CN111004145B - Chiral optical amide substituted alpha, beta-diamino acid derivative and preparation method and application thereof - Google Patents
Chiral optical amide substituted alpha, beta-diamino acid derivative and preparation method and application thereof Download PDFInfo
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- CN111004145B CN111004145B CN201911268230.5A CN201911268230A CN111004145B CN 111004145 B CN111004145 B CN 111004145B CN 201911268230 A CN201911268230 A CN 201911268230A CN 111004145 B CN111004145 B CN 111004145B
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Abstract
The invention discloses a chiral optical pure alkynylamide substituted alpha, beta-diamino acid derivative and a preparation method and application thereof. The structure of the derivative is shown as a formula (I); wherein, R is1Is benzene, naphthyl, halogenated phenyl, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl; r2Is hydrogen, halogen, C1～2Alkyl radical, C1～2Alkoxy or tert-butylcarbonyl substituted C1～4An alkoxy group; r3Thiophene, furan, naphthyl, benzene, halogenated phenyl, methyl substituted phenyl or methoxy substituted phenyl; r4Is hydrogen, C1～2Alkyl or phenyl. The compound has a novel structure, also has a good anti-tumor effect, particularly has a good effect on human colon cancer, human non-small cell lung cancer, human osteosarcoma and human acute promyelocytic leukemia, and has a great application value in the aspect of anti-tumor effect; meanwhile, the preparation method has the advantages of few reaction steps, simple and safe operation, low cost, high atom economy, high selectivity and high yield.
Description
Technical Field
The invention relates to the technical field of medicine synthesis and anticancer drugs, in particular to a chiral optical alkynylamide-substituted alpha, beta-diamino acid derivative and a preparation method and application thereof.
Background
The carbon atom chiral center and the amide group are widely present in natural products and some common drugs, and have good activity, for example, some antibacterial drugs such as quinolone antibacterial drugs and lipid-lowering drugs such as statin lipid-lowering drugs contain the carbon atom chiral center, but the carbon atom chiral center is particularly important for the influence of the drug activity, and the effect of the carbon atom chiral center is different from that of different isomers, for example, the 'reaction stop' event occurred in the last century. The aryl all-carbon chiral center and the amide are commonly existing structural units in natural products and medicines, and the compounds with the two structures have good biological activity and have a great development prospect in the aspect of anti-tumor; in addition, alkyne amide groups are also widely found in anticancer, antibacterial, anti-inflammatory drugs and many natural products, such as steroidal anti-inflammatory drugs, sulfonamides antibacterial drugs, etc.; however, in the chemical synthesis of the chiral optical alkynylamide-substituted α, β -diamino acid derivative, an amide compound containing two aryl all-carbon chiral centers is generated, so how to construct an alkynylamide compound having two all-carbon chiral centers, and ensure higher purity and better activity, which provides a challenge in a relatively large sense.
In the early stage of research, a derivative containing alpha-aryl-alpha, beta-diamino acid ester is synthesized (patent 201710004520.3), and although the compound has a good inhibitory effect on 3 cancer cells (human colon cancer HCT116 cells, human liver cancer BEL7402 cells and human liver cancer SMMC7721 cells), the type and activity range of the compound still have a large research value and development space and are to be further researched.
Disclosure of Invention
The invention aims to provide a chiral optical alkynylamide substituted alpha, beta-diamino acid derivative. The compound has a novel structure, also has a good anti-tumor effect, particularly has a good effect on human colon cancer, human non-small cell lung cancer, human osteosarcoma or human acute promyelocytic leukemia, particularly has an excellent inhibition effect on human osteosarcoma, can inhibit IC50 to be as low as 0.004 mu M, and has a great application value in the aspect of anti-tumor effect.
The invention also aims to provide a preparation method of the chiral optical alkyne amide substituted alpha, beta-diamino acid derivative.
Still another object of the present invention is to provide the use of chiral optical alkynylamide substituted α, β -diamino acid derivatives.
The above object of the present invention is achieved by the following scheme:
a chiral optically pure alkynylamide substituted alpha, beta-diamino acid derivative, the structure of which is shown in formula (I):
wherein, R is1Is benzene, naphthyl, halogenated phenyl, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl;
R2is hydrogen, halogen, C1～2Alkyl radical, C1～2Alkoxy or tert-butylcarbonyl substituted C1～4An alkoxy group;
R3thiophene, furan, naphthyl, benzene, halogenated phenyl, methyl substituted phenyl or methoxy substituted phenyl;
R4is hydrogen, C1～2Alkyl or phenyl.
