CN109776554B - Dihydrochromone spliced pyrrole spiro-oxoindole compound and preparation method and application thereof - Google Patents
Dihydrochromone spliced pyrrole spiro-oxoindole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an dihydrochromone spliced pyrrole spiro-oxoindole compound, which is prepared by carrying out 1, 3-dipole [3+2] cycloaddition reaction on 3-carboxylic acid substituted chromone, various substituted isatins and sarcosine in an organic solvent according to the molar ratio of 2:3:6 to obtain the dihydrochromone spliced pyrrole spiro-oxoindole compound, wherein the compound contains potential bioactive dihydrochromone and pyrrole spiro-oxoindole skeleton, can provide a compound source for bioactive screening, and has important application value for the screening of medicaments and the pharmaceutical industry. The method has the advantages of simple and easy operation, cheap and easily obtained raw material synthesis, capability of being carried out in various organic solvents, better air stability, wide applicability and good compatibility for various substituent groups. And the compounds have inhibitory activity on human leukemia cells (K562) and PC-3 (human prostate cancer).
Description
Technical Field
The invention relates to the technical field of chemistry and pharmacy, in particular to a dihydrochromone spliced pyrrole spiro-oxindole compound and a preparation method and application thereof.
Background
The splicing of biologically active groups into active molecular scaffolds is an extremely important area of research in organic and medicinal chemistry. (1) Multifunctional oxindole is widely existed in natural products and synthetic drug molecules, and particularly 3-pyrrole spiro oxindole attracts wide attention of many chemists and medicinal and chemical teams because of wide biological activity, for example, natural products 3-pyrrole spiro oxindole compounds pteropodine and alstonine show obvious biological activity. (2) The dihydrochromone backbone is also ubiquitous in natural products and drug molecules. For example, the natural product molecules elaeocarpine, diaporthe B and tephrosin and 12 a-hydroxy-a-toxocarol share a dihydrochromone molecular unit, and the compounds play an important role in relieving pain and realizing economic development. In view of the potential biological activity of the 3-pyrrole spiro oxoindole skeleton, the multi-substituted dihydrochromone skeleton belongs to the potential biological activity skeleton. Therefore, the polysubstituted dihydrochromone framework is spliced to the 3-pyrrole spiro oxoindole framework to synthesize a series of novel oxoindole and dihydrochromone derivatives with potential multi-active functional groups, which can provide a compound source for biological activity screening and has important application value for the screening of medicines and the pharmaceutical industry (as shown in figure 8).
Disclosure of Invention
The purpose of the invention is: the dihydrochromone spliced pyrrole spiro oxindole compound is an important medical intermediate analogue and a drug molecule analogue, has important application value for drug screening and pharmaceutical industry, and is very economical and simple in synthesis method.
The invention also discloses the application of the compounds in preparing the medicines for preventing and treating tumor diseases.
The invention is realized by the following steps: an dihydrochromone-spliced pyrrole spiro oxindole compound has a structure shown in the following general formula (I):
in the formula, R1Is methyl or ethyl or phenyl or benzyl; r2Is hydrogen or chlorine or fluorine or methyl; r3Is fluorine or methyl or hydrogen.
A preparation method of dihydrochromone spliced pyrrole spiro oxindole compound comprises the step of carrying out 1, 3-dipole [3+2] cycloaddition reaction on 3-carboxylic acid substituted chromone, various substituted isatins and sarcosine in an organic solvent according to the molar ratio of 2:3:6 to obtain the dihydrochromone spliced pyrrole spiro oxindole compound.
The synthetic route is exemplified as follows:
wherein the substituents of the compounds in the synthetic route satisfy R1Is methyl or ethyl or phenyl or benzyl; r2Is hydrogen or chlorine or fluorine or methyl; r3Is fluorine or methyl or hydrogen.
The reaction mechanism is as follows:
the organic solvent is acetonitrile, toluene, ethanol or methanol.
3-carboxylic acid substituted chromone, various substituted isatin and sarcosine in an organic solvent at the temperature of 80-100 ℃ for 1-5 hours.
Application of dihydrochromone spliced pyrrole spiro oxindole compound in preparing medicaments for preventing and treating tumor diseases.
