Adenine-based iron ion chelators and their synthesis and applications

Abstract

The application discloses an iron ion chelator based on adenine and synthesis and application thereof, and synthesizes a series of iron ion chelators with high affinity to ribonucleotide reductase, taking adenine as a leading compound, and the iron ion chelators have tridentate coordination donors (OH, N, N or N, N, N). In a salvage synthesis pathway, when the adenine derivatives as DNA synthesis raw materials contact with RR, the iron ions in the active center of the RR are effectively chelated, and then the activity of the RR is inhibited, the synthesis of DNA is blocked, and finally the proliferation of tumor cells is inhibited. The application reasonably utilizes the synthesis of DNA of cancer cells through a free base salvage synthesis pathway, and finds a new breakthrough for the iron ion chelator used for tumor treatment.

Description

Technical Field

[0001] The present invention relates to a metal chelating agent, in particular to the synthesis and application of an adenine-based iron ion chelating agent. Background Art

[0002] Commonly used anti-tumor chemotherapy drugs in clinical practice mainly include organic small molecule drugs, natural medicines, and inorganic metal drugs. The emergence of new copper (Cu), iron (Fe), and ion chelators has opened new doors for cancer drug research and development. Studies have shown that tumor cells metabolize faster than normal cells and require more metal ions such as copper (Cu), iron (Fe), and zinc (Zn). For example, Fe is involved in various life reactions such as erythropoiesis and deoxyribonucleotide (DNA) synthesis. Fe also produces reactive oxygen species (ROS) through redox reactions, which in turn damage cells. Therefore, excessive intracellular Fe ion levels are considered a major cause of cancer.

[0003] Ribonucleotide reductase (RR) is the only enzyme in cells that catalyzes the reduction of four ribonucleotides to their corresponding deoxyribonucleotides. This enzyme is also a key and rate-limiting enzyme in DNA repair, playing a crucial regulatory role in cell proliferation and differentiation. It is also a key enzyme in promoting the rapid proliferation of tumor cells. Iron (Fe) is a key active center in RR. Compared to normal tissue cells, cancer cells have a higher concentration of RR and require more Fe. Therefore, effectively chelating the Fe ions at the RR center will effectively inhibit its activity, thereby inhibiting DNA synthesis and repair.

[0004] Triapine (3-AP), an Fe ion chelator discovered by Australian researchers Des R. Richardson and others and currently in Phase II clinical trials, lacks DNA targeting due to its high 60% plasma protein binding rate. This makes it prone to off-target effects after in vivo administration, which may be the main reason for 3-AP's limited efficacy and adverse reactions. Furthermore, Phase II clinical trial data for 3-AP have not met expectations, and adverse reactions of varying degrees have occurred, leading to a stagnation in 3-AP's clinical trials. Summary of the Invention

[0005] The present invention provides an adenine-based iron ion chelator, its synthesis and application. Adenine (also known as vitamin B4, an important base compound that assists in the synthesis of DNA and RNA and an important component of the human genetic material) is used as a lead compound to synthesize a series of iron ion chelators having a tridentate coordination donor (OH, N, N or N, N, N) and a high affinity for ribonucleotide reductase.

[0006] One purpose of the present invention is to provide an adenine-based iron ion chelator, which includes 18 compounds numbered Z1-Z18.

[0007] Another object of the present invention is to provide a method for synthesizing an adenine-based iron ion chelator.

[0008] Another object of the present invention is to provide an application of the iron ion chelator for preparing anti-tumor drugs.

[0009] To achieve the above object, the technical solutions adopted by the present invention are as follows:

[0010] The present invention has 18 adenine-based iron ion chelating agents, numbered Z1-Z18, and their chemical formulas are:

[0011]

[0012]

[0013]

[0014] The present invention discloses a method for synthesizing an adenine-based iron ion chelating agent. Different aldehydes and 6-hydrazinopurine are dissolved in ethanol, glacial acetic acid is added dropwise, and the mixture is refluxed at 65°C for 4 hours. A light yellow solid is obtained by filtration, and finally, the solid is dried in a drying oven at 65°C to obtain iron ion chelating agents Z1-Z18.

