CN110229110B - Micromolecule heterocyclic dimer and application - Google Patents

Micromolecule heterocyclic dimer and application Download PDF

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CN110229110B
CN110229110B CN201910558243.XA CN201910558243A CN110229110B CN 110229110 B CN110229110 B CN 110229110B CN 201910558243 A CN201910558243 A CN 201910558243A CN 110229110 B CN110229110 B CN 110229110B
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dimer
small molecule
human
cells
heterocyclic dimer
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刘天军
王佳雯
李国梁
洪阁
王文智
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Institute of Biomedical Engineering of CAMS and PUMC
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Abstract

The invention discloses a small molecular heterocyclic dimer for treating tumors and application thereof. The small molecule heterocyclic dimer has the following structure:
Figure DDA0002107479540000011
experiments prove that: the small molecular heterocyclic dimer has wide tumor suppression spectrum and strong anti-tumor activity, and has IC of human cervical cancer cells HeLa, human hepatoma cells Hep G2, human breast cancer cells MCF-7, human pharyngeal squamous carcinoma cells FaDu and human non-small cell lung cancer cells A54950Reaches the level of mu M which is far higher than that of the contrast medicament ligustrazine, and has the IC of human mammary gland cells MCF 10A50Higher than tumor cells, and has the characteristics of high efficiency and low toxicity. The small molecular heterocyclic dimer has potential application value in the development of antitumor drugs.

Description

Micromolecule heterocyclic dimer and application
Technical Field
The invention belongs to the field of organic synthesis and medicines, particularly relates to a micromolecule heterocyclic dimer for treating tumors and application thereof, and particularly relates to application of the micromolecule heterocyclic dimer formed by aliphatic diamine or alicyclic diamine and two micromolecule heterocycles in preparation of antitumor medicines.
Background
Cancer is a major public health problem worldwide. According to the statistics of the world health organization, malignant tumor is the second leading cause of death of residents in developing and developed countries[1,2]. Chemotherapy is a systemic treatment, and one of the most effective methods for treating various tumors, but the effectiveness of traditional chemotherapy is also influenced by drug toxicity and drug resistance[3]. Aiming at the key path of cancer cell proliferation, the search for new antitumor drugs is imminent.
In the biological world, multivalency is defined as the simultaneous binding of multiple ligands to a receptor, and the multivalency can increase the affinity of multivalent ligands by 100-fold and 1000-fold compared to monovalent ligands[4]. While the bivalent one is one of the polyvalencies, and two ligands are bound together by a linker to form homo-or heterodimers with an affinity several hundred times higher than that of the monovalent ligands[5]。
In recent years, scholars at home and abroad design and synthesize many different types of dimers for biological activity evaluation, particularly antitumor drug screening. In 1997 Beekman et al[6]The artemisinin derivative dimers were found to have 100 to 500 times higher anticancer activity than the corresponding monomers by linking the artemisinin derivative monomers at the C-10 position using ether linkages to form dimers. In the same year, Chaires et al[7]Reports that the daunomycin dimer has high affinity to DNA and can obviously inhibit breast cancer cells MCF-7 and drug-resistant strains thereofProliferation of MCF/VP-16. In addition, Portugal et al[8]Dimerization of daunomycin was found to increase the specificity of the DNA sequence. The efficiency of daunomycin dimer in suppressing transcription from a promoter containing the SP-1 protein binding site is 15 times that of its monomer. 2001, Hu et al[9]It was reported that cytotoxicity of esterketones against the human leukemia cell line MDA MB 231 could be increased 180-fold due to dimerization (monomeric IC)50528 μ M for dimer 2.8 μ M); and Liang et al[10,11]The studies show that the esterketone dimer can induce apoptosis by inhibiting Rel/NF-kB activity. In 2005, Rahman et al[12]It is reported that indole-3-carbinol and dimers thereof can induce breast cancer cell apoptosis by inhibiting the activity of Akt and NF-kB. Furthermore, Wang et al[13]The study shows that the indole-3-methanol dimer can obviously inhibit the expression of estrogen receptors, and the protein inhibition rate is 20 times higher than that of the monomer thereof, which is probably one of the mechanisms of inhibiting the proliferation of breast cancer cells. In 2006, Pires et al[14]A series of emetine dimers were reported to reverse doxorubicin resistance in MCF-7/DX1 cells. 2012, Chauthe et al[15]Reports that phloroglucinol dimer can obviously inhibit the proliferation of colon cancer cells HCT 116; 2014, Cheng et al[16]Reports that oleanolic acid dimer can selectively induce apoptosis of hepatoma cell Hep G2 by activating caspase-3/9; same year, Wu et al[17]A series of novel carboline dimers are reported to have obvious inhibition effects on the growth of human renal cell adenocarcinoma cells 769-P and human oral epidermoid carcinoma cells KB in vitro. Not only does monomer dimerization increase its affinity for the receptor, the binding site for the ligand can also be altered upon dimerization. In addition, studies have shown that the properties of the linker (rigidity, hydrophobicity, length) can also improve the overall efficacy of the dimer. Therefore, the design and development of the dimer are beneficial to finding effective antitumor drugs.
