Adenine-based iron ion chelating agent and synthesis and application thereof

Abstract

The invention discloses an iron ion chelating agent based on adenine as well as synthesis and application of the iron ion chelating agent, and adenine is taken as a lead compound to synthesize a series of iron ion chelating agents which have tridentate coordination donors (OH, N, N or N, N, N) and have high affinity with ribonucleotide reductase. In the remedial synthesis route, when the adenine derivatives are used as DNA synthesis raw materials to be in contact with RR, iron ions in the active center of the adenine derivatives are effectively chelated, then the activity of the adenine derivatives is inhibited, DNA synthesis is blocked, and finally tumor cell proliferation is inhibited. According to the invention, cancer cells are reasonably utilized to synthesize DNA through a free base remediation synthesis route, and a new breakthrough is found for the iron ion chelating agent for tumor treatment.

Description

Technical Field

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

[0002] Commonly used anti-tumor chemotherapy drugs in clinical practice mainly include organic small molecule drugs, natural drugs and inorganic metal drugs. The emergence of new copper (Cu), iron (Fe) and ion chelators has opened a new door for the development of tumor drugs. 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 many life reactions such as erythropoiesis and deoxyribonucleotide (DNA) synthesis in life activities. Fe also produces reactive oxygen species (ROS) through redox reactions, which in turn damages cells. Therefore, excessive intracellular Fe ion content is considered to be an important cause of cancer.

[0003] Ribonucleotide reductase (RR) is the only enzyme in the cell that catalyzes the reduction of four ribonucleotides to generate corresponding deoxyribonucleotides. The enzyme is also a key enzyme and rate-limiting enzyme for DNA repair, plays an important regulatory role in cell proliferation and differentiation, and is also a key enzyme that promotes the rapid proliferation of tumor cells. Fe is an important active center of RR. Compared with normal tissue cells, the concentration of RR in cancer cells is higher, requiring more Fe. Therefore, effectively chelating the Fe ions in the RR center will effectively inhibit its activity, thereby inhibiting the synthesis and repair of DNA.

[0004] Triapine (3-AP), an Fe ion chelator discovered by Australian Des R. Richardson et al. and currently in Phase II clinical trials, lacks targeting to DNA due to its high binding rate to plasma proteins of 60%. It is easy to cause off-target effects after in vivo administration, which may be the main reason for the limited efficacy of 3-AP and the occurrence of adverse reactions. In addition, the Phase II clinical trial data of 3-AP did not achieve the expected effect, or there were adverse reactions of varying degrees, resulting in a stagnation in the clinical trials of 3-AP. Summary of the invention

[0005] The present invention provides an adenine-based iron ion chelator and 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 having a high affinity for ribonucleotide reductase.

[0006] One object of the present invention is to provide an adenine-based iron ion chelator, wherein the iron ion chelator comprises 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 purpose, the technical solution adopted by the present invention is as follows:

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

[0011]

[0012]

[0013]

[0014] The present invention discloses a synthesis method of an adenine-based iron ion chelating agent, wherein different aldehydes and 6-hydrazinopurine are dissolved in ethanol, glacial acetic acid is added dropwise, the mixture is refluxed at 65° C. for 4 hours, a light yellow solid is obtained by filtering, and finally, the mixture 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 route of Z1-Z16 is:

[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] Further, 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 iron ion chelators Z1-Z18 of the present invention, when these adenine derivatives are used as raw materials for DNA synthesis and contact RR in the salvage synthesis pathway, effectively chelate the Fe ions in its active center, thereby inhibiting its activity, blocking the synthesis of DNA, and ultimately inhibiting the proliferation of tumor cells. The present invention rationally utilizes cancer cells to synthesize DNA through the free base salvage synthesis pathway, and finds a new breakthrough for the use of Fe ion chelators in tumor treatment.

[0042] At present, the only anticancer Fe ion chelators used in clinical research in the world are thiosemicarbazone compounds (such as 3-AP) discovered by Des R. Richardson et al. in Australia. The research on adenine Z1-Z18 iron ion chelators disclosed by the applicant will effectively break the history of China's lack of independent research and development of anticancer Fe ion chelators. It will provide new alternative drugs, 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 ion chelators in cancer cells;

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

[0045] The present invention is further described below with reference to the embodiments and drawings, but is not intended to limit the present invention.

