CN102627614B - Diquinazoline diselenide compound as well as preparation method and bioactivity thereof - Google Patents

Diquinazoline diselenide compound as well as preparation method and bioactivity thereof Download PDF

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CN102627614B
CN102627614B CN201210086997.8A CN201210086997A CN102627614B CN 102627614 B CN102627614 B CN 102627614B CN 201210086997 A CN201210086997 A CN 201210086997A CN 102627614 B CN102627614 B CN 102627614B
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CN102627614A (en
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刘刚
刘春萍
徐胜广
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Ludong University
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Abstract

The invention discloses an anti-tumor drug-diquinazoline diselenide compound as well as a preparation method and bioactivity thereof, which are the compound represented by the following general formula and the preparation method thereof. In the general formula, R1, R2, R3, R4 and R5 are as defined in the specification. The invention introduces the anti-tumor drug-diquinazoline diselenide compound prepared by the steps of with 4-chlorinated quinazoline and sodium diselenide or potassium diselenide or lithium diselenide as raw materials and water, ethanol, isopropanol, absolute ethanol, N,N-dimethyl formamide, dioxane, dimethyl sulfoxide or a mixture thereof as a solvent, reacting and synthesizing. The compounds a, h have proliferation inhibition effects on breast cancer cells MDA-MB-435 and have good anti-cancer activity.

