CN113200994B - Application of podophyllotoxin carboxylate derivatives in preparation of anti-tumor products - Google Patents

Application of podophyllotoxin carboxylate derivatives in preparation of anti-tumor products Download PDF

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CN113200994B
CN113200994B CN202110457881.XA CN202110457881A CN113200994B CN 113200994 B CN113200994 B CN 113200994B CN 202110457881 A CN202110457881 A CN 202110457881A CN 113200994 B CN113200994 B CN 113200994B
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podophyllotoxin
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phenylacetic acid
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ester derivatives
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CN113200994A (en
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江沛
孙文学
赵世媛
王长水
刘蒙蒙
聂素珍
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JINING NO1 PEOPLE'S HOSPITAL
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract

The invention relates to benzene sulfonamide phenylacetic acid podophyllotoxin carboxylic ester derivatives, a synthesis method and application thereof, belongs to the technical field of chemical pharmacy, and particularly relates to podophyllotoxin derivatives and application thereof in tumor inhibition. Corresponding benzene sulfonamide phenylacetic acid and podophyllotoxin are connected through a synthesis means to obtain corresponding ester derivatives, and in vitro anti-tumor activity research shows that the podophyllotoxin carboxylic ester derivatives have strong inhibition activity on tumor cell strains.

Description

Application of podophyllotoxin carboxylate derivatives in preparation of anti-tumor products
One, the technical field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to preparation of benzenesulfonamide phenylacetic acid podophyllotoxin carboxylic ester derivatives and application of the benzenesulfonamide phenylacetic acid podophyllotoxin carboxylic ester derivatives in tumor inhibition.
Second, background Art
The natural product is an important source for finding the medicine and plays an important role in health care and disease prevention. Podophyllotoxin (PPT) belongs to cyclolignin, is a core component of podophyllotoxin resin, is an effective natural product, and has been used as a therapeutic, antirheumatic, antiviral and anticancer drug for a long time. In recent years, extensive research has been conducted on structural modifications of PPT and its semisynthetic derivatives, such as etoposide, teniposide, which have been used in the clinical treatment of a variety of malignancies, including lung and testicular cancer, lymphoma, and non-lymphocytic leukemia. However, these drugs often exhibit toxic side effects in clinical treatments, which limits their clinical use.
Researches show that phenylacetic acid as an intermediate of important medicaments has various biological activities of bacteriostasis, inflammation diminishing, anxiety resisting, cancer resisting and the like. Such as: the lumiracoxib is a non-steroidal anti-inflammatory drug and is mainly used for treating rheumatoid arthritis; ibuprofen and sertraline have anti-inflammatory and analgesic effects; 4-hydroxyphenylacetic acid is considered to be a potential hypertonic and anoxic inhibitor with the activity of resisting anxiety, inhibiting bacteria and preventing and treating pulmonary edema. In addition, the p-aminophenylacetic acid can be used for synthesizing non-steroidal anti-inflammatory drugs of felbinac, antirheumatic drugs of acrtalci and the like.
It is well known that sulfonamides are earlier synthetic antibacterial drugs and some compounds containing benzenesulfonamide structural units have been shown to induce diuresis, inhibit cancer, inhibit HIV-1 protease, antagonize alpha1-adrenergic receptor, etc.
Based on the structure, the invention connects the structural units containing benzenesulfonyl and p-aminophenylacetic acid, introduces the structural units into the podophyllotoxin, designs and synthesizes a series of benzene sulfonamide phenylacetic acid podophyllotoxin ester derivatives so as to obtain the high-efficiency and low-toxicity antitumor drugs.
Third, the invention
The invention aims to solve the problem of providing a benzene sulfonamide phenylacetic acid podophyllotoxin ester derivative, a preparation method thereof and application thereof in tumor inhibition.
The structural formula of the benzenesulfonamide phenylacetic acid podophyllotoxin ester derivative is shown as a formula I:
Figure GDA0003569577130000021
Figure GDA0003569577130000031
Figure GDA0003569577130000041
the invention relates to a benzene sulfonamide phenylacetic acid podophyllotoxin ester derivative with a structure shown in a formula I, which is an active functional compound obtained by semisynthesis of podophyllotoxin and corresponding carboxylic acid.