[0015] Among the iron ion chelating agents, the synthetic routes of Z1-Z16 are:

[0016]

[0017] in,

[0018] Z1: R1=H, R2=H, R3=Methyl, R4=H;

[0019] Z2: R1=OH, R2=H, R3=H, R4=H;

[0020] Z3: R1=H, R2=H, R3=H, R4=H;

[0021] Z4: R1=H, R2=H, R3=OH, R4=H;

[0022] Z5: R1=H, R2=OH, R3=H, R4=OH;

[0023] Z6: R1=H, R2=H, R3=F, R4=H;

[0024] Z7: R1=H, R2=H, R3=CL, R4=H;

[0025] Z8: R1=H, R2=H, R3=Br, R4=H;

[0026] Z9: R1=H, R2=H, R3=Trifluoromethoxy, R4=H;

[0027] Z10: R1=H, R2=OH, R3=Methyl, R4=H;

[0028] Z11: R1=H, R2=H, R3=Tert-Butyl, R4=H;

[0029] Z12: R1=H, R2=H, R3=Ph, R4=Ph;

[0030] Z13: R1=Ehyl, R2=H, R3=H, R4=H;

[0031] Z14: R1=H, R2=H, R3=Methoxy, R4=H;

[0032] Z15: R1=H, R2=Tert-Butyl, R3=Tert-Butyl, R4=H;

[0033] Z16: R1=H, R2=Methoxy, R3=H, R4=H;

[0034] The synthetic route of iron ion chelator Z17 is:

[0035]

[0036] The synthetic route of iron ion chelator Z18 is:

[0037]

[0038] Furthermore, in the synthesis method, the molar ratio of different aldehydes to 6-hydrazinopurine is 1:1;

[0039] The molar ratio of 6-hydrazinopurine to ethanol is 1:114;

[0040] The volume ratio of ethanol to glacial acetic acid is 10:1.

[0041] The Z1-Z18 iron ion chelators of the present invention, when used as raw materials for DNA synthesis in the salvage synthesis pathway, effectively chelate the Fe ions at the active center of RR, thereby inhibiting its activity, blocking DNA synthesis, and ultimately suppressing tumor cell proliferation. This invention rationally utilizes the free base salvage synthesis pathway used by cancer cells to synthesize DNA, providing a new breakthrough for the use of Fe ion chelators in tumor treatment.

[0042] Currently, the only anticancer Fe ion chelators used in clinical research worldwide are thiosemicarbazone compounds (such as 3-AP) discovered by Des R. Richardson et al. in Australia. The applicant's disclosed research on adenine Z1-Z18 iron ion chelators will effectively break China's history of not independently developing anticancer Fe ion chelators. This research will provide new drug candidates, reliable experimental data, and theoretical basis for domestic anticancer clinical trials using Fe ion chelators, and provide strong support for the development of new metal ion chelators as innovative anticancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Schematic diagram of the anti-tumor mechanism of adenine-based iron chelators in cancer cells;

[0044] Figure 2 : This is the crystal structure of the Z7-Fe complex in the example. DETAILED DESCRIPTION

[0045] The present invention will be further described below with reference to the embodiments and drawings, but the present invention is not limited thereto.

[0046] Example 1

[0047] The synthesis route of chelating agent Z1 is:

[0048]

[0049] The synthesis method of Z1 is:

[0050] 5-Methylsalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z1.

[0051] The structure of the synthesized chelating agent Z1 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0052] Z1, 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),11.82(s,1H),11.32(s,1H),8.31(t,J=19.8Hz,3H),

[0053] 7.12(s,1H),7.05(d,J=8.1Hz,1H),6.81(d,J=8.2Hz,1H),2.24(s,3H). 13C NMR (126MHz, DMSO-d6) δ155.07,152.37,145.40,141.31,131.47,130.75,127.97,118.77,117.03,20.31.HRMS: m / z 269.1073[M+H].

[0054] Example 2

[0055] The synthesis route of chelating agent Z2 is:

[0056]

[0057] The synthesis method of Z2 is:

[0058] 3-Hydroxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z2.