By adopting the technical scheme, the 3-carboxylic acid substituted chromone, various substituted isatins and sarcosine are subjected to 1, 3-dipole [3+2] cycloaddition reaction in an organic solvent according to the molar ratio of 2:3:6 to obtain the dihydrochromone spliced pyrrole spiro oxindole compound, and the compound contains potential bioactive dihydrochromone and pyrrole spiro oxindole skeleton, can provide a compound source for bioactive screening, and has important application value for drug screening and pharmaceutical industry. And the compound has inhibitory activity on human leukemia cells (K562). The method has the advantages of simple and easy operation, cheap and easily obtained raw material synthesis, capability of being carried out in various organic solvents, better air stability, wide applicability and good compatibility for various substituent groups.
Drawings
FIGS. 1 and 2 are data of the spectrum of compound 3a according to an embodiment of the present invention;
FIGS. 3 and 4 are spectra data for compound 3b of the example of the present invention;
FIGS. 5 and 6 are data of the spectrum of compound 3c according to the example of the present invention;
FIG. 7 is a single crystal diagram of compounds 3d and 3n according to an embodiment of the present invention;
FIG. 8 shows the design and inventive step of the synthesized compound of the present invention.
Detailed Description
The embodiment of the invention comprises the following steps: 38.1mg of 3-carboxylic acid chromone 1a (0.2mmol), 48.3mg of N-methylindolyl 2a (0.3mmol), 53.4mg of sarcosine (0.60mmol) and 5.0mL of EtOH solution are sequentially added into a reaction tube, reacted for 4 hours in an oil bath at 80 ℃, detected by TLC to be almost complete, and directly loaded and purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate): 4:1) to obtain 56.1mg of compound 3a, a pale yellow solid, a melting point: 88.8-89.3 ℃, dr: 11: 1; the yield was 84%. The results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.09(s,3H),3.05(s,3H),3.53(d,J＝8.8Hz,1H),3.69-3.77(m,2H),5.29-5.33(m,1H),6.78(d,J＝8.0Hz,1H),6.89-6.96(m,2H),7.06-7.10(m,1H),7.22-7.25(m,1H),7.29-7.32(m,1H),7.40-7.44(m,1H),7.61-7.64(m,1H)；13C NMR(CDCl3,100MHz)δ:25.9,34.5,57.3,60.8,74.2,108.3,118.3,121.4,123.0,123.5,126.6,129.6,136.3,144.4,160.7,189.6；HRMS(ESI-TOF)m/z:Calcd.for C20H18N2NaO3[M+Na]+:357.1210；Found:357.1214.
the compounds 3b to 3o were obtained by the same production method of the compounds 3b to 3o as the compound 3a in the same charge ratio as the compound 3a, and the reaction yields and dr values are shown in tables 1 and 2, but it should be emphasized that the compounds of the present invention are not limited to those shown in table 1.
Table 1 shows the chemical structure of dihydrochromone spliced pyrrole spiro oxindole compound
Table 2 shows the chemical structure of dihydrochromone-pyrrole spiro-oxoindole compound
This example prepared compound 3b as a pale yellow solid, melting point: 161.5-163.8 ℃; yield: 68%, 8:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.20(s,3H),3.63(d,J＝5.6Hz,1H),3.79-3.86(m,2H),4.78-4.85(m,2H),5.39-5.42(m,1H),6.70(d,J＝5.2Hz,1H),6.98-7.01(m,1H),7.03(d,J＝5.2Hz,1H),7.10-7.13(m,1H),7.23-7.33(m,7H),7.48-7.51(m,1H),7.75(d,J＝5.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:34.7,43.7,57.5,61.1,74.5,109.5,118.3,121.5,123.1,126.7,127.3,127.5,128.7,136.5,143.6,160.8,175.0,189.6；HRMS(ESI-TOF)m/z:Calcd.for C26H22N2NaO3[M+Na]+:433.1523；Found:433.1527.
this example prepared compound 3c as a pale yellow solid, melting point: 57.5-63.1 ℃; yield: 73%, 14:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.26-2.28(m,3H),3.63-3.67(m,1H),3.76-3.80(m,2H),5.36-5.38(m,1H),6.76-6.80(m,1H),6.89-6.95(m,2H),7.11-7.16(m,1H),7.23-7.33(m,5H),7.40-7.43(m,3H),7.67-7.71(m,1H)；13C NMR(CDCl3,100MHz)δ:34.7,58.0,61.0,74.5,109.7,118.4,121.6,123.6,126.7,126.8,128.1,129.6,136.5,144.6,160.8,174.8,190.0；HRMS(ESI-TOF)m/z:Calcd.for C25H20N2NaO3[M+Na]+:419.1366；Found:419.1368.
