CN114195814A - Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application - Google Patents
Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application Download PDFInfo
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Abstract
The invention discloses a hydroxynaphthalenone-phenylboronic acid compound, a preparation method and application thereof. The compound disclosed by the invention is shown as a formula (I). The compound can be triggered and activated by high-level Reactive Oxygen Species (ROS) in tumors, so that the o-naphthoquinone compound with anti-tumor activity is released, shows good anti-tumor activity at a cell level and an animal level on average, has good safety, and can be used for preparing anti-tumor drugs.
Description
Technical Field
The invention relates to an organic compound in the field of pharmaceutical chemistry, in particular to a hydroxynaphthalenone-phenylboronic acid compound, a preparation method and application thereof.
Background
The o-naphthoquinone compound is widely present in natural products, and most of the natural products have wide biological activities, such as antioxidant, antibacterial, apoptosis-inducing activities, etc., because it contains highly reactive small molecules. In recent years, especially in the field of antitumor drugs, natural o-naphthoquinone compounds show strong antitumor activity, and tanshinone IIA and beta-lapachone, for example, have entered clinical phase II research, and thus have attracted much attention. (Mini-Reviews in medical Chemistry,2020,20(19), 2019-. Research shows that the o-naphthoquinone compound exerts antitumor activity mainly through three mechanisms: firstly, an alkylation medium is generated, and the synthesis of DNA is inhibited so as to generate cytotoxicity; secondly, inhibiting the activity of a plurality of key enzymes in the tumor cells, such as pyruvate kinase, topoisomerase and the like, so that the tumor cells are subjected to apoptosis; thirdly, the oxidative stress level in the tumor cells is greatly increased, and the redox balance of the tumor cells is broken, thereby inducing the tumor cell apoptosis (Current Cancer Drug Targets,2017,17(2), 122-. The o-naphthoquinone compound has good anti-tumor activity, but clinical tests show that the o-naphthoquinone compound has systemic toxic and side effects on normal tissues, so that the clinical application of the o-naphthoquinone compound is greatly limited. The o-quinone group is a main reason for causing toxic and side effects of the compounds, and is not only a pharmacophore but also a toxic group of the compounds. The o-naphthoquinone compound not only can be metabolized in tumor tissues to exert antitumor activity, but also can be reductively metabolized under the catalysis of single electron oxidoreductase (such as cytochrome P450 reductase, xanthine oxidase, etc.) in normal tissues in vivo to generate semiquinone free radical and ROS, thereby generating toxicity to normal cells (European Journal of Medicinal Chemistry 2017,129, 27-40). Therefore, the selectivity of the o-naphthoquinone compound on tumor cells is improved, the toxic and side effects of the o-naphthoquinone compound are reduced, and the o-naphthoquinone compound has great clinical application value.
The prodrug strategy is widely applied in the field of antitumor drugs, and can improve the targeting property of the antitumor drugs, thereby remarkably reducing the systemic toxic and side effects of the antitumor drugs. It is now generally accepted that ROS levels in tumor tissues can reach significantly higher concentrations, up to 100. mu.M, than in normal tissues. (Journal of Medicinal Chemistry 2021,64(1), 298-. Therefore, based on the characteristics, the ROS-responsive prodrug can be designed, so that the selectivity of the o-naphthoquinone compound on tumor cells is improved, and systemic toxic and side effects caused by metabolism of the o-naphthoquinone compound by the one-electron oxidoreductase in normal cells are avoided. Boronic acid or boronic ester groups are reported to be specific triggering groups for ROS and have been widely used in recent years in the design of ROS-targeted fluorescent probes and anti-tumor prodrugs.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides a hydroxynaphthone-phenylboronic acid compound which can be triggered and activated by high-level Reactive Oxygen Species (ROS) in tumors to release an o-naphthoquinone compound with anti-tumor activity, shows a good anti-tumor effect at a cellular level and an animal level, and has good safety. The invention also provides a preparation method and application of the compound, and the compound can be used for preparing antitumor drugs.
The technical scheme is as follows: the hydroxy naphthalenone-phenylboronic acid compound or the pharmaceutically acceptable salt thereof has a structure shown in a general formula (I):
wherein R is1Represents hydrogen, or mono-or polysubstituted C1～C4Alkyl or C containing single or multiple hetero atoms1～C8Alkyl chain, wherein the hetero atom is selected from nitrogen or oxygen atom, wherein C1～C4Alkyl groups may be further substituted with hydroxy; r2Represents hydrogen, or mono-or polysubstituted halogen, nitro, hydroxy, amino, C1～C4Alkoxy radical, C1～C4An alkyl group; r3a、R3b、R4a、R4b、R5a、R5bThe same or different, each represents hydrogen, C1～C4An alkyl group; r6Represents hydrogen, or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, C1～C4Alkoxy radical, C1～C4An alkyl group; either singly or doubly, and R when ← B is a double bond3b、R4bIs absent; n represents 0 or 1; m represents 0 to 4, and when m represents 0, R1In the absence of the presence of the agent,the general formula of the compound is shown as (II):
wherein R is7a、R7bIdentical or different, each represents hydrogen or C1～C4An alkyl group.
As a preferred embodiment of the present invention, R3a、R3b、R4a、R4b、R5a、R5bIdentical or different, each represents hydrogen or methyl.
As a preferred embodiment of the present invention, said R7a、R7bIdentical or different, each represents hydrogen or methyl.
As a preferred embodiment of the present invention, said R6Represents hydrogen, or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, methoxy or methyl.
In a preferred embodiment of the present invention, when m represents 1 to 4, B forms a heterocyclic structure with two oxygen atoms connected thereto as follows:
as a specific embodiment of the present invention, the compound of the present invention is as follows:
the preparation method of the hydroxynaphthalenone-phenylboronic acid compound or the pharmaceutically acceptable salt thereof comprises the following steps of: compound III and
and reacting to obtain a target object I, wherein the reaction temperature is 40-100 ℃, the reaction time is 2-12 h, and the reaction solvent can be dioxane, acetone, tetrahydrofuran, DMF, acetonitrile, dichloromethane and the like. Organic base or inorganic base such as triethylamine, N-diisopropylethylamine, imidazole, 4-dimethylaminopyridine, potassium hydroxide, sodium carbonate, potassium carbonate and the like is added in the reaction. Reducing agents such as palladium carbon/hydrogen, sodium hydrosulfite, lithium aluminum hydride, sodium borohydride, sodium sulfite, zinc powder and the like are also added in the reaction; meanwhile, the compound I can be purified by adopting a common separation method, such as recrystallization, column chromatography and the like:
the pharmaceutical composition comprises the hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention also comprises hydrates, stereoisomers, solvates and pharmaceutically acceptable salts of the compounds of the general formula I. They have the same pharmacological activity as the compounds of the general formula I.