[0046] Example 1

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

[0048]

[0049] The synthesis method of Z1 is:

[0050] Weigh 5-methylsalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z1;

[0051] The structure of the synthesized chelating agent Z1 was characterized by NMR carbon hydrogen 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 of chelating agent Z2, the synthetic route is:

[0056]

[0057] The synthesis method of Z2 is:

[0058] Weigh 3-hydroxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z2;

[0059] The structure of the synthesized chelating agent Z2 was characterized by NMR carbon hydrogen 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] Weigh salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z3;

[0066] The structure of the synthesized chelating agent Z3 was characterized by NMR carbon hydrogen 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, the synthetic route is:

[0071]

[0072] Synthesis method of Z4:

[0073] Weigh 5-hydroxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z4;

[0074] The structure of the synthesized chelating agent Z4 was characterized by NMR carbon hydrogen 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] The synthesis of chelating agent Z5, the synthetic route is:

[0078]

[0079] Synthesis method of Z5:

[0080] Weigh 4,6-dihydroxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z5;

[0081] The structure of the synthesized chelating agent Z5 was characterized by NMR carbon hydrogen spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0082] Z5, 1 H NMR (500MHz, DMSO-d6) δ13.12(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 (126MHz, 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] The synthesis of chelating agent Z6, the synthetic route is:

[0085]

[0086] Synthesis method of Z6:

[0087] Weigh 5-fluorosalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z6;

[0088] The structure of the synthesized chelating agent Z6 was characterized by NMR carbon hydrogen spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0089] Z6, 1H NMR(500MHz,DMSO-d6)δ13.26(s,1H),12.01(s,1H),11.36(s,1H),8.35-8.28 (m,3H),7.27(s,1H),7.09(td,J=8.6,3.1Hz,1H),6.90(dd,J=8.9,4.7Hz,1H). 13 CNMR (126MHz, DMSO-d6) δ153.47,152.35,143.87,141.54,119.85,118.36,117.50,117.31,115.89.HRMS: m / z273.0822[M+H].

[0090] Example 7

[0091] The synthesis of chelating agent Z7, the synthetic route is:

[0092]

[0093] Synthesis method of Z7:

[0094] Weigh 5-chlorosalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z7;

[0095] The structure of the synthesized chelating agent Z7 was characterized by NMR carbon hydrogen spectroscopy and high-resolution mass spectrometry. The results are as follows:

[0096] Z7, 1 H NMR (500MHz, DMSO-d6) δ13.27(s,1H),11.99(s,1H),11.60(s,1H),8.35-8.28(m,3H),7.48(s,1H),7.26(dd,J=8.7,2.6Hz,1H),6.93(d,J=8.7Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ155.95,152.37,143.69,141.57,130.27,129.61,123.03,120.92,119.10.HRMS: m / z289.0526[M+H].

[0097] Example 8

[0098] The synthesis of chelating agent Z8, the synthetic route is:

[0099]

[0100] Synthesis method of Z8:

[0101] Weigh 5-bromosalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z8;

[0102] The structure of the synthesized chelating agent Z8 was characterized by NMR carbon hydrogen 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 of chelating agent Z9, the synthetic route is:

[0106]

[0107] Synthesis method of Z9:

[0108] Weigh 5-trifluoromethoxy salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z9;

[0109] The structure of the synthesized chelating agent Z9 was characterized by NMR carbon hydrogen 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 of chelating agent Z10, the synthesis route is:

[0113]

[0114] Synthesis method of Z10:

[0115] Weigh 4-hydroxy-5-methyl salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z10;

[0116] The structure of the synthesized chelating agent Z10 was characterized by NMR carbon hydrogen 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] Embodiment 11

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

[0120]

[0121] Synthesis method of Z11:

[0122] Weigh 5-tert-butyl salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z11;

[0123] The structure of the synthesized chelating agent Z11 was characterized by NMR carbon hydrogen 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 of chelating agent Z12, the synthetic route is:

[0128]

[0129] Synthesis method of Z12:

[0130] Weigh 2-hydroxy-1-naphthaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z12;

[0131] The structure of the synthesized chelating agent Z12 was characterized by NMR carbon hydrogen 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 of chelating agent Z13, the synthetic route is:

[0135]

[0136] Synthesis method of Z13:

[0137] Weigh 3-ethoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z13;

[0138] The structure of the synthesized chelating agent Z13 was characterized by NMR carbon hydrogen 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] Embodiment 14