this example prepared compound 3d: light yellow solid, melting point: 165.3-167.5 ℃; yield: 87%, 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.14(s,3H),2.36(s,3H),3.06(s,3H),3.56(d,J＝8.8Hz,1H),3.77(s,2H),5.34(s,1H),6.71(d,J＝7.6Hz,1H),6.93-6.99(m,2H),7.11-7.14(m,2H),7.43-7.47(m,1H),7.66(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.1,25.8,34.5,57.2,60.8,74.5,108.0,118.2,121.0,121.4,124.3,126.5,129.9,132.5,136.3,142.1,160.6,189.8；HRMS(ESI-TOF)m/z:Calcd.for C21H20N2NaO3[M+Na]+:371.1366；Found:371.1367.
this example prepares compound 3e as a pale yellow solid, melting point: 161.5-162.4 ℃; yield: 81%, 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.13(s,3H),3.44(s,3H),3.49-3.54(m,1H),3.76(d,J＝4.4Hz,2H),5.33-5.36(m,1H),6.95-7.05(m,3H),7.17(d,J＝6.4Hz,1H),7.26(d,J＝7.2Hz,1H),7.45-7.49(m,1H),7.67(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:34.3,45.9,57.6,60.7,73.9,109.9,115.7,118.2,121.0,121.5,122.1,123.7,126.6,1319,136.5,140.2,151.6,160.6,189.6；HRMS(ESI-TOF)m/z:Calcd.for C20H17ClN2NaO3[M+Na]+:391.0820；Found:391.0825.
this example prepared compound 3f as a pale yellow solid, melting point: 58.3-61.3 ℃; yield: 72%, 20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.05(s,3H),2.25(s,3H),3.45(d,J＝5.6Hz,1H),3.65-3.70(m,2H),5.21-5.26(m,1H),6.68(d,J＝5.6Hz,1H),6.71-6.75(m,2H),7.03-7.05(m,1H),7.18-7.20(m,2H),7.24-7.27(m,1H),7.49(d,J＝5.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.9,25.8,34.5,57.2,60.9,74.4,108.3,118.2,118.6,122.8,122.9,123.4,126.5,128.3,129.5,144.5,147.9,160.7,174.9,189.1；HRMS(ESI-TOF)m/z:Calcd.for C21H20N2NaO3[M+Na]+:371.1366；Found:371.1369.
this example prepares compound 3g as a pale yellow solid, melting point: 109.3-110.7 ℃; yield: 87%, 20:1 dr; nuclear magnetic resonance and high resolution mass spectrometryThe results were as follows:1H NMR(CDCl3,400MHz)δ:2.06(s,3H),2.25(s,3H),2.28(s,3H),2.98(s,3H),3.45(d,J＝8.8Hz,1H),3.68(d,J＝5.6Hz,2H),5.22-5.27(m,1H),6.63(d,J＝8.0Hz,1H),6.67-6.71(m,2H),7.02-7.06(m,2H),7.48(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.2,22.0,25.9,34.6,57.1,60.9,74.5,76.7,108.0,118.2,118.6,122.8,124.3,126.5,129.8,132.4,142.1,147.9,160.7,189.1；HRMS(ESI-TOF)m/z:Calcd.for C22H22N2NaO3[M+Na]+:385.1523；Found:385.1527.
this example prepared compound 3h as a pale yellow solid, melting point: 173.0-177.7 ℃; yield: 64 percent, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.06(s,3H),2.28(s,3H),3.00(s,3H),3.46(d,J＝8.8Hz,1H),3.66-3.68(m,2H),5.22-5.28(m,1H),6.65(d,J＝8.0Hz,1H),6.89-6.92(m,1H),7.02(s,1H),7.06-7.13(m,2H),7.22-7.28(m,1H)；13C NMR(CDCl3,100MHz)δ:21.3,26.1,34.7,57.0,60.9,74.7,108.3,111.7(d,JCF＝23.5Hz),120.0,120.1,124.0(d,JCF＝25.1Hz),124.4,130.1,132.7,142.1,157.0,157.1,157.2(d,JCF＝241.0Hz),174.8,189.4；HRMS(ESI-TOF)m/z:Calcd.for C21H19FN2NaO3[M+Na]+:389.1272；Found:389.1275.