The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, powder, syrup, liquid, suspending agents and injection, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.
The compound or the pharmaceutically acceptable salt thereof can be used for preparing the medicine for treating malignant tumors.
The malignant tumors of the invention are pancreatic cancer, lung cancer, leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, renal cancer and glia.
Has the advantages that: the hydroxy naphthone-phenylboronic acid compound provided by the invention is obviously superior to an o-naphthoquinone compound in safety. The derivative can be triggered and activated by high-level Reactive Oxygen Species (ROS) in tumors to release an o-naphthoquinone compound with anti-tumor activity, has the anti-tumor activity equivalent to that of an o-naphthoquinone raw drug, and is obviously superior to the o-naphthoquinone raw drug in selectivity. The clinical dosage is 0.01 mg-1000 mg/day, and can be adjusted according to the severity of the disease or different dosage forms.
Drawings
FIG. 1 is a diagram showing the structure of X-single crystal diffraction of Compound I-2.
Detailed Description
Synthesis of intermediate
Synthetic routes to compounds of general formula I:
1. preparation of 2-hydroxy-3- (3-hydroxypropyl) naphthalene-1, 4-dione (2a)
2-hydroxy is reacted withThe ylnaphthalene-1, 4-dione (0.87g,5mmol) was dissolved in anhydrous DMF (15mL), followed by the addition of 3-bromopropan-1-ol (0.77g,5.5mmol), triethylamine (0.76mL,5.5mmol) and sodium iodide (0.75g,5 mmol). The reaction was stirred at 50 ℃ for 8 h. After the reaction, the reaction mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate, and the organic phases were separately saturated with NaHCO3The aqueous solution (50mL) and the saturated NaCl solution (50mL) were washed successively with anhydrous Na2SO4And (5) drying. Purification by silica gel column chromatography on petroleum ether/ethyl acetate (20:1) gave a yellow solid (383mg, 33%).1H NMR(300MHz,CDCl3)δ8.20(dd,J＝5.7,3.9Hz,1H),8.14(dd,J＝5.7,3.9Hz,1H),7.79(dd,J＝5.7,3.9Hz,2H),6.95(s,1H),2.31(t,J＝7.1Hz,2H),1.78(t,J＝7.1Hz,2H),1.22(s,6H)；m/z(EI-MS):232[M]+。
2. Preparation of 3, 4-dihydro-2H-benzo [ H ] chromene-5, 6-dione (3a)
Dissolve 2a (2.32g,10mmol) in anhydrous DCM (50mL), add concentrated sulfuric acid (5.00g,50mmol) slowly to the reaction in an ice-water bath and stir at RT for 4 h. After quenching the reaction with water (60mL), the mixture was extracted with ethyl acetate and the organic phases were separately quenched with saturated NaHCO3The aqueous solution (50mL) and the saturated NaCl solution (50mL) were washed successively with anhydrous Na2SO4And (5) drying. Purification by silica gel column chromatography on petroleum ether/ethyl acetate (20:1) gave a red solid (0.58g, 25%). mp 158-.1H NMR(300MHz,DMSO)δ:8.07(dd,J＝1.8Hz,1H),7.82(dd,J＝1.8Hz,1H),7.64(dt,J＝1.8Hz,1H),7.53(dt,J＝1.8Hz,1H),2.58(t,J＝6.6Hz,2H),1.86(t,J＝6.5Hz,2H),1.47(s,6H)；m/z(EI-MS):232[M]+。
Preparation of compounds
Example 1: preparation of Compound I-1
3a (2.30g,10mmol), 4-bromomethylbenzeneboronic acid (4.30g,20mmol) and sodium borohydride (1.51g,40mmol) were dissolved in N, N-dimethylformamide (100mL) and water (100mL), and sodium hydroxide (1.20g,30mmol) was added to the reaction solution. The reaction was stirred at 50 ℃ for 3 h. After the reaction, the reaction mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate, and the organic phases were separately saturated with NaHCO3Aqueous solution (50mL), saturated NaCl solutions (50mL) were washed sequentially with anhydrous Na2SO4And (5) drying. Purification by silica gel column chromatography using petroleum ether/ethyl acetate (20:1) afforded a white solid (520mg, 15%).1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.63–7.57(m,2H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.37–7.30(m,2H),7.18(dt,J＝7.4,1.0Hz,2H),4.25–4.18(m,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z[M+H]+calculated for C20H20BO5:351.1398,found:351.1398.
Example 2: preparation of Compound I-2
Compound I-2(102mg, 32%) was synthesized in the same manner as Compound I-1, except that 4-bromo-2-methylbutan-2-ol (10mmol) was used instead of 3-bromopropan-1-ol.1H NMR (300MHz, DMSO-d) δ:7.80(s,2H),7.64(d, J ═ 7.7Hz,1H),7.50(d, J ═ 7.7Hz,2H),7.43(d, J ═ 7.7Hz,2H),7.39-7.34(m,1H),6.38(d, J ═ 7.6Hz,2H),5.76(s,1H),3.08(d, J ═ 11.8Hz,1H),2.94(d, J ═ 11.8Hz,1H),2.39-2.25(m,1H),1.96(dt, J ═ 15.1,6.7Hz,1H),1.55(t, J ═ 6.6Hz,2H),1.28(s,3H),0.88(s,3H), and the single crystal structure of the compound was confirmed by single crystal diffraction. ESI-HRMS m/z calculated for C22H24BO5[M+H]+379.1711,found 379.1715.