The invention proves that tumor cell strains MCF-7 human breast cancer cells, HeLa human cervical cancer cells and HepG through in-vitro tumor cell inhibition activityThe-2 human liver cancer cells and the A549 human lung cancer cells have stronger inhibitory activity, wherein the compound 7e has the best inhibitory activity and IC on HeLa50The value reaches 1.61 mu M, which is shown in the attached figures 1,2, 3 and 4 in detail. Toxicity experiments prove that the compound has lower toxic and side effects on human normal kidney epithelial cells (293T), and the compound 7e has lower toxicity on 293T cells and IC50The value is 426.87 mu M, which is obviously superior to podophyllotoxin and IC50The value was 27.84. mu.M, as detailed in FIG. 5.
Compared with the prior art, the invention has the following beneficial effects:
compared with podophyllotoxin, the obtained benzenesulfonamide phenylacetic acid podophyllotoxin ester derivative has obvious tumor cell inhibiting activity, and partial compounds have obviously better tumor cell inhibiting activity than parent molecular podophyllotoxin and low toxic side effect. Meanwhile, the compound 7e has the strongest inhibitory activity on HeLa cells. The research aims to deeply explore the action mechanism of the medicine by means of flow, western blot and laser confocal.
Fourthly, the method comprises the following steps: drawings
FIG. 1 shows the inhibition of HeLa cell proliferation by compounds 1e-17e and podophyllotoxin
FIG. 2 shows the inhibition of MCF-7 cell proliferation by compounds 1e-17e and podophyllotoxin
FIG. 3 shows the inhibition of HepG-2 cell proliferation by Compounds 1e-17e and Podophyllotoxin
FIG. 4 shows the inhibition of A549 cell proliferation by compounds 1e-17e and podophyllotoxin
FIG. 5 shows the inhibition of 293T cell proliferation by Compounds 1e-17e and Podophyllotoxin
FIG. 6 shows the induction of human cervical carcinoma HeLa apoptosis by Compound 7e and Podophyllotoxin
Fifthly: Detailed Description
Example one: preparation of benzene sulfonamide phenylacetic acid podophyllotoxin ester derivatives of formula I
Dissolving 5.58mmol of p-aminophenylacetic acid in 20ml of water, stirring at room temperature, adjusting the pH to 8-9 by using a saturated sodium carbonate solution, and continuing stirring until the acid is completely dissolved in the water. 6mmol of benzenesulfonyl chloride containing different substituents was added to the reaction system, and the mixture was stirred at room temperature overnight. After the reaction is finished, dropwise adding a hydrochloric acid solution with the concentration of 1mol/L into the reaction system until the PH value is 1-2, precipitating a large amount of solids, and then carrying out vacuum filtration, water washing and drying on the solids by using a Buchner funnel to obtain light yellow solids, thus obtaining the intermediate product benzenesulfonamide phenylacetic acid derivative. The product can be used directly for the next chemical synthesis or can be further purified by recrystallization from methanol.
0.175mmol of podophyllotoxin and 0.035mmol of 4-Dimethylaminopyridine (DMAP) are weighed and dissolved in 30mL of dichloromethane, 0.35mmol of N, N-Dicyclohexylcarbodiimide (DCC) is added into a reaction system while stirring, and 0.263mmol of different substituted benzene sulfonamide phenylacetic acid is respectively added into the reaction system under the ice bath condition to continue stirring and react for 6 hours. The progress of the reaction was checked by TLC (ethyl acetate: petroleum ether: 1:2 to 1:5) to confirm the progress of the reaction. After the reaction is finished, the system is placed in a refrigerator at the temperature of 20 ℃ below zero to be frozen overnight and filtered, so that benzene sulfonamide phenylacetic acid containing different substituents and DMAP which do not participate in the reaction in the system and impurities generated in the reaction are removed. Concentrating the filtrate at low temperature under reduced pressure to 5-6mL by using a rotary evaporator, performing thin layer chromatography by using a mixed solvent of ethyl acetate and petroleum ether (V: V ═ 1:2) as a developing agent, and separating to obtain a light yellow target product, namely the benzenesulfonamide phenylacetic acid podophyllotoxin ester derivative.
The physicochemical data for the corresponding compounds are as follows:
compound 1 e:1H NMR(600MHz,CDCl3)δ7.75(t,J＝7.3Hz,2H),7.54(t,J＝7.1Hz,1H),7.48(t,J＝7.4Hz,1H),7.39(d,J＝7.7Hz,2H),7.37–7.35(m,1H),7.16(d,J＝8.3Hz,2H),6.62(s,1H),6.53(s,1H),6.35(s,2H),6.00–5.96(m,2H),5.84(d,J＝9.4Hz,1H),4.59(d,J＝4.4Hz,1H),4.15(dd,J＝15.4,8.2Hz,2H),3.81(s,3H),3.73(s,6H),3.70(s,1H),3.64(d,J＝2.8Hz,2H),2.77–2.69(m,1H).