The heterocyclic compound is commonly present in a drug molecular structure, comprises an imidazole ring, an indole ring, a pyridine ring, a piperidine ring and the like, and is an important functional group for drug activity. It has multiple clinical applications, especially in the anti-tumor aspect. 2012, Huang et al[18]Report aIndole compound SK228 can remarkably inhibit proliferation and IC of various human lung cancer cells and esophageal cancer cells50Is 0.28-1.86 μ M. 2014 Hou et al[19]A series of N- (piperidine-4-acyl) benzamide derivatives are designed and synthesized by taking a piperidine ring as a heterocyclic fragment for screening antitumor drugs, and the results show that the derivatives have obvious inhibition effect on the proliferation of a hepatoma cell line Hep G2 and IC50Minimum 0.25. mu.M, and can regulate AMPK phosphorylation, activate downstream signaling proteins, and inhibit cell cycle in a p53/p 21-dependent manner.
The invention provides a series of novel micromolecule heterocyclic dimers, which are obtained by conjugating two heterocyclic micromolecules with the same chemical structure together by using aliphatic diamine or alicyclic diamine. The small molecular heterocyclic dimer has wide tumor suppression spectrum and strong anti-tumor activity, and has IC of human cervical cancer cells HeLa, human hepatoma cells Hep G2, human breast cancer cells MCF-7, human pharyngeal squamous carcinoma cells FaDu and human non-small cell lung cancer cells A54950Reaches the level of mu M which is far higher than that of the control drug ligustrazine, and has IC of human mammary cells MCF 10A50Higher than tumor cells, and has the characteristics of high efficiency and low toxicity. The small molecular heterocyclic dimer has potential application value in the development of antitumor drugs.
Reference documents
[1]Siegel R L,Miller K D,Jemal A.Cancer statistics,2017[J].CA:a cancer journal for clinicians,2017,67(1):7-30.
[2]Vainshelboim B,Jan Müller,Lima R M,et al.Cardiorespiratory fitness,physical activity and cancer mortality in men[J].Preventive Medicine,2017,100:89-94.
[3]Holohan C,Van Schaeybroeck S,Longley D B,et al.Cancer drug resistance:an evolving paradigm[J].Nature Reviews Cancer,2013,13(10):714-726.
[4]Fries E,Helenius A.Binding of Semliki Forest virus and its spike glycoproteins to cells[J].Eur J Biochem,1979,97(1):213-220.
[5]Chow L M,Chan T H.Novel classes of dimer antitumour drug candidates[J].Curr Pharm Des,2009,15(6):659-674.
[6]Beekman A C,Barentsen A R,Woerdenbag H J,et al.Stereochemistry-dependent cytotoxicity of some artemisinin derivatives[J].J Nat Prod,1997,60(4):325-330.