[0059] The structure of the synthesized chelating agent Z2 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0060] Z2,1H NMR(500MHz,DMSO-d6)δ13.25(s,1H),11.85(s,1H),11.38(s,1H),9.00(s,1H),8.32(d,J=26.8Hz,3H),6.88–6.59(m,3H).13C NMR (126MHz, DMSO-d6) δ172.51,152.43,146.23,145.95,145.65,141.37,121.24,121.18,119.43,117.33.HRMS: m / z271.0865[M+H].

[0061] Example 3

[0062] The synthesis route of chelating agent Z3 is:

[0063]

[0064] Synthesis method of Z3:

[0065] Salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, and ethanol (20 mL, 343 mmol) was added. Glacial acetic acid (0.2 mL, 3.5 mmol) was then added dropwise. The mixture was refluxed at 65°C for 4 h. A light yellow solid was obtained by filtration and dried in a forced air drying oven at 65°C to obtain Z3.

[0066] The structure of the synthesized chelating agent Z3 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0067] Z3, 1 H NMR (500MHz, DMSO-d6) δ13.25(s,1H),11.84(s,1H),11.53(s,1H),8.34(d,J=

[0068] 8.1Hz, 3H), 7.34 (s, 1H), 7.25 (t, J = 7.6Hz, 1H), 6.93–6.88 (m, 2H). 13 C NMR (126MHz, DMSO-d6) δ157.32,152.41,145.33,141.38,130.86,119.56,119.22,118.77,117.26.HRMS: m / z255.0916[M+H].

[0069] Example 4

[0070] The synthesis of chelating agent Z4 is as follows:

[0071]

[0072] Synthesis method of Z4:

[0073] 5-Hydroxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z4.

[0074] The structure of the synthesized chelating agent Z4 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0075] Z4, 1 H NMR (500MHz, DMSO-d6) δ13.22(s,1H),11.76(s,1H),10.87(s,1H),8.93(s,1H),8.32(d,J=15.0Hz,2H),8.21(s,1H),6.86–6.52(m,3H). 13 C NMR (126MHz, DMSO-d6) δ152.41,150.07,145.28,141.31,119.13,118.73,118.32,117.81,115.77.HRMS: m / z271.0865[M+H].

[0076] Example 5

[0077] Synthesis of chelator Z5, the synthetic route is as follows:

[0078]

[0079] Synthesis method of Z5:

[0080] Take 4, 6-dihydroxy salicylaldehyde (3 mmol) and 6-hydrazine purine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop acetic acid (0.2 mL, 3.5 mmol), reflux at 65 ℃ for 4 h, filter to get light yellow solid, dry in a blast drying oven at 65 ℃ to get Z5;

[0081] The structure of the synthesized chelator Z5 is characterized by nuclear magnetic resonance carbon hydrogen spectrum and high resolution mass spectrum, and the results are as follows:

[0082] Z5, 1 H NMR (500 MHz, DMSO-d6) δ 13.12 (s, 1H), 11.53 (s, 1H), 9.63 (s, 1H), 8.54 (s, 1H), 8.26-8.20 (m, 2H), 5.83 (s, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 160.93, 159.33, 152.44, 142.55, 140.74, 118.47, 100.16, 94.87. HRMS: m / z 287.0814 [M+H].

[0083] Example 6

[0084] Synthesis of chelator Z6, the synthetic route is as follows:

[0085]

[0086] Synthesis method of Z6:

[0087] Take 4, 6-dihydroxy salicylaldehyde (3 mmol) and 6-hydrazine purine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop acetic acid (0.2 mL, 3.5 mmol), reflux at 65 ℃ for 4 h, filter to get light yellow solid, dry in a blast drying oven at 65 ℃ to get Z5;

[0088] The structure of the synthesized chelator Z6 is characterized by nuclear magnetic resonance carbon hydrogen spectrum and high resolution mass spectrum, and the results are as follows:

[0089] Z6, 1H NMR (500 MHz, DMSO-d6) δ 13.26 (s, 1H), 12.01 (s, 1H), 11.36 (s, 1H), 8.35-8.28 (m, 3H), 7.27 (s, 1H), 7.09 (td, J = 8.6, 3.1 Hz, 1H), 6.90 (dd, J = 8.9, 4.7 Hz, 1H). 13 CNMR (126 MHz, DMSO-d6) δ 153.47, 152.35, 143.87, 141.54, 119.85, 118.36, 117.50, 117.31, 115.89. HRMS: m / z 273.0822 [M+H].