compound 2 e:1H NMR(600MHz,CDCl3)δ7.83–7.79(m,2H),7.61(td,J＝7.9,1.1Hz,1H),7.54(dd,J＝8.7,4.6Hz,1H),7.48(s,1H),7.45(td,J＝7.8,0.8Hz,1H),7.21(d,J＝5.5Hz,2H),6.61(s,1H),6.52(s,1H),6.35(s,2H),5.99(dd,J＝17.0,1.0Hz,2H),5.85(d,J＝9.4Hz,1H),4.58(d,J＝4.5Hz,1H),4.14–4.10(m,2H),3.81(s,3H),3.73(s,6H),3.70(d,J＝4.1Hz,1H),3.67(d,J＝3.9Hz,2H),2.70(dq,J＝14.3,8.9Hz,1H).
compound 3 e:1H NMR(600MHz,CDCl3)δ8.61(t,J＝1.8Hz,1H),8.34(dt,J＝17.3,8.6Hz,1H),8.03(d,J＝7.9Hz,1H),7.72(s,1H),7.19(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),6.62(s,1H),6.52(s,1H),6.36(s,2H),5.98(dd,J＝14.2,1.0Hz,2H),5.85(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.21(dd,J＝9.1,7.3Hz,1H),4.15–4.11(m,1H),3.80(s,3H),3.72(s,6H),3.70(s,1H),3.67(d,J＝6.3Hz,2H),2.81–2.73(m,1H).
compound 4 e:1H NMR(600MHz,CDCl3)1H NMR(600MHz,CDCl3)δ8.22(d,J＝8.8Hz,1H),7.92(d,J＝8.5Hz,1H),7.18(d,J＝8.4Hz,1H),7.12(t,J＝9.0Hz,1H),7.07(d,J＝8.3Hz,2H),6.65(d,J＝8.3Hz,2H),6.61(s,1H),6.52(d,J＝6.2Hz,1H),6.36(d,J＝6.5Hz,2H),5.98(d,J＝15.5Hz,2H),5.84(t,J＝9.4Hz,1H),4.58(t,J＝3.8Hz,1H),4.22(dt,J＝15.0,7.5Hz,1H),4.17–4.10(m,1H),3.81(s,3H),3.74(s,6H),3.66(d,J＝3.9Hz,1H),3.60(s,2H),2.80–2.73(m,1H).
compound 5 e:1H NMR(600MHz,CDCl3)δ8.01(d,J＝15.5Hz,1H),7.94(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),6.95(d,J＝15.5Hz,1H),6.81(s,1H),6.57(s,1H),6.41(s,2H),6.05(d,J＝8.7Hz,1H),6.00(dd,J＝10.3,1.1Hz,2H),4.64(d,J＝4.1Hz,1H),4.44(dd,J＝9.1,6.7Hz,1H),4.27(t,J＝9.7Hz,1H),3.81(s,3H),3.78(s,6H),3.72(s,1H),2.99(dd,J＝14.5,4.3Hz,1H),2.75(q,J＝7.6Hz,2H),1.20–1.01(m,3H).
compound 6 e:1H NMR(600MHz,CDCl3)δ7.55(d,J＝7.9Hz,1H),7.49(d,J＝8.0Hz,1H),7.37(td,J＝8.0,5.5Hz,1H),7.22–7.20(m,1H),7.18(d,J＝8.4Hz,2H),7.10(d,J＝8.3Hz,2H),6.62(s,1H),6.53(s,1H),6.36(s,2H),5.98(dd,J＝15.9,1.1Hz,2H),5.85(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.22–4.18(m,1H),4.13(t,J＝9.9Hz,1H),3.81(s,3H),3.73(s,6H),3.70–3.67(m,1H),3.66(d,J＝5.1Hz,2H),2.80–2.72(m,1H).
compound 7 e:1H NMR(600MHz,CDCl3)δ7.78(dd,J＝8.8,5.0Hz,2H),7.17(d,J＝8.3Hz,2H),7.08(dd,J＝12.2,8.5Hz,4H),6.61(s,1H),6.53(s,1H),6.36(s,2H),5.98(dd,J＝15.5,1.0Hz,2H),5.84(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.24–4.19(m,1H),4.13(t,J＝9.9Hz,1H),3.80(s,3H),3.73(s,6H),3.68(s,1H),3.65(d,J＝3.8Hz,H),2.81–2.73(m,1H).