[7]Chaires J B,Leng F,Przewloka T,et al.Structure-based design of a new bisintercalating anthracycline antibiotic[J].J Med Chem,1997,40(3):261-266.
[8]Portugal J,Martín B,Vaquero A,et al.Analysis of the effects of daunorubicin and WP631 on transcription[J].Curr Med Chem,2001,8(1):1-8.
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Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a small molecular heterocyclic dimer with high-efficiency low-toxicity antitumor activity.
The second purpose of the invention is to provide the application of the small molecular heterocyclic dimer as the antitumor drug.
The purpose of the invention is realized by the following technical scheme:
a small molecule heterocyclic dimer having the following structure:
Figure BDA0002107479520000041
Figure BDA0002107479520000042
wherein the content of the first and second substances,
Figure BDA0002107479520000043
Figure BDA0002107479520000044
x ═ H or Cl or Br or I or NO2And Y is N or O or S.
An application of small molecule heterocyclic dimer in preparing antitumor drugs.
The small molecular heterocyclic dimer has a remarkable anti-tumor effect, can be used for preventing and treating various common clinical tumors such as cervical cancer, liver cancer, breast cancer, head and neck cancer, lung cancer and the like, has the best treatment effect on the head and neck cancer, has low toxicity on normal breast cells, and has the characteristics of high efficiency and low toxicity.
Drawings
FIG. 1 is a synthetic scheme of a small molecule heterocyclic dimer according to example 1 of the present invention.
FIG. 2 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 1 of the present invention.
FIG. 3 is a synthetic scheme of a small molecule heterocyclic dimer according to example 2 of the present invention.
FIG. 4 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 2 of the present invention.
FIG. 5 is a synthetic scheme of a small molecule heterocyclic dimer according to example 3 of the present invention.
FIG. 6 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 3 of the present invention.
FIG. 7 is a synthetic scheme of a small molecule heterocyclic dimer of example 4 of the present invention.
FIG. 8 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 4 of the present invention.
FIG. 9 is a synthetic scheme of a small molecule heterocyclic dimer of example 5 of the present invention.
FIG. 10 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 5 of the present invention.
FIG. 11 is a synthetic scheme of a small molecule heterocyclic dimer of example 6 of the present invention.
FIG. 12 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 6 of the present invention.
FIG. 13 is a synthetic scheme of a small molecule heterocyclic dimer of example 7 of the present invention.
FIG. 14 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 7 of the present invention.
FIG. 15 is a synthetic scheme of a small molecule heterocyclic dimer of example 8 of the present invention.
FIG. 16 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 8 of the present invention.
FIG. 17 is a synthetic scheme of a small molecule heterocyclic dimer of example 9 of the present invention.
FIG. 18 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 9 of the present invention.
FIG. 19 is a synthetic scheme of a small molecule heterocyclic dimer of example 10 of the present invention.
FIG. 20 is a high resolution mass spectrum of a small molecule heterocyclic dimer of example 10 of the present invention.
FIG. 21 is a synthetic scheme of a small molecule heterocyclic dimer of example 11 of the present invention.
FIG. 22 is a high resolution mass spectrum of the small molecule heterocyclic dimer of example 11 of the present invention.
FIG. 23 is a synthetic scheme of a small molecule heterocyclic dimer of example 12 of the present invention.
FIG. 24 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 12 of the present invention.
FIG. 25 is a synthetic scheme for a small molecule heterocyclic dimer of example 13 of the present invention.
FIG. 26 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 13 of the present invention.
FIG. 27 is a synthetic scheme of a small molecule heterocyclic dimer of example 14 of the present invention.
FIG. 28 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 14 of the present invention.
FIG. 29 is a synthetic scheme for a small molecule heterocyclic dimer of example 15 of the present invention.
FIG. 30 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 15 of the present invention.
FIG. 31 is a synthetic scheme for a small molecule heterocyclic dimer of example 16 of this invention.
FIG. 32 is a high resolution mass spectrum of a small molecule heterocyclic dimer of example 16 of the present invention.