Example 3: preparation of Compound I-3
Compound I-3(91mg, 35%) was synthesized in the same manner as Compound I-1 using 6-chloro-8-fluoro-2-hydroxynaphthalene-1, 4-dione (5mmol) in place of 2-hydroxynaphthalene-1, 4-dione and pinacol ester of 4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.56(d,J＝2.2Hz,1H),7.18(dd,J＝8.1,2.2Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),4.25–4.18(m,2H),3.31(q,J＝0.9Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝12.6,7.1,4.4Hz,2H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C26H28BClFO5:485.1697,found:485.1706.
Example 4: preparation of Compound I-4
Compound I-4(68mg, 34%) was synthesized in the same manner as Compound I-1, except that 6-methyl-2-hydroxynaphthalene-1, 4-dione (5mmol) was used instead of 2-hydroxynaphthalene-1, 4-dione, 3-bromo-2, 2-dimethylpropan-1-ol (5mmol) was used instead of 3-bromopropan-1-ol, and 2- (4-bromomethylphenyl) -1,3, 2-dioxaborolan (10mmol) was used instead of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.40(d,J＝2.2Hz,1H),7.27(ddd,J＝8.2,1.9,0.8Hz,1H),7.16(d,J＝8.1Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),4.18(t,J＝6.1Hz,2H),3.35(dt,J＝14.1,0.9Hz,1H),3.30(dt,J＝14.1,0.9Hz,1H),2.37(s,3H),2.04–1.96(m,1H),1.86(dt,J＝12.4,6.1Hz,1H),1.28(s,3H),1.26(s,6H),1.23(s,3H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C29H36BO5:475.2650,found:475.2652.
Example 5: preparation of Compound I-5
Compound I-5(86mg, 39%) was synthesized in the same manner as in compound I-1 using 4-bromo-2-methylbutan-2-ol (5mmol) in place of 3-bromopropan-1-ol and 4-bromomethylbenzeneboronic acid pinacol ester (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.68-7.64(m,2H),7.53-7.45(m,3H),7.35(td,J＝7.6,1.4Hz,1H),6.60(d,J＝8.0Hz,2H),4.01(s,1H),3.11(s,2H),2.54(dt,J＝17.3,5.6Hz,1H),2.10(dt,J＝17.4,7.6Hz,1H),1.62(t,J＝6.6Hz,2H),1.35(s,3H),1.32(s,12H),1.00(s,3H).ESI-HRMS m/z calculated for C28H34BO5[M+H]+461.2494,found 461.2506.
Example 6: preparation of Compound I-6
Compound I-6(163mg, 34%) was synthesized in the same manner as Compound I-1 except that 3-bromo-3-methylbutan-2-ol was replaced with 2-bromo-2-methylpropan-1-ol (10mmol), 2-hydroxynaphthalene-1, 4-dione was replaced with 5-hydroxy-2-hydroxynaphthalene-1, 4-dione (10mmol) and 4-bromomethylbenzeneboronic acid was replaced with 4-bromomethylbenzeneboronic acid pinacol ester (10 mmol).1H NMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.33–7.26(m,1H),7.12(dt,J＝7.7,1.1Hz,2H),7.06(dd,J＝8.0,1.2Hz,1H),6.85(dd,J＝8.2,1.3Hz,1H),4.13–4.02(m,2H),3.35(dt,J＝1.9,1.1Hz,2H),1.30(s,3H),1.26(s,6H),1.25(s,3H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C27H32BO6:462.2214,found:462.2217.
Example 7: preparation of Compound I-7
Compound I-7(168mg, 36%) was synthesized in the same manner as Compound I-1 except that 1-bromo-2-methylpropan-2-ol (10mmol) was used instead of 3-bromo-3-methylbutan-2-ol, 7-methyl-2-hydroxynaphthalene-1, 4-dione (10mmol) was used instead of 2-hydroxynaphthalene-1, 4-dione, and 4-bromomethylbenzeneboronic acid was used instead of 4-bromomethylbenzeneboronic acid (10 mmol).1H NMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.57(d,J＝8.3Hz,1H),7.23–7.18(m,1H),7.15–7.08(m,3H),3.34(t,J＝1.0Hz,2H),2.78(s,1H),2.63(s,1H),2.29(s,3H),1.39(s,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C28H34BO5:461.2494,found:461.2497.
Example 8: preparation of Compound I-8
Compound I-8(72mg, 34%) was synthesized in the same manner as Compound I-18, except that 7-hydroxy-2-hydroxynaphthalene-1, 4-dione (5mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione, 3-bromo-3-methylbutan-2-ol was used in place of 3-bromo-2-buten-1-ol (5mmol) and 4-bromomethylbenzeneboronic acid pinacol ester (10mmol) was used in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.95(s,1H),7.75–7.69(m,2H),7.58(d,J＝8.9Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),6.90(d,J＝2.3Hz,1H),6.72(dd,J＝8.9,2.3Hz,1H),5.65(tq,J＝4.0,1.8Hz,1H),4.49(tq,J＝4.1,1.0Hz,2H),3.42–3.31(m,2H),2.22(dt,J＝2.0,1.1Hz,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C27H30BO6:461.2130,found:461.2131.
Example 9: preparation of Compound I-9
Compound I-9(33mg, 15%) was synthesized in the same manner as Compound I-1 except that 5-chloro-2-hydroxynaphthalene-1, 4-dione (5mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione, 1-bromo-2, 3-dimethylbuten-3-ol (5mmol) was used in place of 3-bromo-3-methylbutan-2-ol, and 4-bromomethylbenzeneboronic acid pinacol ester (10mmol) was used in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.51(t,J＝8.0Hz,1H),7.41(dd,J＝7.7,1.3Hz,1H),7.28(dd,J＝8.1,1.2Hz,1H),7.12(dt,J＝7.7,1.1Hz,2H),6.76(q,J＝1.3Hz,1H),3.38–3.34(m,2H),1.90(d,J＝1.3Hz,3H),1.45(s,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C29H33BClO5:507.2104,found:507.2106.
Example 10: preparation of Compound I-10
Compound I-10(209mg, 32%) was synthesized in the same manner as Compound I-18, except that 7-methoxy-2-hydroxynaphthalene-1, 4-dione (5mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione, 1-bromopropen-2-ol (5mmol) was used in place of 3-bromo-3-methylbutan-2-ol, and 4-bromomethylbenzeneboronic acid pinacol ester (10mmol) was used in place of 4-bromomethylbenzeneboronic acid.1HNMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.65(d,J＝7.9Hz,1H),7.13(dt,J＝7.8,1.0Hz,2H),6.97(d,J＝2.2Hz,1H),6.89(dd,J＝7.9,2.4Hz,1H),3.81(s,3H),3.46–3.34(m,2H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C27H30BO6:461.2130,found:461.2133.