[0090] Example 7

[0091] Synthesis of chelator Z7, the synthetic route is as follows:

[0092]

[0093] Synthesis method of Z7:

[0094] 5-chlorosalicylaldehyde (3 mmol) and 6-hydrazinyl purine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise, refluxed at 65°C for 4h, filtered to obtain light yellow solid, and dried in a blast drying oven at 65°C to obtain Z7;

[0095] The structure of the synthesized chelator Z7 was characterized by nuclear magnetic resonance hydrogen spectrum and high resolution mass spectrum, and the results were as follows:

[0096] Z7, 1 H NMR (500 MHz, DMSO-d6) δ 13.26 (s, 1H), 12.01 (s, 1H), 11.36 (s, 1H), 8.35-8.28 (m, 3H), 7.27 (s, 1H), 7.09 (td, J = 8.6, 3.1 Hz, 1H), 6.90 (dd, J = 8.9, 4.7 Hz, 1H). 13 CNMR (126 MHz, DMSO-d6) δ 153.47, 152.35, 143.87, 141.54, 119.85, 118.36, 117.50, 117.31, 115.89. HRMS: m / z 273.0822 [M+H].

[0097] Example 8

[0098] Synthesis of chelator Z8, the synthetic route is as follows:

[0099]

[0100] Synthesis method of Z8:

[0101] 5-Bromosalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z8.

[0102] The structure of the synthesized chelating agent Z8 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0103] Z8, 1 H NMR (500MHz, DMSO-d6) δ13.29(s,1H),11.93(s,1H),11.60(s,1H),8.34–8.28(m,3H),7.59(s,1H),7.38(dd,J=8.6,2.6Hz,1H),6.88(d,J=8.7Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ156.33,152.38,143.68,141.59,133.14,132.42,121.47,119.58,118.77,110.48.HRMS: m / z 333.0021[M+H].

[0104] Example 9

[0105] The synthesis route of chelating agent Z9 is:

[0106]

[0107] Synthesis method of Z9:

[0108] 5-Trifluoromethoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z9.

[0109] The structure of the synthesized chelating agent Z9 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0110] Z9, 1H NMR (500MHz, DMSO-d6) δ13.29(s,1H),12.02(s,1H),11.68(s,1H),8.36-8.31(m,3H),7.47(s,1H),7.24(d,J=8.6Hz,1H),6.99(d,J=8.9Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ156.05,152.39,143.57,141.59,140.87,123.65,122.98,121.73,120.14,119.70,118.88,118.57.HRMS:m / z 339.0739[M+H].

[0111] Example 10

[0112] The synthesis route of chelating agent Z10 is as follows:

[0113]

[0114] Synthesis method of Z10:

[0115] 4-Hydroxy-5-methylsalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z10.

[0116] The structure of the synthesized chelating agent Z10 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0117] Z10, 1 H NMR (500MHz, DMSO-d6) δ13.16(s,1H),11.65(s,2H),9.73(s,1H),8.38–8.07(m,3H),7.07–6.83(m,1H),6.42(d,J=8.3Hz,1H),2.04(s,3H). 13 C NMR (126MHz, DMSO-d6) δ158.17,157.16,152.45,146.61,141.10,128.94,118.56,111.11,110.86,107.04,8.79.HRMS: m / z 285.1022[M+H].

[0118] Example 11

[0119] The synthesis route of chelating agent Z11 is:

[0120]

[0121] Synthesis method of Z11:

[0122] 5-tert-Butyl salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, and ethanol (20 mL, 343 mmol) was added. Glacial acetic acid (0.2 mL, 3.5 mmol) was then added dropwise. The mixture was refluxed at 65°C for 4 h. A pale yellow solid was obtained by filtration and dried in a forced air drying oven at 65°C to obtain Z11.