FIG. 33 is a synthetic scheme for a small molecule heterocyclic dimer of example 17 of this invention.
FIG. 34 is a high resolution mass spectrum of a small molecule heterocyclic dimer of example 17 of the present invention.
FIG. 35 is a synthetic scheme for a small molecule heterocyclic dimer of example 18 of this invention.
FIG. 36 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 18 of the present invention.
FIG. 37 is a synthetic scheme for a small molecule heterocyclic dimer of example 19 of this invention.
FIG. 38 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 19 of the present invention.
FIG. 39 is a synthetic scheme for a small molecule heterocyclic dimer of example 20 of this invention.
FIG. 40 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 20 of the present invention.
FIG. 41 is a synthetic scheme of a small molecule heterocyclic dimer of example 21 of this invention.
FIG. 42 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 21 of the present invention.
FIG. 43 is a synthetic scheme for a small molecule heterocyclic dimer of example 22 of this invention.
FIG. 44 is a high resolution mass spectrum of a small molecule heterocyclic dimer of example 22 of the present invention.
FIG. 45 is a synthetic scheme for a small molecule heterocyclic dimer of example 23 of this invention.
FIG. 46 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 23 of the present invention.
FIG. 47 is a synthetic scheme of a small molecule heterocyclic dimer of example 24 of this invention.
FIG. 48 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 24 of the present invention.
FIG. 49 is a synthetic scheme for a small molecule heterocyclic dimer of example 25 of the present invention.
FIG. 50 is a high resolution mass spectrum of a small molecule heterocyclic dimer according to example 25 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are intended only for a better understanding of the invention and do not limit the scope of the invention:
EXAMPLE 1 Synthesis of octanediamine-ligustrazine dimer
0.633g of ligustrazine acid, 0.864g of EDCI, 1.59mL of triethylamine and 10mL of anhydrous dichloromethane are sequentially added into a round bottom bottle, stirred and dissolved, then 0.250g of octanediamine is added, the reaction is stirred at normal temperature for 12 hours, 20mL of dichloromethane is added, the mixture is sequentially washed with water (2X 30mL) and saturated saline (1X 30mL), dried by anhydrous sodium sulfate, filtered, decompressed and evaporated to dryness. The residue was subjected to silica gel column chromatography and eluted with petroleum ether/acetone (5/1-4/1) to give 0.517g of a white solid in 68% yield (see FIG. 1 for the synthetic scheme and FIG. 2 for the characterization scheme).
EXAMPLE 2 Synthesis of decamethylenediamine-ligustrazine dimer
0.530g of ligustrazine acid, 0.723g of EDCI, 1.33mL of triethylamine and 10mL of anhydrous dichloromethane are sequentially added into a round-bottomed bottle, stirred and dissolved, then 0.250g of decamethylenediamine is added, stirred at normal temperature and reacted for 12 hours, 20mL of dichloromethane is added, water (2X 30mL) and saturated saline (1X 30mL) are sequentially used for washing, anhydrous sodium sulfate is dried, filtered, and decompressed and evaporated to dryness. The residue was subjected to silica gel column chromatography and eluted with petroleum ether/acetone (5/1-4/1) to give 0.451g of a white solid in 66% yield (FIG. 3 for the synthetic scheme and FIG. 4 for the characterization scheme).
EXAMPLE 3 Synthesis of Dodecanediamine-ligustrazine dimer
0.456g of ligustrazine acid, 0.621g of EDCI, 1.14mL of triethylamine and 10mL of anhydrous dichloromethane are sequentially added into a round-bottomed flask, stirred and dissolved, then 0.250g of dodecanediamine is added, the reaction is stirred at normal temperature for 12 hours, 20mL of dichloromethane is added, and the mixture is sequentially washed with water (2X 30mL) and saturated saline (1X 30mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with petroleum ether/acetone (5/1-4/1) to give 0.445g of a white solid in a yield of 72% (see FIG. 5 for the synthetic scheme and FIG. 6 for the characterization scheme).