compound 8 e:1H NMR(600MHz,CDCl3)δ7.84(td,J＝8.6,6.2Hz,1H),7.18(d,J＝8.5Hz,2H),7.15(s,1H),7.11(dd,J＝11.1,5.5Hz,2H),6.92(ddd,J＝11.7,7.6,5.6Hz,1H),6.60(s,1H),6.53(s,1H),6.36(s,2H),5.99(dd,J＝16.9,1.1Hz,2H),5.84(d,J＝9.3Hz,1H),4.59(d,J＝4.5Hz,1H),4.18(dd,J＝9.1,7.3Hz,1H),4.14(d,J＝7.1Hz,1H),3.82(s,3H),3.74(s,6H),3.67(s,1H),3.64(d,J＝4.7Hz,2H),2.75(dtd,J＝14.6,10.3,7.3Hz,1H).
compound 9 e:1H NMR(600MHz,CDCl3)δ7.53(d,J＝8.6Hz,1H),7.44–7.39(m,1H),7.36(t,J＝2.0Hz,1H),7.20(d,J＝8.5Hz,1H),7.17(d,J＝8.6Hz,1H),6.94(t,J＝8.8Hz,2H),6.62(s,1H),6.53(d,J＝3.4Hz,1H),6.35(s,2H),5.99(dd,J＝16.3,1.1Hz,2H),5.84(d,J＝9.4Hz,1H),4.58(d,J＝4.5Hz,1H),4.09(dd,J＝12.9,6.7Hz,2H),3.82(s,3H),3.74(s,6H),3.67(s,1H),3.64(d,J＝5.6Hz,2H),2.74–2.67(m,1H).
compound 10 e:1H NMR(600MHz,CDCl3)δ8.02–7.97(m,1H),7.68–7.65(m,1H),7.51–7.45(m,1H),7.29(d,J＝2.1Hz,1H),7.15–7.11(m,4H),6.61(s,1H),6.52(s,1H),6.35(s,2H),6.01–5.96(m,2H),5.83(d,J＝9.4Hz,1H),4.58(d,J＝4.5Hz,1H),4.07(d,J＝8.9Hz,2H),3.82(s,3H),3.73(s,6H),3.64(s,1H),3.62(d,J＝4.3Hz,2H),2.69(dq,J＝14.7,9.0Hz,1H).
compound 11 e:1H NMR(600MHz,CDCl3)δ7.94(d,J＝1.7Hz,1H),7.68–7.63(m,2H),7.36(s,1H),7.20(d,J＝8.4Hz,2H),7.08(d,J＝8.1Hz,2H),6.62(s,1H),6.53(s,1H),6.36(s,2H),5.99(dd,J＝15.7,1.0Hz,2H),5.85(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.22–4.19(m,1H),4.13(t,J＝9.9Hz,1H),3.81(s,3H),3.73(s,6H),3.70(s,1H),3.67(d,J＝5.9Hz,2H),2.77(ddd,J＝12.3,9.4,6.3Hz,1H).
compound 12 e:1H NMR(600MHz,CDCl3)δ7.63–7.61(m,2H),7.57–7.53(m,2H),7.18(d,J＝8.4Hz,2H),7.08(dd,J＝10.4,5.3Hz,2H),6.61(s,1H),6.53(s,1H),6.36(s,2H),5.99(dd,J＝14.8,1.1Hz,2H),5.85(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.24(dd,J＝9.1,7.2Hz,1H),4.14(t,J＝8.4Hz,1H),3.81(s,3H),3.73(s,6H),3.69(s,1H),3.66(d,J＝4.6Hz,2H),2.82–2.74(m,1H).
compound 13 e:1H NMR(600MHz,CDCl3)δ7.65(d,J＝8.2Hz,2H),7.16(dt,J＝17.0,8.4Hz,4H),7.07(d,J＝8.4Hz,2H),6.62(s,1H),6.52(s,1H),6.36(s,1H),6.01–5.96(m,2H),5.85(d,J＝9.3Hz,2H),4.59(d,J＝4.4Hz,1H),4.18(dd,J＝9.0,7.4Hz,1H),4.13(q,J＝3.6Hz,1H),3.80(s,6H),3.72(s,3H),3.67(s,1H),3.65(d,J＝2.5Hz,2H),2.80–2.72(m,1H),2.34(s,3H).