[0123] The structure of the synthesized chelating agent Z11 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0124] Z11, 1 H NMR (500MHz, DMSO-d6) δ13.23(s,1H),11.88(s,1H),11.37(s,1H),8.32(d,J=

[0125] 12.4Hz, 3H), 7.28 (d, J = 6.8Hz, 2H), 6.84 (d, J = 8.8Hz, 1H), 1.27 (s, 9H). 13 C NMR (126MHz, DMSO-d6) δ155.12,152.42,145.83,141.62,141.32,127.99,127.20,118.74,118.40,116.89,34.19,31.74.HRMS:m / z 311.1542[M+H].

[0126] Example 12

[0127] The synthesis route of chelating agent Z12 is:

[0128]

[0129] Synthesis method of Z12:

[0130] 2-Hydroxy-1-naphthaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z12.

[0131] The structure of the synthesized chelating agent Z12 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0132] Z12, 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),12.59(s,1H),11.87(s,1H),9.30(s,1H),8.37(d,J=6.7Hz,2H),8.07 (d,J=8.4Hz,1H),7.87(d,J=8.6Hz,2H),7.59(t,J=7.4Hz,1H),7.39(t,J=7.4Hz,1H),7.23(d,J=8.9Hz,1H). 13 C NMR(126MHz,DMSO-d6)δ157.11,152.54,142.55,141.40,132.00,129.39,128 .26,127.88,123.78,120.61,119.91,118.78,109.27,56.50,19.03.HRMS:m / z 305.1073[M+H].

[0133] Example 13

[0134] The synthesis route of chelating agent Z13 is as follows:

[0135]

[0136] Synthesis method of Z13:

[0137] 3-Ethoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, ethanol (20 mL, 343 mmol) was added, and glacial acetic acid (0.2 mL, 3.5 mmol) was added dropwise. The mixture was refluxed at 65°C for 4 h, and a light yellow solid was obtained by filtration. The solid was dried in a forced air drying oven at 65°C to obtain Z13.

[0138] The structure of the synthesized chelating agent Z13 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0139] Z13, 1 H NMR (500MHz, DMSO-d6) δ13.25 (s, 1H), 11.89 (d, J = 45.5Hz, 1H), 11.47 (s, 1H),

[0140] 8.61–8.20(m,3H),7.19–6.70(m,3H),4.20–3.98(m,2H),1.37(q,J=7.3Hz,3H). 13C NMR (126MHz, DMSO-d6) δ152.43,147.77,147.33,145.65,141.50,122.56,119.23,119.10,118.80,114.82,64.29,15.36.HRMS:m / z 299.1178[M+H].

[0141] Example 14

[0142] The synthesis of chelating agent Z14 is as follows:

[0143]

[0144] Synthesis method of Z14:

[0145] 5-Methoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, and ethanol (20 mL, 343 mmol) was added. Glacial acetic acid (0.2 mL, 3.5 mmol) was then added dropwise. The mixture was refluxed at 65°C for 4 h. A pale yellow solid was obtained by filtration and dried in a forced air drying oven at 65°C to obtain Z14.

[0146] The structure of the synthesized chelating agent Z14 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0147] Z14, 1 H NMR (500MHz, DMSO-d6) δ13.22(s,1H),11.92(s,1H),11.11(s,1H),8.31(t,J=

[0148] 19.4Hz,3H),6.92(s,1H),6.84(s,2H),3.72(s,3H). 13 C NMR (126MHz, DMSO-d6) δ152.67,152.43,152.35,151.36,145.07,141.37,119.14,118.78,118.02,117.45,114.36,55.94.HRMS: m / z285.1022[M+H].

[0149] Example 15

[0150] The synthesis of chelating agent Z15 is as follows:

[0151]

[0152] Synthesis method of Z15:

[0153] Weigh 4,5-di-tert-butyl salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) into a round-bottom flask, add ethanol (20 mL, 343 mmol), and then add glacial acetic acid (0.2 mL, 3.5 mmol) dropwise. Reflux at 65°C for 4 h, filter to obtain a light yellow solid, and dry it in a forced air drying oven at 65°C to obtain Z15.