Example 4 Synthesis of decamethylenediamine-cinnamic acid dimer
0.400g of cinnamic acid, 0.211g of decamethylenediamine, 0.517g of EDCI, 0.030g of DMAP, and 10mL of anhydrous dichloromethane were sequentially added to a round-bottomed flask, and the reaction was stirred at room temperature for 12 hours. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.329g of a white solid in 62% yield (FIG. 7 for the synthetic scheme and FIG. 8 for the characterization scheme).
Example 5 Synthesis of Decanediamine-nicotinic acid dimer
0.400g of nicotinic acid, 0.254g of decamethylene diamine, 0.623g of EDCI, 0.036g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.378g of a white solid in 67% yield (FIG. 9 for the scheme and FIG. 10 for the characterization).
Example 6 Synthesis of decamethylenediamine-benzoic acid dimer
0.400g of benzoic acid, 0.256g of decamethylene diamine, 0.628g of EDCI, 0.036g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.397g of a white solid in 70% yield (see scheme 11 for synthesis and figure 12 for characterization).
Example 7 Synthesis of decamethylenediamine-naphthoic acid dimer
0.400g of naphthoic acid, 0.182g of decamethylenediamine, 0.445g of EDCI, 0.026g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.325g of a white solid in 64% yield (FIG. 13 for the synthetic scheme and FIG. 14 for the characterization scheme).
Example 8 Synthesis of decamethylenediamine-furoic acid dimer
0.400g of furoic acid, 0.280g of decamethylenediamine, 0.684g of EDCI, 0.040g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.363g of a white solid in 62% yield (FIG. 15 for the synthetic scheme and FIG. 16 for the characterization scheme).
Example 9 Synthesis of decamethylene diamine-picolinic acid dimer
0.400g of picolinic acid, 0.254g of decamethylenediamine, 0.623g of EDCI, 0.036g of DMAP and 10mL of anhydrous dichloromethane were sequentially added to a round-bottomed flask, and the mixture was stirred at room temperature for reaction for 12 hours. A white solid precipitated out, was filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL) and dried to give 0.395g of a white solid in 70% yield (FIG. 17 for the synthetic scheme and FIG. 18 for the characterization).
EXAMPLE 10 Synthesis of decamethylenediamine-quinoline-3-carboxylic acid dimer
0.400g of quinoline-3-carboxylic acid, 0.181g of decamethylene diamine, 0.443g of EDCI, 0.026g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.300g of a white solid in 59% yield (FIG. 19 for the synthetic scheme and FIG. 20 for the characterization scheme).
EXAMPLE 11 Synthesis of decamethylenediamine-quinoline-6-carboxylic acid dimer
0.400g of quinoline-6-carboxylic acid, 0.181g of decamethylene diamine, 0.443g of EDCI, 0.025g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A pale yellow solid was precipitated, filtered with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.372g of a pale yellow solid in 73% yield (see scheme 21 for synthesis and figure 22 for characterization).
EXAMPLE 12 Synthesis of decamethylenediamine-1H-benzimidazole-5-carboxylic acid dimer
0.400g of 1H-benzimidazole-5-carboxylic acid, 0.193g of decamethylene diamine, 0.473g of EDCI, 0.027g of DMAP and 10mL of anhydrous DMF are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. The brick red solid precipitated out, was filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.388g of brick red solid in 75% yield (FIG. 23 for the synthetic scheme, FIG. 24 for the characterization).
EXAMPLE 13 Synthesis of decamethylenediamine-benzofuran-2-carboxylic acid dimer
0.400g of benzofuran-2-carboxylic acid, 0.193g of decamethylenediamine, 0.473g of EDCI, 0.027g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.220g of a white solid in 43% yield (FIG. 25 for the synthetic scheme and FIG. 26 for the characterization scheme).