[0142] The synthesis of chelating agent Z14, the synthetic route is:

[0143]

[0144] Synthesis method of Z14:

[0145] Weigh 5-methoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z14;

[0146] The structure of the synthesized chelating agent Z14 was characterized by NMR carbon hydrogen 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] Embodiment 15

[0150] The synthesis of chelating agent Z15, the synthetic route is:

[0151]

[0152] Synthesis method of Z15:

[0153] Weigh 4,5-di-tert-butyl salicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z15;

[0154] The structure of the synthesized chelating agent Z15 was characterized by NMR carbon hydrogen 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, the synthetic route is:

[0158]

[0159] Synthesis method of Z16:

[0160] Weigh 4-methoxysalicylaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then drop glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z16;

[0161] The structure of the synthesized chelating agent Z16 was characterized by NMR carbon hydrogen 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] Embodiment 17

[0165] The synthesis of chelating agent Z17, the synthetic route is:

[0166]

[0167] Synthesis method of Z17:

[0168] Weigh pyridine carboxaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) into a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 Z17;

[0169] The structure of the synthesized chelating agent Z17 was characterized by NMR carbon hydrogen 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] Embodiment 18

[0173] The synthesis of chelating agent Z18, the synthetic route is:

[0174]

[0175] Synthesis method of Z18:

[0176] Weigh quinoline-2-carboxaldehyde (3 mmol) and 6-hydrazinopurine (3 mmol) in a round-bottom flask, add ethanol (20 mL, 343 mmol), then dropwise add glacial acetic acid (0.2 mL, 3.5 mmol), 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 NMR carbon hydrogen 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] Embodiment 19

[0181] Taking the iron ion chelator Z7 as an example, the Z7-Fe complex was synthesized according 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), and 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 hours. The mixture was cooled and crystallized to obtain Z7-Fe crystals. The crystal structure data was collected and analyzed by a single crystal diffractometer. The crystal data has been uploaded to the Cambridge Crystal 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), and 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 0.66μM, and Z7 was able to effectively chelate Fe ions. The experimental results were in line with the expected assumptions. Z7 and other series of 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 on human neuroepithelioma cell line (SK-N-MC) 50 μM)

[0192]

[0193] The anti-tumor mechanism of adenine-based Fe ion chelators in cancer cells, such as Figure 1 As shown, 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 then killing cancer cells.

Claims

1. An adenine-based iron ion chelator, characterized in that: The iron ion chelating agent has 18 compounds, numbered Z1-Z18, and their chemical formulas are:

2. The method for synthesizing an iron ion chelator according to claim 1, wherein: The method comprises: dissolving different aldehydes and 6-hydrazinopurine in ethanol respectively, then dropping glacial acetic acid, 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-Z18; Among the iron ion chelating agents, the synthetic route of Z1-Z16 is: in, Z1: R1=H, R2=H, R3=Methyl, R4=H; Z2: R1=OH, R2=H, R3=H, R4=H; Z3: R1=H, R2=H, R3=H, R4=H; Z4: R1=H, R2=H, R3=OH, R4=H; Z5: R1=H, R2=OH, R3=H, R4=OH; Z6: R1=H, R2=H, R3=F, R4=H; Z7: R1=H, R2=H, R3=CL, R4=H; Z8: R1=H, R2=H, R3=Br, R4=H; Z9: R1=H, R2=H, R3=Trifluoromethoxy, R4=H; Z10: R1=H, R2=OH, R3=Methyl, R4=H; Z11: R1=H, R2=H, R3=Tert-Butyl, R4=H; Z12: R1=H, R2=H, R3=Ph, R4=Ph; Z13: R1=Ehyl, R2=H, R3=H, R4=H; Z14: R1=H, R2=H, R3=Methoxy, R4=H; Z15: R1=H, R2=Tert-Butyl, R3=Tert-Butyl, R4=H; Z16: R1=H, R2=Methoxy, R3=H, R4=H; The synthetic route of iron ion chelator Z17 is: The synthetic route of iron ion chelator Z18 is:

3. The method for synthesizing the iron ion chelator according to claim 2, characterized in that: In the synthesis method, the molar ratio of different aldehydes 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 chelator according to claim 1, characterized in that: The application of the iron ion chelating agents Z1-Z18 in the preparation of anti-tumor drugs.

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