Example 11: preparation of Compound I-11
Compound I-11(91mg, 36%) was synthesized in the same manner as Compound I-1 except that 6-bromo-2-hydroxynaphthalene-1, 4-dione (5mmol) was used instead of 2-hydroxynaphthalene-1, 4-dione, 1, 3-dimethyl-2-buten-2-ol (5mmol) was used instead of 3-bromo-3-methylbutan-2-ol, and 4-bromomethylbenzeneboronic acid pinacol ester (10mmol) was used instead of 4-bromomethylbenzeneboronic acid.1HNMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.60(dd,J＝8.3,2.5Hz,1H),7.54(d,J＝2.5Hz,1H),7.24(d,J＝8.2Hz,1H),7.13(dt,J＝7.7,1.0Hz,2H),3.45–3.34(m,2H),2.29(s,3H),1.26(s,6H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C27H29BO5:523.1286,found:523.1288.
Example 12: preparation of Compound I-12
Compound I-12(37mg, 17%) was synthesized in the same manner as Compound I-4 except that 6-bromo-2-hydroxynaphthalene-1, 4-dione (5mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione.1H NMR(300MHz,CDCl3-d)δ:7.75–7.65(m,2H),7.65–7.59(m,2H),7.52(d,J＝7.9Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.06(s,2H),3.83(ddd,J＝13.4,6.0,3.3Hz,4H),3.34(q,J＝0.8Hz,2H),1.95(dddd,J＝19.8,9.3,6.2,3.3Hz,2H),1.02(s,3H),0.97(s,3H).ESI-HRMS m/z[M+H]+calculated for C25H27BIO5:545.0991,found:545.0995.
Example 13: preparation of Compound I-13
Compound I-13(35mg, 19%) was synthesized in the same manner as Compound I-1 using 6-nitro-2-hydroxynaphthalene-1, 4-dione (5mmol) in place of 2-hydroxynaphthalene-1, 4-dione, 3-bromo-2-methyl-2-buten-1-ol (5mmol) in place of 3-bromopropan-1-ol and 2- (4-bromomethylphenyl) -1,3, 2-dioxaborolan (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:8.52(d,J＝2.1Hz,1H),8.24(dd,J＝8.5,2.1Hz,1H),7.65–7.60(m,2H),7.57(d,J＝8.5Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.72(dq,J＝7.3,1.0Hz,2H),3.83(ddd,J＝13.4,6.0,3.3Hz,4H),3.36(dt,J＝14.3,1.1Hz,1H),3.29(dt,J＝14.3,1.1Hz,1H),2.16(p,J＝1.0Hz,3H),1.95(dddd,J＝19.8,9.3,6.1,3.3Hz,2H),1.89(q,J＝0.9Hz,3H).ESI-HRMS m/z[M+H]+calculated for C25H25BNO7:462.1719,found:462.1723.
Example 14: preparation of Compound I-14
Compound I-14(33mg, 15%) was synthesized in the same manner as Compound I-4 except that 6-amino-2-hydroxynaphthalene-1, 4-dione (5mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione.1H NMR(300MHz,CDCl3-d)δ:7.65–7.59(m,2H),7.16–7.09(m,3H),7.07(d,J＝8.2Hz,1H),6.77(dd,J＝8.2,2.2Hz,1H),4.93(d,J＝5.3Hz,1H),4.80(d,J＝5.3Hz,1H),4.21(ddd,J＝7.0,5.5,4.1Hz,2H),3.83(ddd,J＝13.4,6.0,3.3Hz,4H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),2.01–1.86(m,4H).ESI-HRMS m/z[M+H]+calculated for C23H25BNO5:406.1820,found:406.1823.
Example 15: preparation of Compound I-15
With 6-cyano-2-hydroxynaphthalene-1, 4-dionesCompound I-15(71mg, 18%) was synthesized in the same manner as Compound I-1 except that 2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborane (10mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione and 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.89(d,J＝2.2Hz,1H),7.80(dd,J＝8.4,2.2Hz,1H),7.65–7.59(m,2H),7.29(d,J＝8.3Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.21(ddd,J＝7.0,5.5,4.1Hz,2H),3.78(dd,J＝12.3,4.2Hz,2H),3.72(dd,J＝12.4,4.3Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.80(m,3H),1.03(d,J＝6.5Hz,3H).ESI-HRMS m/z[M+H]+calculated for C25H25BNO5:430.1820,found:430.1824.
Example 16: preparation of Compound I-16
Compound I-16(71mg, 18%) was synthesized in the same manner as Compound I-5 using (2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborolan-5-yl) methanol (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.78(d,J＝12.4Hz,2H),3.71(d,J＝12.3Hz,2H),3.61(d,J＝5.9Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.54(dt,J＝7.7,5.0Hz,2H),2.42(t,J＝5.9Hz,1H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.8Hz,1H),1.34(s,3H),0.82(s,3H).ESI-HRMS m/z[M+H]+calculated for C27H32BO6:463.2286,found:463.2289.
Example 17: preparation of Compound I-17
Compound I-17(91mg, 36%) was synthesized in the same manner as Compound I-1 except that 3-bromo-3-methylbutanol (5mmol) was used instead of 3-bromo-3-methylbutan-2-ol and (2- (4- (bromomethyl) phenyl) -1,3, 2-dioxaborane-5, 5-diyl) dimethanol (10mmol) was used instead of 4-bromomethylbenzylboronic acid.1HNMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.0,1.8Hz,1H),7.65–7.59(m,2H),7.43–7.33(m,2H),7.22(dd,J＝7.7,1.5Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.18(t,J＝6.1Hz,2H),3.75(s,2H),3.70(s,2H),3.54(dd,J＝11.4,5.3Hz,2H),3.48(dd,J＝11.4,5.3Hz,2H),3.36(dt,J＝14.3,1.1Hz,1H),3.30(dt,J＝14.3,0.9Hz,1H),3.20(t,J＝5.3Hz,2H),2.04–1.96(m,1H),1.86(dt,J＝12.4,6.1Hz,1H),1.28(s,3H),1.23(s,3H).ESI-HRMS m/z[M+H]+calculated for C27H32BO7:479.2236,found:479.2239.