Preferably, said R is1Is benzene, naphthyl, 4-bromo-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl or 4-OCH2CH2NHBoc-phenyl;
R2is hydrogen, 2-fluoro, 3-bromo, 4-methoxy or 4-OCH2CH2NHBoc；
R3Is thiophene, furan, naphthyl, benzene, 3-bromo-phenyl, 4-bromo-phenyl, 3, 4-dichloro-phenyl, 4-fluoro-phenyl, -4-trifluoromethyl-phenyl or 4-methoxy-phenyl;
R4is hydrogen, methyl or phenyl.
Preferably, the structure of the compound is shown as one of the following:
the invention also provides a preparation method of the chiral optical pure alkynylamide substituted alpha, beta-diamino acid derivative, which comprises the steps of dissolving raw materials shown in formulas 1,2 and 3 in an anhydrous organic solvent in a mixing manner, and reacting in the presence of a metal catalyst and a chiral phosphoric acid catalyst to obtain a target product shown in formula (I);
preferably, the reaction molar ratio of the raw material shown in the formula 1, the raw material shown in the formula 2, the raw material shown in the formula 3, the metal catalyst and the chiral phosphoric acid catalyst is 1.2-1.8: 1: 1.0-1.5: 0.001-0.02: 0.001-0.05.
Preferably, the reaction also adds
A molecular sieve; the reaction time is 5-8 h; the organic solvent is dichloromethane, 1,2 dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, toluene, xylene or ethyl acetate.
Preferably, the reaction temperature is-5-40 ℃.
Preferably, the
The feeding amount of the molecular sieve and the raw material shown in the formula 2 is 0-500 mg/mmol.
Preferably, the concentration of the raw material shown in formula 2 in the reaction liquid is 0.05-50.5 mol/L.
Preferably, the metal catalyst is one or more of rhodium acetate, rhodium octanoate, rhodium trifluoroacetate, bis [ (Α, Α ', Α' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ], palladium chloride, allyl palladium dichloride, tetratriphenylphosphine palladium, copper trifluoromethanesulfonate, cuprous iodide or copper hexafluorophosphine.
More preferably, the metal catalyst is one or more of rhodium acetate, rhodium octanoate, or bis [ (Α, Α, Α ', Α' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ].
Preferably, the chiral phosphoric acid catalyst is of any one of the following structural formulas:
wherein R is phenyl, p-bromophenyl, p-fluorophenyl, p-methoxyphenyl, p-nitrophenyl, 2-naphthyl, 9-phenanthryl, 9-anthryl, triphenylsilyl, 3, 5-dichlorophenyl, 3, 5-ditrifluoromethylphenyl, 3, 5-dinitrophenyl or 2, 4, 6-triisopropylphenyl.
The application of the alpha, beta-diamino acid derivative substituted by the chiral optical pure alkynylamide in preparing the antitumor drugs is also in the protection range of the invention.
Preferably, the anti-tumor drug is human osteosarcoma cells, human breast cancer cells, human colon cancer cells and human non-small cell lung cancer cells.
Compared with the prior art, the invention has the following beneficial effects:
the compound has a novel structure, also has a good anti-tumor effect, particularly has a good effect on human colon cancer, human non-small cell lung cancer, human osteosarcoma or human acute promyelocytic leukemia, particularly has an excellent inhibition effect on human osteosarcoma, can inhibit IC50 to be as low as 0.004 mu M, and has a great application value in the aspect of anti-tumor effect.
