calculated yield is 53.7%.
1H NMR(500MHz,CDCl3)δ7.82(d,J＝8.5Hz,1H),7.49(d,J＝2.0Hz,1H),7.32(dd,J＝8.5,2.0Hz,1H),4.54(t,J＝5.0Hz,2H),4.39(t,J＝5.0Hz,2H),2.01(s,3H),1.89(d,J＝2.5Hz,6H),1.76–1.65(m,6H)；
HRMS(ESI)calcd C20H22Cl2O4[M+H]+396.0925,found 396.0875。
Example 13 antitumor activity assay:
the novel 1-adamantanecarboxylic acid-2- (substituted benzoyloxy) ethyl ester compounds synthesized in examples 1 to 12 were labeled as compounds to be tested. Test compounds were tested for inhibitory activity against tyrosyl-DNA phosphodiesterase 1(TDP1), tyrosyl-DNA phosphodiesterase 2(TDP2) and topoisomerase I (TOP I). The test method comprises the following steps:
(1) assay for tyrosyl-DNA phosphodiesterase 1(TDP1) inhibitory Activity
Reaction system (40 μ L): 100nM TDP1 Dilution Buffer (200nM TDP1, 10mM Tris-HCl, 50mM KCl, 1mM EDTA, 2mM DTT, pH 7.5) 20. mu.L, 50. mu.M concentration of test compound in DMSO 2. mu.L, Buffer: volume was made up (10mM Tris-HCl, 50mM KCl, 1mM EDTA, pH 7.5). After shaking for 30s and mixing, incubating for 30min at 37 ℃, detecting the background fluorescence value at the position of Ex485nm/Em510 nm by using a microplate reader, adding 20 mu L of Linear Oligonucleotide, and shaking and mixing to detect the reaction fluorescence value at the position of Ex485nm/Em510 nm, thus obtaining the fluorescence value of the Compound group.
The procedure of the Control group fluorescence value test method is repeated with the difference that: the DMSO solution of the test compound at a concentration of 50 μ M was replaced with an equivalent volume of DMSO solvent. Other operating conditions were the same as the Compound group fluorescence value test procedure, and finally the Control group fluorescence value was measured.
The fluorescence values of Blank group were tested as follows: the reaction system (40. mu.L), 2. mu.L of DMSO solvent, was made up to a volume of 40. mu.L with buffer (10mM Tris-HCl, 50mM KCl, 1mM EDTA, pH 7.5). After shaking for 30s and mixing, incubating for 30min at 37 ℃, detecting the background fluorescence value at the position of Ex485nm/Em510 nm by using a microplate reader, adding 20 mu L of Linear Oligonucleotide, and shaking and mixing to detect the reaction fluorescence value at the position of Ex485nm/Em510 nm, namely detecting the fluorescence value of Blank group.
By comparing the difference of fluorescence values of the Control group and the Blank group, the inhibition rate of each compound is calculated, and the calculation formula of the inhibition rate is as follows:
inhibition (%) - (1- (RFU2-RFU3)/(RFU1-RFU3)) × 100% (1-1)
Wherein: RFU1 is the Control group reaction fluorescence value minus the background fluorescence value;
RFU2 is Compound group reaction fluorescence minus background fluorescence;
RFU3 is the Blank group reaction fluorescence minus background fluorescence.
(2) Assay for tyrosyl-DNA phosphodiesterase 2(TDP2) inhibitory Activity
Reaction system (40 μ L): buffer solution (25mM Hepes, 10mM MgCl) was added first2130mM KCl, pH 8.0), adding 1 mu L of DMSO Solution of a compound to be detected with the concentration of 50 mu M, shaking and mixing uniformly, measuring a background absorption value at 405nM by using an enzyme-linked immunosorbent assay, adding 210 mu L of 300nM TDP, mixing uniformly, adding 20 mu L of NPPP Solution, shaking for 1min, putting in a constant-temperature incubator at 37 ℃ for culturing for 90min, and adding 5 mu L of EDTA Stop Solution into each hole to terminate the reaction of the TDP2 and the NPPP. The UV absorbance A of each well at this time was measured at 405nm, i.e., the UV absorbance of Compound group was measured.