Example 18: preparation of Compound I-18
Compound I-18(168mg, 36%) was synthesized in the same manner as Compound I-7 except that 2- (4- (bromomethyl) phenyl) -5, 5-bis (methoxymethyl) -1,3, 2-dioxaborane (10mmol) was used in place of 4-bromomethylbenzeneboronic acid pinacol ester.1H NMR(300MHz,CDCl3-d)δ:7.65–7.55(m,3H),7.23–7.18(m,1H),7.15–7.08(m,3H),3.64(s,4H),3.49(s,4H),3.34(t,J＝1.0Hz,2H),3.32(s,6H),2.78(s,1H),2.63(s,1H),2.29(s,3H),1.39(s,3H).ESI-HRMS m/z[M+H]+calculated for C29H36BO7:507.2549,found:507.2553.
Example 19: preparation of Compound I-19
Compound I-19(163mg, 34%) was synthesized in the same manner as Compound I-6 except that 5-bromo-2-hydroxynaphthalene-1, 4-dione (10mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione and N- ((2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxolan-5-yl) methyl) -2-methoxyethan-1-amine (10mmol) was used in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.75–7.69(m,2H),7.33–7.26(m,1H),7.12(dt,J＝7.7,1.1Hz,2H),7.06(dd,J＝8.0,1.2Hz,1H),6.85(dd,J＝8.2,1.3Hz,1H),4.13–4.02(m,2H),3.35(dt,J＝1.9,1.1Hz,2H),1.30(s,3H),1.26(s,6H),1.25(s,3H),1.21(s,6H).ESI-HRMS m/z[M+H]+calculated for C29H36BBrNO6:584.1814,found:584.1817.
Example 20: preparation of Compound I-20
Compound I-20(91mg, 35%) was synthesized in the same manner as in compound I-1 using 2- (2- (((2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborolan-5-yl) methyl) amino) ethoxy) -N, N-dimethylethan-1-amine (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.6Hz,1H),7.65–7.59(m,2H),7.40(td,J＝6.9,1.4Hz,1H),7.34(ddd,J＝8.4,6.9,1.6Hz,1H),7.24(dd,J＝7.9,1.4Hz,1H),7.12(dt,J＝7.7,1.0Hz,2H),4.25–4.18(m,2H),3.76(d,J＝12.4Hz,2H),3.69(d,J＝12.3Hz,2H),3.59–3.53(m,4H),3.49(p,J＝5.0Hz,1H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.80(dt,J＝4.9,3.4Hz,2H),2.69(d,J＝4.9Hz,2H),2.62–2.52(m,4H),1.92(dtt,J＝12.6,7.1,4.4Hz,2H),0.91(s,3H).ESI-HRMS m/z[M+H]+calculated for C31H42BN2O6:549.3130,found:549.3135.
Example 21: preparation of Compound I-21
Compound I-21(31mg, 15%) was synthesized in the same manner as Compound I-1 except that 8-fluoro-2-hydroxynaphthalene-1, 4-dione (5mmol) was used in place of 2-hydroxynaphthalene-1, 4-dione and 2- (4- (bromomethyl) phenyl) -5- (2,5,8, 11-tetraoxadodecyl) -5-methyl-1, 3, 2-dioxaborane (10mmol) was used in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.65–7.58(m,3H),7.42(td,J＝7.1,4.9Hz,1H),7.15–7.09(m,2H),7.09–7.04(m,1H),4.25–4.18(m,2H),3.80(d,J＝12.5Hz,2H),3.72(d,J＝12.4Hz,2H),3.65–3.51(m,14H),3.37(s,3H),3.31(dt,J＝2.2,1.1Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝12.6,7.1,4.4Hz,2H),0.81(s,3H).ESI-HRMS m/z[M+H]+calculated for C32H41BFO9:599.2822,found:599.2827.
Example 22: preparation of Compound I-22
Compound I-22(102mg, 32%) was synthesized in the same manner as Compound I-1 except that 2-bromopropen-1-ol (10mmol) was used instead of 3-bromopropan-1-ol.1H NMR(300MHz,CDCl3-d)δ:7.77(dd,J＝7.9,1.5Hz,1H),7.63–7.57(m,2H),7.53(d,J＝0.9Hz,1H),7.49–7.37(m,3H),7.19(dt,J＝7.4,1.0Hz,2H),3.45–3.34(m,2H).ESI-HRMS m/z calculated for C20H18BO5[M+H]+349.1242,found 349.1246.
Example 23: preparation of Compound I-23
2- (4- (bromomethyl) phenyl) -1,3, 2-dioxaborane (10mmol) instead of 4-bromomethylbenzylboronic acid has been combined withCompound I-23(36mg, 17%) was synthesized in the same manner as in object I-2.1H NMR(300MHz,CDCl3-d)δ:7.67-7.60(m,2H),7.51-7.42(m,3H),7.34(td,J＝7.6,1.4Hz,1H),6.59(d,J＝8.0Hz,2H),4.14(t,J＝5.5Hz,4H),4.01(s,1H),3.10(s,2H),2.54(dt,J＝17.3,5.6Hz,1H),2.21-2.10(m,1H),2.08-1.97(m,2H),1.65-1.57(m,2H),1.36(s,3H),1.07(s,3H).ESI-HRMS m/zcalculated for C25H28BO5[M+H]+419.2024,found 419.2027.
Example 24: preparation of Compound I-24
Compound I-24(45mg, 23%) was synthesized in the same manner as Compound I-2 except that 2- (4- (bromomethyl) phenyl) -5, 5-dimethyl-1, 3, 2-dioxaborane (10mmol) was used instead of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dq,J＝7.7,1.3Hz,2H),3.49(s,4H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.88(dd,J＝7.6,4.9Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.86(s,6H).ESI-HRMS m/z calculated for C27H32BO5[M+H]+447.2337,found 447.2339.