Meanwhile, the compound is prepared into a target product by taking a diazo compound, alkynylamide and aryl imine as raw materials, taking metal rhodium as a catalyst and chiral phosphoric acid as a chiral catalyst and carrying out one-step reaction in an organic solvent; the preparation method uses cheap and easily-obtained raw materials, has few reaction steps, is simple and safe to operate, has low cost and few generated wastes, and has the advantages of high atom economy, high selectivity and high yield.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials. Example 1 preparation of compounds 1 to 30:
the preparation reaction is as follows:
mixing aromatic imine (0.40mmol) shown in formula 2, metal rhodium (0.004mmol, metal catalyst), alkynylamide (0.48mmol) shown in formula 3, chiral phosphoric acid (0.01mmol),
dissolving a molecular sieve (400mg) in 8.0mL of organic solvent methyl tert-butyl ether to prepare a mixed solution 1, and dissolving the diazo compound (0.6mmol) shown in the formula 1 in 8.0mL of organic solvent methyl tert-butyl ether to prepare a solution 2; adding the solution 2 into the mixed solution 1 at 0 ℃ for 1h by using a syringe pump; stirring vigorously; after the dropwise addition of the mixed solution is finished, stirring for 5-8 h at the temperature of 0 ℃ until the diazo compound is completely consumed; will reactFiltering the solution, and separating and purifying by column chromatography to obtain a pure product, namely the target product.
The structures of the prepared compounds 1 to 27 are shown in table 1, and the specific map data are as follows:
spectral data for compound 1:1H NMR(400MHz,CDCl3)(δ,ppm)7.47(d,J＝8.4Hz,2H),7.37–7.31(m,7H),7.21(d,J＝8.4Hz,2H),6.65(d,J＝8.9Hz,2H),6.34(d,J＝8.9Hz,2H),5.54(d,J＝3.3Hz,1H),4.96(s,1H),3.89–3.87(m,2H),3.72(s,3H),3.45(d,J＝4.7Hz,2H),2.93(s,1H),1.43(s,9H)；
spectral data for compound 2:1H NMR(400MHz,CDCl3)(δ,ppm)7.47(d,J＝8.4Hz,2H),7.39–7.29(m,7H),7.22(d,J＝8.4Hz,2H),6.66(d,J＝8.9Hz,2H),6.35(d,J＝8.9Hz,2H),6.27(d,J＝5.0Hz,1H),5.54(d,J＝5.1Hz,1H),3.71(s,3H),3.68(s,3H),2.91(s,1H)；
spectral data for compound 3:1H NMR(400MHz,CDCl3)7.49–7.26(m,11H),6.66(d,J＝8.9Hz,2H),6.38(d,J＝8.9Hz,2H),6.28(d,J＝5.2Hz,1H),5.57(d,J＝5.3Hz,1H),3.71(s,3H),3.68(s,3H),2.89(s,1H)；
spectral data for compound 4:1H NMR(400MHz,CDCl3)(δ,ppm)7.47(d,J＝8.4Hz,2H),7.40–7.31(m,6H),7.22(d,J＝8.4Hz,2H),7.10–7.03(m,2H),6.66–6.59(m,2H),6.41(d,J＝7.7Hz,2H),5.64(d,J＝5.6Hz,1H),3.73(s,3H),2.93(s,1H)；
spectral data for compound 5:1H NMR(400MHz,CDCl3)(δ,ppm)1H NMR(500MHz,CDCl3)δ7.39(d,J＝7.4Hz,2H),7.35–7.30(m,8H),6.65(d,J＝8.5Hz,2H),6.37(d,J＝8.6Hz,2H),6.33(d,J＝3.9Hz,1H),5.57(d,J＝3.7Hz,1H),4.95(s,1H),3.87(t,J＝4.7Hz,2H),3.72(s,3H),3.44(d,J＝4.4Hz,2H),2.90(s,1H),1.43(s,9H)；