this example prepared compound 3i as a pale yellow solid, melting point: 159.2 to 160.0 ℃; yield: 78%, 14:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.10(s,3H),2.24(s,3H),3.51(d,J＝6.8Hz,1H),3.68-3.76(m,2H),4.65-4.73(m,2H),5.27-5.31(m,1H),6.48(d,J＝6.0Hz,1H),6.86-6.90(m,1H),6.92(d,J＝6.4Hz,2H),7.03(s,1H),7.14-7.22(m,5H),7.37-7.40(m,1H),7.65(d,J＝6.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.1,34.7,43.7,57.4,61.1,74.6,109.2,118.3,121.0,121.4,124.5,126.6,127.3,127.4,128.6,129.9,132.6,135.9,136.4,141.2,160.8,189.6；HRMS(ESI-TOF)m/z:Calcd.for C27H24N2NaO3[M+Na]+:447.1679；Found:447.1683.
this example prepared compound 3j as a pale yellow solid, melting point: 51.3-55.3 ℃; yield: 63%, 6:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.19(s,3H),2.36(s,3H),3.59(d,J＝5.6Hz,1H),3.78-3.84(m,2H),4.77-4.84(m,2H),5.36-5.39(m,1H),6.69(d,J＝5.2Hz,1H),6.80(d,J＝5.2Hz,1H),6.84(s,1H),7.09-7.12(m,1H),7.21-7.27(m,3H),7.28-7.32(m,3H),7.36-7.41(m,1H),7.65(d,J＝5.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:22.0,34.7,43.6,57.3,61.1,74.4,109.4,118.2,122.8,123.0,123.6,126.5,127.3,127.4,128.6,129.4,143.5,148.0,160.8,175.0,188.8；HRMS(ESI-TOF)m/z:Calcd.for C27H24N2NaO3[M+Na]+:447.1679；Found:447.1682.
this example prepared compound 3k: light yellow solid, melting point: 66.8-68.9 ℃; yield: 69%, 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.22(s,3H),2.25(s,3H),2.32(s,3H),3.47(s,1H),3.57(d,J＝8.4Hz,1H),3.79-3.81(m,1H),4.97(d,J＝16.4Hz,1H),5.10(d,J＝16.4Hz,1H),5.35(d,J＝5.2Hz,1H),6.75-6.79(m,2H),7.02-7.06(m,2H),7.13(d,J＝7.2Hz,2H),7.18-7.23(m,2H),7.27-7.31(m,2H),7.64(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.8,22.1,34.9,45.0,57.8,61.2,73.9,118.3,118.6,120.0,121.8,122.8,123.2,125.8,125.9,126.6,127.0,128.7,133.7,137.8,141.9,148.2,160.9,175.9,189.0；HRMS(ESI-TOF)m/z:Calcd.for C28H26N2NaO3[M+Na]+:461.1836；Found:461.1832.
this example prepared compound 3l as a pale yellow solid, melting point: 164.4-168.8 ℃; yield: 56%, 11:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.10(s,3H),3.40(s,3H),3.46(d,J＝8.8Hz,1H),3.71(d,J＝5.2Hz,2H),4.69(s,2H),5.25-5.30(m,1H),6.50-6.53(m,1H),6.81-6.87(m,1H),6.90-7.02(m,2H),7.10-7.24(m,6H),7.26-7.29(m,1H)；13C NMR(CDCl3,100MHz)δ:34.8,43.9,57.3,61.1,74.7,110.3,111.6(d,JCF＝23.3Hz),112.0,116.1(d,JCF＝24.1Hz),119.0(d,JCF＝8.3Hz),120.1(d,JCF＝7.4Hz),121.1(d,JCF＝7.3Hz),124.3(d,JCF＝24.6Hz),127.3,127.8,128.9,135.3,139.4,145.5,149.2,157.1,157.3(d,JCF＝241.1Hz),158.5,159.7(d,JCF＝240.4Hz),174.9,188.9；HRMS(ESI-TOF)m/z:Calcd.for C26H20F2N2NaO3[M+Na]+:469.1334；Found:469.1336.