Example 25: preparation of Compound I-25
Compound I-25(37mg, 21%) was synthesized in the same manner as Compound I-2 except that 2- (4- (bromomethyl) phenyl) -5-methyl-1, 3, 2-dioxaborane (10mmol) was used instead of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.78(dd,J＝12.3,4.2Hz,2H),3.72(dd,J＝12.4,4.3Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.91–1.80(m,2H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),1.03(d,J＝6.5Hz,3H).ESI-HRMS m/z calculated for C26H30BO5[M+H]+433.2181,found 433.2186.
Example 26: preparation of Compound I-26
With 2- (4- (bromomethyl) phenyl) -5- (methoxy)Compound I-26(67mg, 56%) was synthesized in the same manner as in Compound I-2, substituting 4-bromomethylbenzeneboronic acid with ylmethyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol).1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.77–3.66(m,4H),3.48(s,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),3.24(s,3H),2.54(dt,J＝7.7,5.0Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.8Hz,1H),1.34(s,3H),0.82(s,3H).ESI-HRMS m/z calculated for C28H34BO6[M+H]+477.2443,found 477.2448.
Example 27: preparation of Compound I-27
Compound I-27(38mg, 25%) was synthesized in the same manner as Compound I-2 except that (2- (4- (bromomethyl) phenyl) -1,3, 2-dioxaborane-5, 5-diyl) dimethanol (10mmol) was used in place of 4-bromomethylbenzylboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.75(s,2H),3.70(s,2H),3.54(dd,J＝11.4,5.3Hz,2H),3.48(dd,J＝11.4,5.3Hz,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),3.20(t,J＝5.3Hz,2H),2.54(dt,J＝7.7,5.0Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H).ESI-HRMS m/z calculated for C27H32BO7[M+H]+479.2236,found 479.2239.
Example 28: preparation of Compound I-28
Compound I-28(56mg, 34%) was synthesized in the same manner as in compound I-2, except that 2- (4- (bromomethyl) phenyl) -5- ((2-methoxyethoxy) methyl) -5-methyl-1, 3, 2-dioxaborane (10mmol) was used in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),3.80(d,J＝12.4Hz,2H),3.72(d,J＝12.5Hz,2H),3.63–3.51(m,4H),3.48(t,J＝4.3Hz,2H),3.37(s,3H),3.34–3.25(m,2H),2.54(dt,J＝7.7,5.0Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.81(s,3H).ESI-HRMS m/z calculated for C30H38BO7[M+H]+521.2705,found 521.2707.
Example 29: preparation of Compound I-29
Compound I-29(25mg, 16%) was synthesized in the same manner as Compound I-2 using 2- (4- (bromomethyl) phenyl) -5- ((2- (2-methoxyethoxy) ethoxy) methyl) -5-methyl-1, 3, 2-dioxaborane (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dq,J＝7.7,1.3Hz,2H),3.80(d,J＝12.4Hz,2H),3.72(d,J＝12.4Hz,2H),3.65–3.55(m,9H),3.54(d,J＝11.5Hz,1H),3.35(d,J＝16.2Hz,4H),3.32–3.25(m,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.81(s,3H).ESI-HRMS m/zcalculated for C32H42BO8[M+H]+565.2967,found 565.2968.
Example 30: preparation of Compound I-30
Compound I-30(33mg, 21%) was synthesized in the same manner as Compound I-2 except that 4-bromomethylbenzeneboronic acid was replaced with 2- (4- (bromomethyl) phenyl) -5- (2,5,8, 11-tetraoxadodecyl) -5-methyl-1, 3, 2-dioxaborane (10 mmol).1H NMR(300MHz,CDCl3-d)δ:7.73(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,2H),7.41(ddd,J＝7.0,6.0,2.1Hz,1H),7.37–7.30(m,2H),7.12(dq,J＝7.7,1.3Hz,2H),3.80(d,J＝12.4Hz,2H),3.72(d,J＝12.4Hz,2H),3.65–3.51(m,14H),3.35(d,J＝16.2Hz,4H),3.28(dt,J＝14.3,1.1Hz,1H),2.54(dt,J＝7.7,4.9Hz,2H),1.88(dd,J＝7.6,4.8Hz,1H),1.79(dd,J＝7.6,4.9Hz,1H),1.34(s,3H),0.81(s,3H).ESI-HRMS m/z calculated for C34H46BO9[M+H]+609.3229,found 609.3231.
Example 31: preparation of Compound I-31
Compound I-31(45mg, 27%) was synthesized in the same manner as Compound I-1 except that dimethyl (4- (bromomethyl) phenyl) borate (10mmol) was used instead of 4-bromomethylbenzylboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.61–7.56(m,2H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.36–7.32(m,2H),7.11(dt,J＝7.8,1.0Hz,2H),4.25–4.18(m,2H),3.64(s,6H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C22H24BO5[M+H]+379.1711,found 379.1715.
Example 32: preparation of Compound I-32
Compound I-32(63mg, 47%) was synthesized in the same manner as Compound I-1 using (4- (bromomethyl) -2-chloro-6-fluorophenyl) boronic acid (10mmol) in place of 4-bromomethylbenzylboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.35(qt,J＝3.6,1.8Hz,3H),6.89(ddt,J＝8.1,2.1,1.1Hz,1H),4.25–4.18(m,2H),3.36(dt,J＝13.7,1.1Hz,1H),3.30(dt,J＝13.7,1.0Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C20H18BClFO5[M+H]+403.0914,found 403.0917.
Example 33: preparation of Compound I-33
Compound I-33(27mg, 19%) was synthesized in the same manner as Compound I-1 using 3-iodo-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.56(dd,J＝7.1,2.2Hz,1H),7.47(d,J＝2.1Hz,1H),7.43–7.31(m,3H),7.03(dt,J＝7.1,1.0Hz,1H),4.25–4.18(m,2H),3.48–3.37(m,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C20H19BIO5[M+H]+477.0365,found 477.0365.
Example 34: preparation of Compound I-34
Compound I-34(35mg, 24%) was synthesized in the same manner as Compound I-1 using 3-methyl-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.54(dd,J＝7.5,2.2Hz,1H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.37–7.32(m,2H),7.30(d,J＝2.2Hz,1H),7.05(dt,J＝7.5,1.1Hz,1H),4.25–4.18(m,2H),3.38–3.28(m,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C21H22BO5[M+H]+365.1555,found 365.1558.