Control group ultraviolet absorbance test method steps the above Compound group ultraviolet absorbance test process is repeated, except that: the DMSO solution of the test compound at a concentration of 50 μ M was replaced with an equivalent volume of DMSO solvent. And other operating conditions are the same as the testing process of the ultraviolet absorbance of the Compound group, and finally the ultraviolet absorbance of the Control group is measured.
The procedure for testing the ultraviolet absorbance of Blank group is as follows: buffer solution (25mM Hepes, 10mM MgCl) was added first2130mM KCl, pH 8.0), adding 1 mu L of DMSO solvent, shaking and mixing uniformly, measuring a background absorption value at 405nm by using an enzyme-linked immunosorbent assay, adding 20 mu L of NPPP Solution after mixing uniformly, shaking for 1min, culturing for 90min in a constant-temperature incubator at 37 ℃, and adding 5 mu L of EDTA Stop Solution to each hole to terminate the reaction of TDP2 and NPPP. The UV absorbance A of each well at this time was measured at 405nm, and the UV absorbance of Blank group was finally measured.
Calculating the inhibition rate of each compound, wherein the inhibition rate is calculated by the formula:
inhibition (%) - (1- (a2-A3)/(a1-A3)) × 100% (1-2)
Wherein: a1 is the reaction ultraviolet absorption minus the background ultraviolet absorption of Control group;
a2 is Compound group reaction UV absorption minus background UV absorption;
a3 is the Blank group reaction UV absorption minus background UV absorption.
(3) Test for topoisomerase I (TOP I) inhibitory Activity
The inhibition activity of the compound to be tested on TOP I is tested by adopting a DNA loose experiment, and the test concentration of the compound to be tested is 50 mu M.
Reaction system (20 μ L): mu.l of 0.2. mu.g/. mu.l negative supercoiled plasmid p322 DNA 1. mu.l, 0.5. mu.g/. mu.l of Top 11. mu.l, 1. mu.l of a DMSO solution of the test compound at a concentration of 50. mu.M, buffer solution: (20mM Tris, pH 7.5,0.1mM EDTA,10mM MgCl2,100mM KCl, 50. mu.g/mL acetylated BSA) make up the volume. After the samples were prepared, they were incubated at 37 ℃ for half an hour. After incubation, 4. mu.L of 6 Xloading buffer was added and mixed, and the mixture was applied to a sample well of 0.8% agarose gel and electrophoresed at 4.6V/cm for 1.5 hours. Electrophoresis junctionAfter completion, the agarose gel was stained in an aqueous solution of 1 Xgel red for 0.5 hour, and quantitatively analyzed by a Fluor-S multimager gel imaging system to determine the optical density of the sample, i.e., the optical density S of the loose band1。
Optical density value S of supercoiled strip2The test method (2): only 0.2. mu.g/. mu.L of the minus supercoiled plasmid p322 DNA was added in 1. mu.L, followed by mixing with a buffer solution: (20mM Tris, Ph 7.5,0.1mM EDTA,10mM MgCl2100mM KCl, 50. mu.g/mL acetylated BSA). The subsequent operation was as above, and the optical density of the blank, i.e., the optical density of the supercoiled bands, S, was measured2。
The inhibition rate of each compound was calculated. The inhibition rate calculation formula is as follows:
inhibition ratio (%) - (S)1/S2)×100％
In the formula: s1An optical density value for the loose strip; s2The optical density value of the supercoiled strip.
The test results are shown in Table 1.