EXAMPLE 14 Synthesis of decamethylenediamine-benzothiophene-2-carboxylic acid dimer
0.400g of benzothiophene-2-carboxylic acid, 0.176g of decamethylenediamine, 0.430g of EDCI, 0.025g of DMAP and 10mL of anhydrous DMF are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A pale yellow solid was precipitated, which was filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.232g of a pale yellow solid in 46% yield (see FIG. 27 for the synthetic scheme and FIG. 28 for the characterization pattern).
EXAMPLE 15 Synthesis of decamethylenediamine-1-methyl-3-indolecarboxylic acid dimer
0.400g of 1-methyl-3-indoleacid, 0.179g of decamethylenediamine, 0.438g of EDCI, 0.025g of DMAP and 10mL of anhydrous dichloromethane were sequentially added to a round-bottomed flask, and the mixture was stirred at room temperature for reaction for 12 hours. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL) and dried to give 0.202g of a white solid in 40% yield (FIG. 29 for the scheme and 30 for the characterization).
EXAMPLE 16 Synthesis of decamethylenediamine-6-indolecarboxylic acid dimer
0.400g of 6-indolecarboxylic acid, 0.194g of decamethylenediamine, 0.476g of EDCI, 0.027g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL) and dried, yielding 0.243g of white solid in 47% yield (FIG. 31 for the synthetic scheme, FIG. 32 for the characterization).
Example 17 Synthesis of dimer decamethylenediamine-4-chlorocinnamic acid
0.200g of 4-chlorocinnamic acid, 0.086g of decamethylenediamine, 0.210g of EDCI, 0.012g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.160g of a white solid in 64% yield (FIG. 33 for the synthetic scheme and FIG. 34 for the characterization scheme).
EXAMPLE 18 Synthesis of decamethylenediamine-3, 4-dimethoxycinnamic acid dimer
0.200g of 3, 4-dimethoxycinnamic acid, 0.075g of decamethylenediamine, 0.184g of EDCI, 0.011g of DMAP and 10mL of anhydrous dichloromethane were added in this order to a round-bottomed flask, and the reaction was stirred at room temperature for 12 hours. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.143g of a white solid in 59% yield (FIG. 35 for the synthetic scheme and FIG. 36 for the characterization scheme).
EXAMPLE 19 Synthesis of decamethylenediamine-3, 4, 5-trimethoxycinnamic acid dimer
0.200g of 3,4, 5-trimethoxycinnamic acid, 0.066g of decamethylenediamine, 0.161g of EDCI, 0.009g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL) and dried to give 0.157g of a white solid in 67% yield (FIG. 37 for the scheme and 38 for the characterization).
EXAMPLE 20 Synthesis of dimer decamethylenediamine-p-aminobenzoic acid
0.400g of p-aminobenzoic acid, 0.168g of decamethylenediamine, 0.559g of EDCI, 0.024g of DMAP and 10mL of anhydrous dichloromethane were sequentially added to a round-bottomed flask, and the mixture was stirred at room temperature for reaction for 12 hours. To the reaction mixture was added 20mL of purified water, to precipitate a pale yellow solid, which was filtered, washed with dichloromethane (2 × 2.5mL) and water (3 × 5mL) in this order, dried, and the residue was separated on a thin-layer plate to obtain 0.170g of a pale yellow solid in 31% yield (see scheme 39 for synthesis and figure 40 for characterization).
EXAMPLE 21 Synthesis of dimer decamethylenediamine-3, 5-dimethoxybenzoic acid
0.400g of 3, 5-dimethoxybenzoic acid, 0.151g of decamethylenediamine, 0.370g of EDCI, 0.021g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask, and the mixture is stirred and reacted for 12 hours at normal temperature. A white solid was precipitated, filtered with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.279g of a white solid in 56% yield (FIG. 41 for the synthetic scheme and FIG. 42 for the characterization scheme).
EXAMPLE 22 Synthesis of decamethylenediamine-3, 4, 5-Trimethoxybenzoic acid dimer
0.400g of 3,4, 5-trimethoxybenzoic acid, 0.130g of decamethylene diamine, 0.361g of EDCI, 0.018g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottom flask and stirred for reaction for 12 hours at normal temperature. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL) and dried to give 0.302g of a white solid in 63% yield (FIG. 43 for the synthetic scheme and 44 for the characterization).