Example 35: preparation of Compound I-35
Compound I-35(67mg, 36%) was synthesized in the same manner as Compound I-1 using 2-amino-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.43–7.35(m,2H),7.35–7.30(m,2H),6.78(dt,J＝2.1,1.0Hz,1H),6.73(ddt,J＝7.9,2.0,1.0Hz,1H),5.49(d,J＝6.6Hz,1H),5.28(d,J＝6.6Hz,1H),4.25–4.18(m,2H),3.23(dt,J＝2.0,1.0Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C20H21BNO5[M+H]+366.1507,found366.1511.
Example 36: preparation of Compound I-36
Compound I-36(72mg, 39%) was synthesized in the same manner as Compound I-1 using 2-nitro-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:8.20(dt,J＝2.0,1.1Hz,1H),7.74(dd,J＝7.1,1.4Hz,1H),7.42(d,J＝7.6Hz,1H),7.40–7.37(m,1H),7.37–7.30(m,3H),4.25–4.18(m,2H),3.38(dt,J＝2.0,0.9Hz,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C20H19BNO7[M+H]+396.1249,found 396.1254.
Example 37: preparation of Compound I-37
Compound I-37(38mg, 21%) was synthesized in the same manner as in compound I-1 using 2-methoxy-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.45–7.30(m,4H),7.02(q,J＝1.1Hz,1H),6.93–6.87(m,1H),4.25–4.18(m,2H),3.77(s,3H),3.32–3.28(m,2H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.98–1.86(m,2H).ESI-HRMS m/z calculated for C21H22BO6[M+H]+381.1504,found 381.1507.
Example 38: preparation of Compound I-38
Compound I-38(42mg, 24%) was synthesized in the same manner as Compound I-1 using 2-methoxy-3-cyano-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.65–7.59(m,2H),7.40(ddd,J＝7.2,6.1,2.0Hz,1H),7.38–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),4.25–4.18(m,2H),3.83–3.75(m,2H),3.75–3.69(m,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.28(dt,J＝14.3,1.1Hz,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H),1.67–1.56(m,4H).ESI-HRMS m/zcalculated for C24H26BO5[M+H]+405.1868,found 405.1870.
Example 39: preparation of Compound I-39
Compound I-39(38mg, 21%) was synthesized in the same manner as Compound I-1 using 2-methoxy-3-cyano-4-bromomethylbenzeneboronic acid (10mmol) in place of 4-bromomethylbenzeneboronic acid.1H NMR(300MHz,CDCl3-d)δ:7.74(dd,J＝7.1,1.4Hz,1H),7.66–7.60(m,2H),7.40(ddd,J＝7.1,6.1,2.0Hz,1H),7.38–7.30(m,2H),7.12(dt,J＝7.7,1.0Hz,2H),5.45(s,2H),4.72(s,1H),4.25–4.18(m,2H),3.35(dt,J＝14.3,1.1Hz,1H),3.32–3.25(m,1H),2.56(ddd,J＝7.3,5.9,4.6Hz,2H),1.92(dtt,J＝18.8,7.1,4.3Hz,2H).ESI-HRMS m/z calculated for C21H20BO5[M+H]+363.1398,found 363.1399.
Thirdly, pharmacological experiments and results of the partial compounds of the invention:
(1) compound quilt H2O2Determination of activation Release
Target prodrug (1mM), internal standard solution (1mM, diclofenac acid) and appropriate amount of PBS buffer solution are added into a 1.5mL microcentrifuge tube for dilution, so as to ensure that the final total volume is 1 mL. Placing the centrifuge tube in a constant temperature mixing instrument, adding H2O2(5mM,5equiv) then mix at 37 ℃ and time was started at 1h and 2h based on this timeAnd h later sampling. The concentration change of the prodrug was detected by Shimadzu LC-MS at 254 nm. Each test needs to be repeated three more times.
TABLE 1 Change in the content of a part of the inventive Compounds over time
From the above results, it can be seen that the compounds of the present invention can be represented in H2O2Under the stimulation, the o-quinone compound is quickly and quantitatively released.
In addition, the study of the invention also finds that the compounds in the examples show extremely high stability after being incubated in the test buffer solution and the plasma for 24 hours, and the o-quinone compound cannot be released, so that the compounds have the potential advantage of being released not in blood and normal tissues but selectively in tumor tissues with high ROS levels, and therefore, the compounds have selectivity.
The hydroxynaphthone-phenylboronic acid compound can be selectively oxidized and broken by high-level ROS in tumor cells, so that the connecting chain releases the o-naphthoquinone technical product through 1, 6-elimination and autoxidation, and the selective anti-tumor effect is achieved. The mechanism of triggering, activating and releasing the hydroxy naphthalenone-phenylboronic acid derivative by high ROS of tumor cells is shown as follows:
(2) determination of toxicity of Compounds on tumor cells
The experimental method comprises the following steps: and (3) adopting an MTT colorimetric method, wherein the culture time is 48-72 h. Addition of H to the tumor cell culture medium in non-cytotoxic concentrations2O2(50-100. mu.M) to stimulate tumor cells, mimicking the high oxidative stress and high ROS level status of tumor cells in tumor tissues. The antiproliferative activity of the compounds in a variety of tumor cells is then determined by the addition of varying concentrations of the test compound. In 96-well plates at 3.0X 10, respectively3Inoculation in well, each oneCompound and non-cytotoxic concentration of H2O2After incubation, six concentration gradients (100,33.3,11.1,3.7,1.2,0.4 μ M) were set, with three replicate wells per concentration. The optical density value (OD) was measured at a wavelength of 570nm using a microplate reader. The IC was calculated using Grapad Prism 8 software using solvent control treated tumor cells as a control group50。
TABLE 2 inhibitory Effect of partial compounds of the present invention on tumor cells A549, Mia PaCa-2, PANC-1, MV4-11 and on normal cells L02, HUVEC (IC)50:μM)：
A549: human lung cancer cells; mia PaCa-2, PANC-1: human pancreatic cancer cells; MV 4-11: human leukemia cells; l02: human normal hepatocytes; HUVEC: human umbilical vein endothelial cells
As can be seen from Table 2, the compounds of the present invention have strong activity against tumor cell proliferation, which is comparable to beta-lapachone; meanwhile, the compounds have no killing effect on normal cells, and the safety is obviously superior to that of the o-quinone compound positive drug beta-lapachone.