[0154] The structure of the synthesized chelating agent Z15 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0155] Z15, 1 H NMR (500MHz, DMSO-d6) δ13.23(s,1H),11.88(s,2H),8.37(s,2H),8.34(s,1H),7.26(s,1H),7.12(s,1H),1.43(s,9H),1.28(s,9H). 13 C NMR (126MHz, DMSO-d6) δ154.37,152.54,147.52,141.32,140.54,136.03,125.75,125.15,118.60,118.10,35.23,34.31,31.81,29.91.HRMS:m / z 367.2168[M+H].

[0156] Example 16

[0157] The synthesis of chelating agent Z16 is as follows:

[0158]

[0159] Synthesis method of Z16:

[0160] 4-Methoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, and ethanol (20 mL, 343 mmol) was added. Glacial acetic acid (0.2 mL, 3.5 mmol) was then added dropwise. The mixture was refluxed at 65°C for 4 h. A pale yellow solid was obtained by filtration and dried in a forced air drying oven at 65°C to obtain Z16.

[0161] The structure of the synthesized chelating agent Z16 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0162] Z16, 1 H NMR (500MHz, DMSO-d6) δ13.24(s,1H),11.88(s,1H),11.50(s,1H),8.35(d,J=

[0163] 4.6Hz,2H),8.29(s,1H),6.98(d,J=7.5Hz,1H),6.92(s,1H),6.83(t,J=7.4Hz,1H),3.80(s,3H). 13 C NMR (126MHz, DMSO-d6) δ172.51,152.41,148.66,147.09,145.42,141.42,122.46,119.08,118.79,113.61,56.15.HRMS: m / z 285.1022[M+H].

[0164] Example 17

[0165] The synthesis of chelating agent Z17 is as follows:

[0166]

[0167] Synthesis method of Z17:

[0168] Pyridinecarboxaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) were weighed into a round-bottom flask, and ethanol (20 mL, 343 mmol) was added. Glacial acetic acid (0.2 mL, 3.5 mmol) was then added dropwise. The mixture was refluxed at 65°C for 4 h. A pale yellow solid was obtained by filtration and dried in a forced air drying oven at 65°C to obtain Z17.

[0169] The structure of the synthesized chelating agent Z17 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0170] Z17, 1 H NMR (500MHz, DMSO-d6) δ11.98 (s, 1H), 8.60 (d, J = 4.0Hz, 1H), 8.41 (s, 2H),

[0171] 8.32(s,2H),7.89(t,J=7.5Hz,1H),7.43–7.31(m,1H). 13 C NMR (126MHz, DMSO-d6) δ152.23,149.83,148.65,145.25,138.76,137.05,124.75,124.30,120.65.HRMS: m / z240.0919[M+H].

[0172] Example 18

[0173] The synthesis of chelating agent Z18 is as follows:

[0174]

[0175] Synthesis method of Z18:

[0176] Weigh quinoline-2-carboxaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) into a round-bottom flask, add ethanol (20 mL, 343 mmol), and then add glacial acetic acid (0.2 mL, 3.5 mmol) dropwise. Reflux at 65°C for 4 h, filter to obtain a light yellow solid, and dry in a forced air drying oven at 65°C to obtain Z18.

[0177] The structure of the synthesized chelating agent Z18 was characterized by C-H NMR spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0178] Z18, 1 H NMR (500MHz, DMSO-d6) δ12.15(s,1H),8.44(t,J=11.5Hz,5H),8.02(t,J=9.0

[0179] Hz,2H),7.78(t,J=7.6Hz,1H),7.62(t,J=7.4Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ152.27,147.90,136.81,130.44,129.26,128.42,128.21,127.49,118.53.HRMS: m / z290.1076[M+H].