compound 14 e:1H NMR(600MHz,CDCl3)δ7.65(t,J＝8.6Hz,1H),7.53(d,J＝8.6Hz,1H),7.38–7.33(m,2H),7.23(dd,J＝7.3,2.1Hz,2H),7.14–7.12(m,2H),6.51(s,1H),6.40(s,1H),6.37(s,2H),5.99(dd,J＝4.3,1.2Hz,2H),5.85(d,J＝16.8Hz,1H),4.77(d,J＝9.4Hz,1H),4.61(dd,J＝8.7,6.8Hz,1H),4.09(dd,J＝11.6,7.4Hz,1H),3.81(s,3H),3.78(s,2H),3.77(s,1H),3.76(s,6H),2.83(d,J＝4.7Hz,1H),2.60(dd,J＝10.2,4.9Hz,2H),1.66–1.59(m,2H),1.42(d,J＝5.2Hz,3H).
compound 15 e:1H NMR(600MHz,CDCl3)δ7.70(d,J＝8.4Hz,2H),7.25(s,1H),7.21(s,1H),7.17(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),6.62(s,1H),6.53(s,1H),6.36(s,2H),6.01–5.95(m,2H),5.84(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.22(dd,J＝9.1,7.3Hz,1H),4.12(dd,J＝12.9,6.9Hz,1H),3.80(s,3H),3.73(s,6H),3.68(s,1H),3.65(d,J＝4.1Hz,2H),2.90–2.87(m,1H),2.82–2.74(m,1H),1.21(d,J＝2.0Hz,3H),1.20(d,J＝2.0Hz,3H).
compound 16 e:1H NMR(600MHz,CDCl3)δ7.82(d,J＝8.8Hz,2H),7.25(s,1H),7.20(d,J＝8.4Hz,2H),7.14(s,1H),7.08(d,J＝8.4Hz,2H),6.61(s,1H),6.53(s,1H),6.36(s,2H),6.01–5.96(m,2H),5.85(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.23(dd,J＝9.1,7.3Hz,1H),4.14(t,J＝7.2Hz,1H),3.81(s,3H),3.73(s,6H),3.69(d,J＝4.2Hz,1H),3.67(d,J＝5.3Hz,2H),2.81–2.74(m,1H).
compound 17 e:1H NMR(600MHz,CDCl3)δ8.09(s,1H),7.59(t,J＝4.1Hz,1H),7.19(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),6.61(s,1H),6.53(s,1H),6.36(s,2H),5.99(d,J＝16.4Hz,2H),5.84(d,J＝9.3Hz,1H),4.59(d,J＝4.4Hz,1H),4.24(dd,J＝9.0,7.3Hz,1H),4.14(t,J＝8.8Hz,1H),3.81(s,3H),3.74(s,6H),3.68(d,J＝8.3Hz,1H),3.66(d,J＝8.5Hz,2H),2.81–2.74(m,1H).
example two: application of benzene sulfonamide phenylacetic acid podophyllotoxin ester derivatives in formula I
MCF-7, HeLa, HepG-2, A549 and 293T human normal kidney epithelial cell strains are taken as detection strains, an MTT colorimetric method is taken as a detection method, and research on in-vitro tumor cell inhibition activity of the benzene sulfonamide phenyl acetic acid podophyllotoxin ester derivatives in the formula I shows that part of the derivatives have obvious in-vitro tumor cell inhibition activity. The results are shown in figures 1,2, 3, 4 and 5.
Example three: compound 7e significantly induces Hela cell apoptosis
Respectively acting compound 7e and PPT (4 mu M) with different concentrations (0,1,2,4,8 mu M) on Hela cells, treating for 24h, collecting cells, centrifuging, and washing the cells twice with PBS; the cells were resuspended with binding buffer in PI/FITC double staining kit, 5. mu.L FITC and 10. mu.L PI were added, stained in the dark for 15 min, and apoptosis was detected by flow cytometry. The results are shown in FIG. 6. With the increase of the dosage, the compound 7e can obviously promote the apoptosis of human cervical carcinoma cells Hela.
The benzene sulfonamide phenylacetic acid podophyllotoxin ester derivative can be prepared into antitumor drugs.

Claims (3)

1. The structural formula of the podophyllotoxin carboxylate derivative is shown as follows:
Figure FDA0003569577120000011
Figure FDA0003569577120000021
2. the process for preparing carboxylic ester derivatives of podophyllotoxin as claimed in claim 1, wherein the podophyllotoxin and the benzenesulfonamide phenylacetic acid containing different substituents in a molar ratio of 1:1.5 are dissolved in dichloromethane, the catalyst is added continuously, the reaction is detected by TLC, and the carboxylic ester derivatives of podophyllotoxin with corresponding structure are obtained by column chromatography.
3. Use of the carboxylic ester derivative containing podophyllotoxin according to claim 1 in the preparation of antitumor drugs.
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