this example prepared compound 3m as a pale yellow solid, melting point: 131.3-133.8 ℃; yield: 76%, 17:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.20(s,3H),3.56(d,J＝8.8Hz,1H),3.67-3.75(m,2H),5.26-5.31(m,1H),6.72(d,J＝7.6Hz,1H),6.85-6.88(m,1H),7.06-7.11(m,2H),7.18-7.28(m,6H),7.34-7.39(m,2H)；13C NMR(CDCl3,100MHz)δ:34.6,57.4,60.8,74.5,109.7,111.5(d,JCF＝23.4Hz),123.5,123.8,123.9(d,JCF＝24.3Hz),128.1,129.5,129.6,144.5,156.9,157.1(d,JCF＝241.5Hz),174.6,189.3；HRMS(ESI-TOF)m/z:Calcd.for C25H19FN2NaO3[M+Na]+:437.1272；Found:437.1276.
this example prepared compound 3n as a pale yellow solid, melting point: 175.9 to 177.1 ℃; yield: 61%, 19:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.15-1.17(m,3H),2.13(s,3H),2.25(s,3H),3.52(d,J＝5.6Hz,1H),3.58-3.70(m,3H),3.75-3.78(m,1H),5.27-5.30(m,1H),6.84(d,J＝5.2Hz,1H),6.89(d,J＝5.6Hz,1H),7.08-7.10(m,1H),7.25-7.28(m,2H),7.31-7.34(m,1H),7.47(s,1H)；13C NMR(CDCl3,100MHz)δ:12.6,20.4,34.4,34.6,57.5,60.9,74.2,108.4,118.0,120.7,122.6,123.7,126.1,128.7,129.5,130.7,137.4,143.4,158.8,174.6,189.7；HRMS(ESI-TOF)m/z:Calcd.for C22H22N2NaO3[M+Na]+:385.1523；Found:385.1523.
this example prepared compound 3o as a pale yellow solid, melting point: 55.4-57.3 ℃;yield: 73%, 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.19-1.23(m,3H),2.22(s,3H),3.54-3.57(m,1H),3.61-3.69(m,1H),3.70-3.76(m,1H),3.79-3.86(m,2H),5.36-5.41(m,1H),6.83-6.86(m,1H),7.04-7.07(m,1H),7.09-7.12(m,2H),7.25-7.30(m,1H),7.38-7.41(m,1H)；13C NMR(CDCl3,100MHz)δ:12.6,34.6,57.2,61.0,74.5,109.2(d,JCF＝8.1Hz),111.5(d,JCF＝23.2Hz),112.0(d,JCF＝24.4Hz),116.0(d,JCF＝23.7Hz),120.1(d,JCF＝7.2Hz),121.2,121.3,124.1(d,JCF＝25.3Hz),130.1,139.4,156.1,157.0,157.1,157.3(d,JCF＝240.3Hz),159.9(d,JCF＝240.1Hz),174.4,188.9；HRMS(ESI-TOF)m/z:Calcd.for C21H18F2N2NaO3[M+Na]+:407.1178；Found:407.1177.
the compound of formula (1) of the invention has important biological activity, and the cytotoxicity test of the compound in vitro on human leukemia cells (K562) and human prostate (PC-3) co-two tumor cells shows that: the dihydrochromone spliced pyrrole spiro oxindole compound with the structure shown in the formula (1) has an inhibiting effect on the growth of tumor cells, and can be possibly developed into a new tumor prevention and treatment drug. It is emphasized, however, that the compounds of the present invention are not limited to the cytotoxicity shown by human prostate (PC-3) and human leukemia cells (K562).
Pharmacological examples: cytotoxicity of Compounds 3c,3g,3l,3m and 3o on K562 cells
K562 (human chronic myelogenous leukemia cells) was cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and 5% CO at 37 deg.C2Incubate in a humidified air incubator for 24 hours.
The cell viability was determined by the modified MTT method. After 24 hours incubation of the cells, newly formulated compounds 3c,3g,3L,3m and 3o in DMSO were added to each well in a concentration gradient such that the final concentration of the compound in the well was 6. mu. mol/L, 12. mu. mol/L, 25. mu. mol/L, 50. mu. mol/based on the total weight of the cellsL and 80. mu. mol/L. After 48 hours, 10. mu.L of MTT (5mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4 hours, the unconverted MTT was removed by centrifugation for 5 minutes, and 150. mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein the compounds 3c,3g,3l,3m and 3o have half inhibitory concentration IC on K562 cells50Analyzed by the sps software (version 19). IC of Compound 3c on K562 tumor cells5035.04 mu mol/L; IC of compound 3g on K562 tumor cells5041.57 mu mol/L; IC of compound 3l on K562 tumor cells5047.53 mu mol/L; IC of compound 3m on K562 tumor cells5021.10 mu mol/L; IC of compound 3o on K562 tumor cells5035.28. mu. mol/L; IC of positive control cisplatin on K562 tumor cells50It was 23.05. mu. mol/L.