In addition, the representative compound of the invention has good anti-tumor cell proliferation activity on leukemia cells (HL-60), breast cancer cells (MCF-7), stomach cancer (HGC-27), liver cancer (HepG2), colon cancer (HCT116), kidney cancer (A498), brain glioma (U251) and the like, which indicates that the compound of the invention has broad-spectrum anti-tumor effect and has treatment potential on the tumors.
TABLE 3 growth Inhibition (IC) of several other tumor cell lines by some of the compounds of the invention50:μM)
(3) In vivo antitumor Activity study
The experimental method comprises the following steps: collecting human pancreatic cancer cells in the growth vigorous stage, preparing cell suspension under the aseptic condition, and inoculating the cell suspension to the armpit of a nude mouse. The diameter of the transplanted tumor of the nude mouse is measured by a vernier caliper, and the animals are grouped into 5 animals each after the tumor grows to a certain size. The antitumor effect of the test object is dynamically observed by using a method for measuring the tumor size. The blank control was given saline; group of compounds: tail vein injection once every other day for 21 days. Tumor-bearing nude mice were sacrificed 21 days later, and tumor masses were isolated and weighed. The data obtained were statistically processed (t-test) and the relative tumor proliferation rate was calculated. And simultaneously, photographing the finally stripped tumor mass to store pictures.
TABLE 4 relative tumor proliferation rates of Mia PaCa-2 transplantable tumors of representative compounds of the invention
As can be seen from Table 4, the representative compounds I-12 and I-22 of the invention have better inhibitory effect on nude mouse Mia PaCa-2 transplantable tumor and have equivalent inhibitory activity with beta-lapachone.
(4) In vivo safety study
The experimental method comprises the following steps: acute toxicity experiments were performed in mice. The in vivo safety of the compounds was assessed by testing the median lethal dose of I-12, I-22 and beta-lapachone. The mice used in the experiment were ICR mice, 10 per group, male and female halves. The blank control was given saline; animals were observed for clinical signs and death hourly for 4 hours after dosing on the day for 14 consecutive days.
TABLE 5 median Lethal Dose (LD) for normal ICR mice of representative compounds of the invention50) Data of
| Group of | Half lethal dose (mg/kg) |
| Ⅰ-7 | 3500.0 |
| Ⅰ-12 | 3200.0 |
| I-14 | 3700.0 |
| I-22 | 3300.0 |
| Beta-lapachone | 160.0 |
As can be seen from Table 5, representative compounds I-12 and I-22 of the present invention have significantly better safety than beta-lapachone and significantly less toxic side effects than beta-lapachone.
Therefore, the hydroxy naphthone-phenylboronic acid derivative has the antitumor activity equivalent to that of an o-naphthoquinone raw material, is obviously superior to the o-naphthoquinone raw material in selectivity, and can be used for preparing antitumor drugs.
Claims (10)
1. A hydroxynaphthalenone-phenylboronic acid compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure shown in a general formula (I):
wherein R is1Represents hydrogen, or mono-or polysubstituted C1～C4Alkyl or C containing single or multiple hetero atoms1～C8Alkyl chain, wherein the hetero atom is selected from nitrogen or oxygen atom, wherein C1～C4Alkyl groups may be further substituted with hydroxy; r2Represents hydrogen, or mono-or polysubstituted halogen, nitro, hydroxy, amino, C1～C4Alkoxy radical, C1～C4An alkyl group; r3a、R3b、R4a、R4b、R5a、R5bThe same or different, each represents hydrogen, C1～C4An alkyl group; r6Represents hydrogen, or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, C1～C4Alkoxy radical, C1～C4An alkyl group; either singly or doubly, and R when ← B is a double bond3b、R4bIs absent; n represents 0 or 1; m represents 0 to 4, and when m represents 0, R1The compound has a general formula shown as (II):
wherein R is7a、R7bIdentical or different, each represents hydrogen or C1～C4An alkyl group.
2. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is3a、R3b、R4a、R4b、R5a、R5bIdentical or different, each represents hydrogen or methyl.
3. The hydroxynaphthalenone-phenylboronic acid compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is7a、R7bIdentical or different, each represents hydrogen or methyl.
4. The hydroxynaphthalenone-phenylboronic acid compound of claim 1, or a pharmaceutically acceptable salt thereof, thatCharacterized in that R is6Represents hydrogen, or mono-or polysubstituted halogen, cyano, nitro, hydroxy, amino, methoxy or methyl.
5. The hydroxynaphthalenone-phenylboronic acid compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein when m represents 1 to 4, B forms a heterocyclic structure with two oxygen atoms connected thereto as follows:
6. the hydroxynaphthalenone-phenylboronic acid compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is represented by:
7. a process for preparing a hydroxynaphthalenone-phenylboronic acid compound or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of: compound III and
and (3) reacting to obtain a target object I, wherein the reaction temperature is 40-100 ℃:
8. a pharmaceutical composition comprising the hydroxynaphthalenone-phenylboronic acid compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a malignant tumour.
10. The use according to claim 9, wherein the malignant tumor is pancreatic cancer, lung cancer, leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, kidney cancer and brain glia.
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| CN110156822A (en) * | 2019-05-17 | 2019-08-23 | 中国药科大学 | A kind of naphthols-phenylboronic acid compound and its preparation method and application |
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| CN110156822A (en) * | 2019-05-17 | 2019-08-23 | 中国药科大学 | A kind of naphthols-phenylboronic acid compound and its preparation method and application |
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| CHARLES SKARBEK等: "rylboronate prodrugs of doxorubicin as promising chemotherapy for pancreatic cancer", 《BIOORGANIC CHEMISTRY》 * |
| JUN LIU等: "Hydrogean Peroxide Inducible Acid-Activatable Prodrug for Targeted Cancer Treatment", 《CHEMMEDCHEM》 * |
| QIANYAN LI等: "Ultrasound combined with core cross-linked nanosystem for enhancing penetration of doxorubicin prodrug/beta-lapachone into tumors", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 * |
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