spectral data for compound 6:1H NMR(400MHz,CDCl3)(δ,ppm)7.65–7.53(m,3H),7.48(t,J＝7.6Hz,1H),7.43–7.28(m,6H),7.08(t,J＝7.6Hz,2H),6.76–6.53(m,2H),6.44(d,J＝7.8Hz,2H),5.73(d,J＝5.1Hz,1H),3.74(s,3H),2.93(s,1H)；
spectral data for compound 7:1H NMR(400MHz,CDCl3)(δ,ppm)7.42–7.30(m,6H),7.24(s,1H),7.06(t,J＝7.6Hz,2H),6.87(d,J＝8.3Hz,2H),6.66–6.52(m,2H),6.44(d,J＝8.1Hz,2H),5.61(d,J＝5.4Hz,1H),3.79(s,3H),3.72(s,3H),2.91(s,1H)；
spectral data for compound 8:1H NMR(400MHz,CDCl3)(δ,ppm)7.47(d,J＝8.4Hz,2H),7.42–7.27(m,6H),7.21(d,J＝8.4Hz,2H),7.06(t,J＝7.8Hz,2H),6.69–6.54(m,2H),6.41(d,J＝7.9Hz,2H),5.64(d,J＝5.5Hz,1H),3.71(s,3H),2.91(s,1H)；
compound 9 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)7.52–7.31(m,9H),7.25(t,J＝7.8Hz,1H),7.11(t,J＝7.6Hz,2H),6.74–6.58(m,2H),6.47(d,J＝8.0Hz,2H),5.65(d,J＝5.4Hz,1H),3.77(s,3H),2.97(s,1H)；
compound 10 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)1H NMR(400MHz,CDCl3)(δ,ppm)8.41(d,J＝8.4Hz,1H),7.90(d,J＝8.0Hz,1H),7.86–7.72(m,2H),7.61–7.28(m,9H),6.99(t,J＝7.8Hz,2H),6.78(d,J＝4.4Hz,1H),6.57(t,J＝7.3Hz,1H),6.52–6.31(m,3H),3.32(s,3H),2.92(s,1H)；
compound 11 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.52(s,1H),7.39–7.35(m,1H),7.33–7.31(m,5H),7.19(d,J＝8.8Hz,2H),6.52(d,J＝7.0Hz,1H),6.37(d,J＝8.8Hz,2H),6.34–6.32(m,1H),6.29–6.26(m,1H),5.81(d,J＝7.0Hz,1H),3.82(s,3H),2.90(s,1H)；
compound 12 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.49(s,1H),7.35–7.33(m,5H),7.28–7.26(m,1H),7.17(d,J＝8.8Hz,1H),7.02–6.96(m,1H),6.95–6.93(m,1H),6.81(d,J＝5.4Hz,1H),6.39(d,J＝8.9Hz,1H),5.92(d,J＝5.4Hz,1H),3.77(s,3H),2.94(s,1H)；
compound 13 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.49(s,1H),7.45–7.40(m,2H),7.39–7.30(m,6H),7.20(dd,J＝8.3,2.0Hz,1H),7.15–7.01(m,2H),6.66(t,J＝7.3Hz,1H),6.61(d,J＝5.4Hz,1H),6.42(d,J＝7.8Hz,2H),5.62(d,J＝5.4Hz,1H),3.74(s,3H),2.95(s,1H)；
compound 14 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.38–7.29(m,11H),7.12(d,J＝8.2Hz,2H),6.76(d,J＝5.4Hz,1H),6.31(d,J＝8.2Hz,2H),5.62(d,J＝5.6Hz,1H),3.72(s,3H),2.91(s,1H)；
compound 15 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.50–7.43(m,4H),7.26–7.22(m,2H),7.18(d,J＝8.4Hz,2H),7.10–7.03(m,2H),6.63(t,J＝7.3Hz,1H),6.54(d,J＝5.9Hz,1H),6.41(d,J＝7.7Hz,2H),5.58(d,J＝5.9Hz,1H),3.74(s,3H),2.94(s,1H)；
compound 16 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.46(d,J＝8.5Hz,2H),7.32(s,1H),7.28(d,J＝8.9Hz,2H),7.20(d,J＝8.4Hz,2H),7.08–7.03(m,2H),6.85(d,J＝8.9Hz,2H),6.64–6.59(m,2H),6.41(d,J＝7.7Hz,2H),5.60(d,J＝5.6Hz,1H),3.78(s,3H),3.73(s,3H),2.92(s,1H)；
compound 17 spectrum data:1H NMR(500MHz,CDCl3)(δ,ppm)7.47(d,J＝8.3Hz,2H),7.34(s,1H),7.28–7.20(m,4H),7.06(t,J＝7.8Hz,2H),6.96(d,J＝8.0Hz,1H),6.90–6.87(m,1H),6.87–6.82(m,1H),6.65–6.59(m,2H),6.43(d,J＝8.1Hz,2H),5.58(d,J＝5.4Hz,1H),3.73(s,3H),3.63(s,3H),2.92(s,1H)；