And (4) experimental conclusion: k562 cells are an effective tool and an evaluation index for testing the cytotoxicity of compounds on tumor cells. The experiment shows that the dihydrochromone spliced pyrrole spiro oxindole compound shown in the formula (1) has stronger cytotoxicity on K562 cells, has the same order of magnitude as cisplatin used as a first-line medicament for tumor treatment, and can be possibly developed into a new medicament with an anti-tumor effect.
Pharmacological example 1: cytotoxicity of Compounds 3m and 3o on PC-3 cells
PC-3 (human prostate cancer) cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and 5% CO at 37 deg.C2Incubate in a humidified air incubator for 24 hours.
The cell viability was determined by the modified MTT method. After 24 hours incubation of the cells, a new 3m and 3o solution of dimethyl sulfoxide was added to each well in a concentration gradient to give final concentrations of the compound in the wells of 5. mu. mol/L, 10. mu. mol/L, 20. mu. mol/L, 40. mu. mol/L and 80. mu. mol/L, respectively. After 48 hours, 10. mu.L of MTT (5mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4 hours, the non-transformed MTT was removed by centrifugation for 5 minutes, and 150. mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein the half inhibitory concentration IC of compounds 3m and 3o on PC-3 cells50Analyzed by the sps software (version 19). IC of compound 3m on PC-3 tumor cells5033.72 mu mol/L; IC of compound 3o on PC-3 tumor cells5045.27 mu mol/L; IC of positive control cisplatin on PC-3 tumor cells50It was 25.71. mu. mol/L.
And (4) experimental conclusion: PC-3 cells are an effective tool and an evaluation index for testing the cytotoxicity of the compound on tumor cells. The experiment shows that the dihydrochromone spliced pyrrole spiro oxindole compound shown in the formula (1) has stronger cytotoxicity to PC-3 cells, has the same order of magnitude as cisplatin used as a first-line medicament for treating tumors, and can be possibly developed into a new medicament with an anti-tumor effect.
From the above pharmacological examples we can see that these compounds show some cytotoxicity to both human leukemia cells (K562) and PC-3 (human prostate cancer) cells. Therefore, the compounds have the potential of being developed into antitumor drugs and are worthy of being further researched.
Claims (5)
1. An dihydro chromone spliced pyrrole spiro oxindole compound is characterized in that: the compound has a structure shown as a general formula (I):
in the formula, R1Is methyl, ethyl, phenyl or benzyl; r2Is hydrogen or chlorine or fluorine or methyl; r3Is fluorine or methyl or hydrogen.
2. A process for the preparation of an dihydrochromone-spiro-oxopyrrole indole compound of claim 1, wherein: carrying out 1, 3-dipole [3+2] cycloaddition reaction on 3-carboxylic acid substituted chromone, various substituted isatins and sarcosine in an organic solvent according to the molar ratio of 2:3:6 to obtain a dihydrochromone spliced pyrrole spiro oxindole compound;
wherein the 3-carboxylic acid is substituted with a compound having the structural formula 1:
the variously substituted isatin 2 are compounds having the structural formula 1:
in the formula, R1Is methyl, ethyl, phenyl or benzyl; r2Is hydrogen or chlorine or fluorine or methyl; r3Is fluorine or methyl or hydrogen.
3. The method for preparing dihydrochromone-spliced pyrrole spiro-oxoindole compound according to claim 2, wherein the method comprises the following steps: the organic solvent is acetonitrile, toluene, ethanol or methanol.
4. The method for preparing dihydrochromone-spliced pyrrole spiro-oxoindole compound according to claim 2, wherein the method comprises the following steps: the reaction temperature of the 3-carboxylic acid substituted chromone, various substituted isatins and sarcosine in the organic solvent is 80-100 ℃, and the reaction time is 1-5 hours.
5. The use of an dihydrochromone-spiro-oxopyrrole indole compound of claim 1 in the preparation of a medicament for the prevention and treatment of neoplastic diseases, wherein: the tumor is a tumor K562.
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