[0180] Example 19

[0181] Taking the iron ion chelator Z7 as an example, the Z7-Fe complex was synthesized with reference to Figure 2 , the synthesis method is:

[0182] The Z7 chelating agent (28.8 mg, 0.1 mmol) was dissolved in methanol (3 mL, 74.15 mmol) and dimethylformamide (DMF) (0.2 mL, 1.29 mmol). Ferric chloride (16.2 mg, 0.1 mmol) was added and the mixture was allowed to stand in a vacuum drying oven at 60°C for 12 h. The resulting mixture was cooled and crystallized to obtain Z7-Fe crystals. The crystal structure data were collected and analyzed by single crystal diffractometry. The crystal data have been uploaded to the Cambridge Crystallographic Database, CCDC: 2248151, http: / / www.ccdc.cam.ac.uk / data_request / cif.

[0183] Reference Figure 2 Taking the crystallization of Z7-Fe as an example, its crystal structure data is shown in Table 1; the bond length and bond angle data of the Z7-Fe crystal structure are shown in Table 2.

[0184] Table 1: Crystal structure data of Z7-Fe

[0185]

[0186] Table 2: Bond length and angle data of Z7-Fe crystal structure

[0187]

[0188] Current studies have found that human neuroepithelioma (SK-N-MC) cell lines are sensitive to Fe ion chelators, so SK-N-MC cells were selected for in vitro proliferation inhibition activity experiments.

[0189] The iron ion chelators Z1-Z18 were subjected to in vitro activity analysis (MTT). Most of the Fe ion chelators showed strong inhibitory effects on human neuroepithelioma cells (SK-N-MC), as shown in Table 3.

[0190] In the activity screening results, the Fe ion chelator Z7 showed excellent anti-cancer cell proliferation effect, and its IC 50 The value reached 0.66 μM, and Z7 was able to effectively chelate Fe ions, which was consistent with the experimental results. Z7 and other Fe ion chelators are expected to be developed into a new generation of anticancer drugs for clinical treatment of malignant tumors.

[0191] Table 3 Inhibitory activity (IC) of chelators Z1-Z18 against human neuroepithelioma cell line (SK-N-MC) 50 μM)

[0192]

[0193] The anti-tumor mechanism of adenine-based Fe ion chelators in cancer cells, e.g. Figure 1 As shown in the figure, after entering the cell, the iron ion chelator can not only chelate the free iron in the cytoplasm to form a complex, thereby damaging the mitochondria and promoting the death of cancer cells; but also after entering the cell nucleus, it can deprive deoxyribonucleic acid reductase (RR) of iron ions, preventing the replication and synthesis of DNA, and thus killing cancer cells.

Claims

1. An adenine-based iron ion chelator, characterized in that: The chemical formulas of the iron ion chelating agents are: 。 2. The method for synthesizing the iron ion chelating agent according to claim 1, wherein: The method comprises the following steps: dissolving aldehyde and 6-hydrazinopurine in ethanol, adding glacial acetic acid dropwise, refluxing at 65° C. for 4 hours, filtering to obtain a light yellow solid, and finally drying in a drying oven at 65° C. to obtain iron ion chelating agents Z1, Z4, Z6, Z7 and Z14; The structural formula of 6-hydrazinopurine is: The aldehyde in the iron ion chelating agent Z1 is 5-methyl salicylaldehyde; The aldehyde in the iron ion chelating agent Z4 is 5-hydroxysalicylaldehyde; The aldehyde in the iron ion chelator Z6 is 5-fluorosalicylaldehyde; The aldehyde in the iron ion chelator Z7 is 5-chlorosalicylaldehyde; The aldehyde in the iron ion chelating agent Z14 is 5-methoxysalicylaldehyde.

3. The method for synthesizing the iron ion chelating agent according to claim 2, wherein: In the synthesis method, the molar ratio of aldehyde to 6-hydrazinopurine is 1:1; The molar ratio of 6-hydrazinopurine to ethanol is 1:114; The volume ratio of ethanol to glacial acetic acid is 10:

1.

4. The use of the iron ion chelating agent according to claim 1, characterized in that: Application of the iron ion chelator in the preparation of anti-tumor drugs.

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