compound 18 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.86–7.82(m,1H),7.80(d,J＝8.5Hz,2H),7.73(d,J＝7.6Hz,1H),7.51–7.43(m,6H),7.27–7.23(m,3H),7.11–7.05(m,2H),6.70–6.63(m,2H),6.44(d,J＝7.8Hz,2H),5.77(d,J＝5.7Hz,1H),3.71(s,3H),2.96(s,1H)；
compound 19 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.46(d,J＝8.3Hz,2H),7.32(s,1H),7.28(d,J＝8.8Hz,2H),7.20(d,J＝8.3Hz,2H),7.06(t,J＝7.8Hz,2H),6.83(d,J＝8.8Hz,2H),6.64–6.59(m,2H),6.41(d,J＝8.0Hz,2H),5.59(d,J＝5.6Hz,1H),4.98(s,1H),3.98(t,J＝4.7Hz,2H),3.72(s,3H),3.50(d,J＝4.5Hz,2H),2.93(s,1H),1.44(s,9H)；
compound 20 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)7.36(d,J＝6.6Hz,6H),7.31(dd,J＝8.5,5.4Hz,2H),7.16(d,J＝8.7Hz,2H),7.07(t,J＝8.5Hz,2H),6.77(d,J＝5.6Hz,1H),6.32(d,J＝8.7Hz,2H),5.64(d,J＝5.6Hz,1H),3.75(s,3H),2.97(s,1H)；
compound 21 spectrum data:1H NMR(400MHz,CDCl3)(δ,ppm)7.51(d,J＝8.4Hz,2H),7.38(m,J＝2.8Hz,6H),7.21(d,J＝8.4Hz,2H),6.92(t,J＝8.0Hz,1H),6.85(d,J＝5.8Hz,1H),6.76(d,J＝7.9Hz,1H),6.58(s,1H),6.35(d,J＝8.1Hz,1H),5.64(d,J＝5.9Hz,1H),3.76(s,3H),2.97(s,1H)；
compound 22 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)7.51(d,J＝8.3Hz,2H),7.38(m,7H),7.22(d,J＝8.2Hz,2H),7.01(m,J＝8.0Hz,1H),6.86(d,J＝5.6Hz,1H),6.33(m,J＝9.1Hz,1H),6.23(d,J＝8.1Hz,1H),6.11(d,J＝11.6Hz,1H),5.65(d,J＝5.6Hz,1H),3.76(s,3H),2.97(s,1H)；
compound 23 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)7.51(d,J＝7.3Hz,2H),7.43–7.33(m,6H),7.24(d,J＝7.5Hz,2H),6.98–6.89(m,2H),6.85(t,J＝7.7Hz,1H),6.58(q,J＝7.7Hz,1H),6.40(t,J＝8.3Hz,1H),5.73(d,J＝5.9Hz,1H),3.76(s,3H),2.95(s,1H)；
compound 24 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)7.48(t,J＝7.7Hz,4H),7.38(s,1H),7.32(s,1H),7.23(d,J＝8.5Hz,2H),7.16(d,J＝8.2Hz,2H),7.03–6.96(m,1H),6.32(t,J＝8.5Hz,1H),6.20(d,J＝7.8Hz,1H),6.07(d,J＝11.6Hz,1H),5.57(d,J＝6.0Hz,1H),3.75(s,3H),2.97(s,1H)；
compound 25 spectral data:1H NMR(400MHz,CDCl3)(δ,ppm)7.50(d,J＝8.2Hz,2H),7.33(d,J＝23.3Hz,2H),7.21(d,J＝8.2Hz,2H),7.07–6.80(m,5H),6.33(t,J＝8.2Hz,1H),6.23(d,J＝8.0Hz,1H),6.10(d,J＝11.6Hz,1H),5.60(d,J＝5.7Hz,1H),3.81(s,3H),3.76(s,3H),2.96(s,1H)；
compound 26 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.75(d,J＝7.7Hz,2H),7.53–7.23(m,11H),7.03(t,J＝7.3Hz,2H),6.61(t,J＝7.2Hz,1H),6.42(d,J＝7.8Hz,2H),5.26(d,J＝7.7Hz,1H),4.56(d,J＝7.5Hz,1H),3.90(s,1H),3.69(s,1H)；
compound 27 spectral data:1H NMR(500MHz,CDCl3)(δ,ppm)7.46(d,J＝8.3Hz,2H),7.41–7.29(m,5H),7.22(d,J＝8.2Hz,3H),7.05(t,J＝7.8Hz,2H),6.81(d,J＝5.5Hz,1H),6.61(t,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,2H),5.63(d,J＝5.6Hz,1H),3.70(s,3H),1.99(s,3H)；
compound 28 spectral data:1H NMR(400MHz,Chloroform-d)δ7.52(s,1H),7.36(m,J＝5.5Hz,3H),7.33–7.27(m,3H),7.20–7.14(m,3H),7.11(m,J＝3.4Hz,1H),7.09–7.01(m,2H),6.61(t,J＝7.3Hz,1H),6.42(d,J＝7.8Hz,2H),5.64(s,1H),3.64(s,3H),2.91(s,1H),2.31(s,3H).