Example 23 Synthesis of octanediamine-cinnamic acid dimer
0.400g of cinnamic acid, 0.177g of octanediamine, 0.518g of EDCI, 0.030g of DMAP, and 10mL of anhydrous dichloromethane were sequentially added to a round-bottomed flask, and the reaction was stirred at room temperature for 12 hours. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL), and dried to give 0.315g of a white solid in 63% yield (FIG. 45 for the synthetic scheme and FIG. 46 for the characterization).
Example 241, 12-diamino-dodecane-cinnamic acid dimer Synthesis
0.400g of cinnamic acid, 0.246g of 1, 12-diaminododecane, 0.518g of EDCI, 0.030g of DMAP and 10mL of anhydrous dichloromethane are sequentially added into a round-bottomed flask, and the reaction is stirred at normal temperature for 12 hours. A white solid was precipitated, filtered off with suction, washed successively with dichloromethane (2X 2.5mL) and water (3X 5mL) and dried to give 0.275g of a white solid in 49% yield (FIG. 47 for the synthetic scheme and FIG. 48 for the characterization scheme).
Example Synthesis of 251, 11-diamino-3, 6, 9-trioxaundecane-cinnamic acid dimer
To a round-bottomed flask were added 0.500g of cinnamic acid, 0.295g of 1, 11-diamino-3, 6, 9-trioxaundecane, 0.647g of EDCI, 0.037g of DMAP, and 10mL of anhydrous dichloromethane in this order, the reaction was stirred at room temperature for 12 hours, 20mL of dichloromethane was added, the reaction mixture was washed with saturated brine (1X 30mL) and water (2X 30mL) in this order, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the residue was separated into thin-layer plates and developed with a developing solvent (chloroform/methanol 35: 1; 50:4) to give 0.178g of a pale yellow oily substance in 28% yield (FIG. 49, FIG. 50 for characterization).
Example 26 in vitro antitumor efficacy evaluation of the small molecule heterocyclic dimers prepared in examples 1-25, comprising the steps of:
(1) cells were collected in logarithmic growth phase and cultured in a medium containing 10% fetal calf serum at 1X 104The density of individual cells/well was seeded in 96-well plates and placed at 37 ℃ in 5% CO2Incubate in incubator for 24h to allow cells to adhere.
(2) Removing culture medium, sequentially adding 100 μ L of a series of medicinal solutions with increasing concentrations prepared according to multiple relation into each well, standing at 37 deg.C and 5% CO2Incubate in incubator for 48 h.
(3) mu.L of MTT solution (1mg/mL) was added to each well, and the mixture was incubated at 37 ℃ with 5% CO2Culturing in an incubator for 4 h. The supernatant was discarded, 150. mu.L of DMSO was added to each well, and the wells were shaken well.
(4) And detecting the absorbance value of each hole at 490nm by using a microplate reader, and calculating the cell growth inhibition rate according to the following formula.
Growth inhibition (%) was (1-dose group OD value/control group OD value) × 100%
Calculating IC according to the relationship between concentration and inhibition rate by SPSS software50Values (see table 1).
TABLE 1 in vitro antitumor Activity of Small molecule heterocyclic dimers (IC)50，μM)
Figure BDA0002107479520000111
The result shows that the small molecular heterocyclic dimer has a remarkable inhibition effect on the growth of various tumor cells, and particularly shows good anti-tumor activity on human pharyngeal squamous cell carcinoma cell strains FaDu.

Claims (2)

1. A small molecule aromatic ring dimer is characterized by having the following structure:
Figure FDA0003585228360000011
wherein the content of the first and second substances,
Figure FDA0003585228360000012
Figure FDA0003585228360000013
x ═ H, Cl, Br, I or NO2And Y is N or O or S.
2. The use of a small molecule aromatic ring dimer according to claim 1 in the preparation of an anti-tumor medicament.
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