TABLE 1 screening test results of antitumor Activity of Compounds Ia to Il
As is clear from Table 1, most of the compounds Ia to Il of the examples of the present invention have certain inhibitory activities against tyrosyl DNA phosphodiesterase 1(TDP1) and topoisomerase I (TOP I). The compounds Ib, Id and Ij show moderate inhibitory activity to TDP1, the inhibition rates of the compounds Ib, Id and Ij are all more than 30%, wherein the inhibition rate of the compound Ij to TDP1 can be up to 76.9%; the inhibition rates of compounds Ib, Id, If, Ig, Ih and Ij to TOP I are all more than 35%, wherein the inhibition rate of compounds Ib to TOP I can reach 55.7%. In addition, the compounds Ie and If also exhibit a certain inhibitory activity on tyrosyl-DNA phosphodiesterase 2(TDP 2).
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (13)
1. A1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is characterized in that: the structural formula is shown as the formula (I):
in the formula (I), R (n) is o-fluorine, o-chlorine or 2, 6-difluoro;
the 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound is applied to preparation of an anti-tumor drug, R (n) is o-chloro or 2, 6-difluoro, and the anti-tumor drug is an anti-tumor drug for inhibiting TDP 1; or R (n) is o-fluorine, and the anti-tumor medicament is an anti-tumor medicament for inhibiting TOP I.
2. The method for synthesizing 2- (substituted benzoyl oxy) ethyl 1-adamantanecarboxylate compound as claimed in claim 1, comprising the following steps:
1) dissolving substituted benzoyl chloride shown in a formula (III) in an organic solvent A to prepare a substituted benzoyl chloride solution;
2) mixing an intermediate 2-hydroxyethyl-1-adamantane formate shown in a formula (II), an organic solvent B and an acid-binding agent, stirring for dissolving, dropwise and slowly adding the substituted benzoyl chloride solution prepared in the step 1) under an ice bath condition, reacting at room temperature after the dropwise adding is finished, monitoring by TLC (thin layer chromatography) until the reaction is finished, filtering a reaction solution, removing the solvent from a filtrate through desolventizing, and carrying out column chromatography separation on the obtained desolventizing residue to obtain a 1-adamantane carboxylic acid-2- (substituted benzoyl oxy) ethyl ester compound shown in the formula (I);
in the formula (III), R (n) is o-fluorine, o-chlorine or 2, 6-difluoro.
3. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 2, wherein the molar ratio of 2-hydroxyethyl-1-adamantanecarboxylic acid ester shown in formula (II) to substituted benzoyl chloride shown in formula (III) is 1: 1-5.0.
4. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 3, wherein the molar ratio of 2-hydroxyethyl-1-adamantanecarboxylic acid ester shown in formula (II) to substituted benzoyl chloride shown in formula (III) is 1: 1-1.5.
5. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 2, wherein the organic solvent A is the same as organic solvent B, and the organic solvent B is tetrahydrofuran or acetonitrile; in the step 1), the concentration of the prepared substituted benzoyl chloride solution is 0.25-0.5 mol/L.
6. The method for synthesizing 2- (substituted benzoyloxy) ethyl 1-adamantanecarboxylate according to claim 5, wherein the organic solvent B is tetrahydrofuran.
7. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 2, wherein in step 2), the acid-binding agent is triethylamine or pyridine, and the molar ratio of 2-hydroxyethyl-1-adamantane formate as shown in formula (II) to the acid-binding agent is 1: 1-5.
8. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 7, wherein in step 2), the acid-binding agent is triethylamine; the molar ratio of the 2-hydroxyethyl-1-adamantane formate shown in the formula (II) to the acid-binding agent is 1: 1.2-2.
9. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 2, wherein in step 2), the molar ratio of 2-hydroxyethyl-1-adamantane formate as shown in formula (II) to organic solvent B is 1: 30-150.
10. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 9, wherein in step 2), the molar ratio of 2-hydroxyethyl-1-adamantane formate as shown in formula (II) to organic solvent B is 1: 70-120.
11. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 2, wherein in step 2), the reaction time is 1-5 hours at room temperature.
12. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 11, wherein in step 2), the reaction time is 2-4 hours at room temperature.
13. The method for synthesizing 1-adamantanecarboxylic acid-2- (substituted benzoyl oxy) ethyl ester compounds as claimed in claim 2, wherein in step 2), the eluent used for column chromatography is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 3-8.
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