compound 29 spectral data:1H NMR(400MHz,Chloroform-d)δ7.40–7.30(m,10H),7.26(s,1H),7.03–6.90(m,3H),6.57(t,J＝7.3Hz,1H),6.46(d,J＝5.4Hz,1H),6.32(d,J＝8.0Hz,1H),5.72(d,J＝5.5Hz,1H),3.75(s,3H),2.91(s,1H),1.98(s,3H).
compound 30 spectral data:1H NMR(400MHz,Chloroform-d)δ7.49(d,J＝1.7Hz,2H),7.40–7.38(m,3H),7.37(s,2H),7.34(t,J＝8.0Hz,4H),7.25–7.22(m,3H),7.07(d,J＝7.6Hz,2H),6.62(t,J＝7.3Hz,1H),6.56(d,J＝6.2Hz,1H),6.48(d,J＝7.8Hz,3H),6.07(d,J＝6.2Hz,1H),3.68(s,3H),2.95(s,1H).
TABLE 1 structures of Compounds 1 to 30
Example 2 inhibitory Activity of test Compounds on tumor cells:
the tumor cells used for the test were: human osteosarcoma cell (Sjsa-1), human breast cancer cell (MCF7), human colon cancer cell (HCT116), and human non-small cell lung cancer cell (A549).
The inhibitory effect of 30 compounds in Table 1 on osteosarcoma cell proliferation was measured by CCK-8 method, and the results are shown in Table 2.
According to the results shown in Table 2, some compounds were selected and tested for their inhibitory effects on proliferation of human osteosarcoma cells, human breast cancer cells, human colon cancer cells, and human non-small cell lung cancer cells by the CCK-8 method, and the test results are shown in Table 3.
The specific test process is as follows:
(1) preparing SJSA-1 osteoma cell strain into single cell suspension, inoculating 100uL of the single cell suspension into a 96-well culture plate, wherein the concentration of the single cell suspension is 6000 cells/well, and CO is2Incubators (37 ℃, 5% CO2, 95% air) overnight;
(2) the compounds were dissolved in DMSO respectively to prepare 10mM stock solutions, which were then diluted in this order to concentrations of 3.3mM, 1.1mM, 0.33mM, 0.11mM, 0.033mM, and 0.011 mM. 0.3uL of each of the above-mentioned concentrations was added to each well of the cells, and 0.3uL of DMSO was added to the control group to give a final concentration of 0.3%, CO2Culturing in an incubator for 48 hours; adopts 1640 culture medium (10% containing newborn bovine serum and 1% double antibody)
(3) After 48h of culture, adding 10uL of CCK-8 reagent into each hole of the cells, incubating for 2 hours at 37 ℃, measuring absorbance A at 450nm by using a Biotek multifunctional enzyme-linked immunosorbent assay, and calculating the inhibition rate of the cells on the growth of tumor cells; the inhibition rate is calculated by the method of [1- (A drug treatment group-A blank control)/(A non-drug treatment group-A blank control) ] x 100%, and A is absorbance.
(4) IC was calculated using GraphPad Prism750(IC50The concentration of drug required to inhibit 50% of cell growth). The results are shown in tables 2 and 3.
TABLE 2 inhibitory Activity of the Compounds on human osteosarcoma cells
| Compound numbering | IC50(μM) | Compound numbering | IC50(μM) |
| 1 | 1.47 | 16 | 0.012 |
| 2 | >3.3 | 17 | 0.85 |
| 3 | >3.3 | 18 | 0.028 |
| 4 | 0.024 | 19 | 0.020 |
| 5 | >3.3 | 20 | 1.516 |
| 6 | 0.023 | 21 | 0.238 |
| 7 | >3.3 | 22 | 0.126 |
| 8 | 0.039 | 23 | 0.220 |
| 9 | -- | 24 | 0.012 |
| 10 | -- | 25 | 0.008 |
| 11 | >3.3 | 26 | >3.3 |
| 12 | >3.3 | 27 | >3.3 |
| 13 | 0.04 | 28 | 1.5 |
| 14 | 0.22 | 29 | 0.21 |
| 15 | 0.018 | 30 | 0.22 |
"- -" indicates no activity.
As can be seen from Table 2, the compounds of the present invention all showed good inhibitory effect on SJSA-1 osteosarcoma cells, especially compounds 4, 8, 13, 15, 16, 18, 19, 24, 25, IC of HCT11650Value of all<100nM, with the best inhibition of compounds 13, 15, 16, 24, 25, IC50Value of all<10nM shows excellent inhibitory action on SJSA-1 osteosarcoma cells, and can inhibit SJSA-1 osteosarcoma cells, which indicates that the compound provided by the invention can be prepared into a medicine for resisting SJSA-1 osteosarcoma cells for application.
TABLE 3 inhibition of various cancer cell lines by compounds
As shown in table 3, the compounds 15, 16, 24, 25 and 29 of the present invention all exhibit a certain degree of inhibition on various tumor cells, wherein especially the compounds 15, 16 and 25 exhibit significant inhibition on 4 tumor cells and specific inhibition on SJSA-1 osteosarcoma tumor cells, and overall, the compounds of the present invention can be prepared into drugs for resisting 4 tumor cells.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. A chiral optically pure alkynylamide substituted α, β -diamino acid derivative having the structure shown in one of the following:
2. the preparation method of chiral optically pure alkynylamide substituted alpha, beta-diamino acid derivative as claimed in claim 1, wherein the raw materials shown in formula 1, formula 2 and formula 3 are mixed and dissolved in anhydrous organic solvent, and reacted in the presence of metal catalyst and chiral phosphoric acid catalyst to obtain the target product shown in formula (I);
(ii) a Wherein R is1、R2、R3、R4Corresponding to the corresponding substituents in the structural formula of the compound of claim 1.
3. The method for preparing chiral optically pure alkynylamide-substituted α, β -diamino acid derivatives according to claim 2, wherein the molar ratio of the raw materials of formula 1, formula 2, formula 3, the metal catalyst and the chiral phosphoric acid catalyst is 1.2-1.8: 1: 1.0-1.5: 0.001-0.02: 0.001-0.05.
4. The process for the preparation of chiral optically pure alkynylamide substituted α, β -diamino acid derivatives as claimed in claim 2, wherein the reaction is further supplemented with
A molecular sieve; the reaction time is 5-8 h; the organic solvent is dichloromethane, 1,2 dichloroethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, toluene, xylene or ethyl acetate.
5. The process for the preparation of a chirally optically pure alkynylamide substituted α, β -diamino acid derivative according to claim 2 wherein the metal catalyst is one or more of rhodium acetate, rhodium octanoate, rhodium trifluoroacetate, bis [ (Α, Α, Α ', Α' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ], palladium chloride, allyl palladium dichloride, tetratriphenylphosphine palladium, copper trifluoromethanesulfonate, cuprous iodide or copper hexafluorophosphine;
the chiral phosphoric acid catalyst has any one of the following structural formulas:
wherein R is phenyl, p-bromophenyl, p-fluorophenyl, p-methoxyphenyl, p-nitrophenyl, 2-naphthyl, 9-phenanthryl, 9-anthryl, triphenylsilyl, 3, 5-dichlorophenyl, 3, 5-ditrifluoromethylphenyl, 3, 5-dinitrophenyl or 2, 4, 6-triisopropylphenyl.
6. The use of chiral optically pure alkynylamide substituted α, β -diamino acid derivatives as claimed in claim 1 for the preparation of antineoplastic agents.
7. The use of claim 6, wherein the anti-tumor drug is a drug against human osteosarcoma cells, human breast cancer cells, human colon cancer cells and/or human non-small cell lung cancer cells.
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