Description

Diquinazoline diselenide compound, preparation method and biological activity
Technical Field
The invention belongs to organic selenium nitrogen heterocyclic quinazoline drugs, and particularly relates to an antitumor drug bisquinazoline diselenide compound, and a preparation method and biological activity thereof.
Background
In recent years, a great deal of research data show that quinazoline compounds show good biological activity, and especially have prominent effect on inhibiting EGF receptor and tyrosine kinase phosphorylation thereof. There are a large number of documents, patents, articles, etc. reported each year. In the aspect of medicine, for example, commercial Iressa (ZD 1839), Tarceva (OSI-774), PD153035, PD16941 and the like have an inhibitory effect on EGFR, and further show an anti-cancer activity, and also have antimalarial, anti-tumor and anti-HIV activities. Quinazoline small molecular compound energyThe tyrosine kinase inhibitor can be combined with EGFR with high selectivity and is strong, and clinical researches show that the tyrosine kinase inhibitor can lead cells to stay at G1And (4) period. In the aspect of pesticides, in particular to quinazoline oxime ether compounds with the activity of resisting Tobacco Mosaic Virus (TMV), Cucumber Mosaic Virus (CMV) and other plant pathogenic bacteria. Quinazoline compounds possess such a wide range of biological activities that they have generated great interest to medical researchers and chemists. In order to find the site of action of quinazoline Compounds, Lim et al (Lim, J. K.; Negash, K.; Hanraham, S. M.; Van Brocklin, H.F. Journal of laboratory Compounds and Radiopharmaceuticals, 2000, 43, 1183-1191) synthesized two bands [ I153035 ] using two different methods as lead Compounds125]The IC of the target compound for EGFR-TK is determined by measuring the purity of the radiolabeled quinazoline compound by HPLC with a spectrophotometer detector500.025 and 0.006 nmol/L respectively, and the activity of inhibiting EGFR is better than PD 153035; the radioactivity is measured, and the action site is found by radioactive tracing measurement. 7-substituted 1, 4-EGF receptor tyrosine kinase inhibitors were reported by Lee et al (Lee, J. Y.; Park, Y. K.; Seo, S. H.; Yang, B. S.; Park, H.; Lee, Y.S. Arch. pharm. Pharm. Med. chem. 2002, 335 (10), 487-494.) in 2002]Dioxane [2, 3-g ]]The quinazoline compound has the activity superior to or close to that of PD153035 through biological tests of EGF receptor tyrosine kinase of A431 cells, HCT116 cells and SUN638 cells. In 2006 Ballard et al (Ballard P, Bradbury R H, Harris C S, et al, bioorg. Med. chem. Lett., 2006, 16 (6), 1633-1637) designed and synthesized a novel class of 4-arylamino quinazoline compounds with inhibitory activity against EGFR, and part of IC of the target compounds50Below 2 nmol/L. In 2007, Wissner et al (Wissner A, Fraser H L, Ingalils C L, et al, bioorg. Med. chem., 2007, 15 (11), 3635-one 3648) report that a novel 4-quinonamine quinazoline compound shows good inhibitory effect on EGFR, and IC of part of target compounds50Can reach 2.6 nmol/L. Gong et al (Gong G, Xie Y, Liu Y, et al, bioorg. Med. chem. Lett., 2009, 19 (4), 1191-Bu 1194) reported a class of 2-thiophene extractionsThe substituted-4-hydrazino substituted quinazoline compounds can promote the conduction activity of NF-kB, which is different from the currently found quinazoline compounds that can block the conduction activity of NF-kB.
Selenium is a trace element necessary for human bodies, is a constituent component of various enzymes, and has the functions of resisting diseases, delaying senility and enhancing the immunity of the organisms in the human bodies, thereby achieving the effect of balancing the environment in the organisms. Selenium has wide biological functions, is an important component of erythrocyte glutathione peroxidase, can participate in the synthesis of coenzyme A and coenzyme Q, is a protective agent for resisting toxic substances in vivo, can promote lymphocytes to generate antibodies, and is also an inducer for promoting the gene regulation and normalization of canceration early-stage disorder. Since the last 70 th generation of scientists discovered selenium to have antitumor effects, subsequent studies demonstrated that selenium is a potent inhibitor of breast, liver, skin, colon and stomach cancers and the like (Wei W Q, Abnet C, Qiao Y L, et al Am. J. Clin. Nutr., 2004, 79 (1), 80-85; Kellen E, Zeegers M, Buntinx F. int. J. Urol., 2006, 13 (9), 11802-11804; Wu X-W, Yu Z-K. Tetrahedron Lett., 2010, 51 (11), 1500-1503). The selenium compound has anticancer effect via multiple mechanisms and multiple targets, and compared with inorganic selenium, the organic selenium has the features of high bioavailability, high bioactivity, low toxicity, less environmental pollution, etc. In recent years, organic selenium compounds such as selenium chitosan selenide, selenium-containing protein, selenium polysaccharide, selenium methionine, selenium carrageenan, selenium tea polyphenol and other selenium micromolecular or biological macromolecule compounds are obviously higher than those of corresponding compounds which are not selenylated in terms of biological activities such as tumor resistance, cardiovascular disease treatment, aging resistance, organism immunity improvement and the like. Representative drugs currently under clinical investigation, such as Ebselen (Ebselen) as an anti-inflammatory and anti-oxidant drug (Schewe T. Gen. Pharmacol-Vasc. S., 1995, 26 (6), 1153-1169; Azad G K, Balsterihna S J, Sathish N, et al biochem. Pharmacol., 2012, 83 (2), and-. The development of new therapeutic drugs using the unique chemical and biological properties of selenium has attracted increasing attention of scientists, and the synthesis of organic selenium compounds with high biological activity and low toxicity remains a major hotspot of current drug research (Ninomiya M, Garud D R, Koketsu M, et al coordin. chem. rev., 2011, 255 (23-24), 2968-2990; plato D, Ib a ñ ez E, Palop J a, et al struct. chem., 2011, 22 (6), 1233-1240; Terazawa R, Garud D R, Hamada N, bio-org. chem., 2010, 18 (19), 7001 med 7008; Bijian K, Zhang Z-W, Xu B, et al. eur. chem. J. 152, 48, 143-143).
In conclusion, with the design and synthesis of the organic metal anticancer compound and the discovery of the action target of a new medicament, a theoretical basis is laid for medicinal chemists to develop innovative medicaments with independent intellectual property rights; with the research of quinazoline compounds in recent years, a plurality of series of novel quinazoline compounds are designed and synthesized, wherein good EGFR inhibitory activity is not shown, and the quinazoline compounds have further research value. Based on the multiple denaturation of a substituent at the 4-position of a quinazoline ring and the multi-mechanism and multi-target anticancer effect of a selenium-containing compound, a new diquinazoline diselenide compound is synthesized, and an innovative anticancer drug with independent intellectual property rights is developed.
Disclosure of Invention
An anti-tumor drug, which is characterized in that the drug is a bis-quinazoline diselenide compound represented by the following general formula (I):
Figure DEST_PATH_IMAGE002
（I）
wherein,
R1、R2、R3、R4and R5Each is hydrogen, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group; but does not include R1、R2、R3、R4And R5Are all hydrogen.
The anti-tumor drug has the general formula (I) shown in the specification, wherein R is1、R4And R5Are each hydrogen, R2And R3Selected from C1-6 alkyl and C1-6 alkoxy.
In the context of the present invention, the C1-6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, isohexyl, tert-hexyl, neohexyl.
In the context of the present invention, C1-6 alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, neopentoxy.
The anti-tumor drug has the general formula (I) shown in the specification, wherein R is1、R3And R5Are each hydrogen, R2And R4Selected from halogen atoms.
In the context of the present invention, the halogen atom may be a fluorine, chlorine, bromine or iodine atom.
The anti-tumor drug has the general formula (I) shown in the specification, wherein R is5Is methyl, R1、R2、R3And R4Selected from halogen atom, C1-6 alkyl, C1-6 alkoxy; in particular R1And R4Is hydrogen, R2And R3Selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, neopentoxy.
The anti-tumor drug is characterized in that the partially synthesized compound is as follows:
a.1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide,
b.1, 2-bis (6, 7-diethoxyquinazolin-4-yl) diselenide,
c.1, 2-bis (2-methyl-6, 7-dimethoxyquinazolin-4-yl) diselenide,
d.1, 2-bis (2-methyl-6, 7-diethoxyquinazolin-4-yl) diselenide,
e.1, 2-bis (2-chloro-6, 7-dimethoxyquinazolin-4-yl) diselenide,
f.1, 2-bis (2-chloro-6, 7-diethoxyquinazolin-4-yl) diselenide,
g.1, 2-bis (6-chloroquinazolin-4-yl) diselenide,
h.1, 2-bis (6, 8-dichloroquinazolin-4-yl) diselenide,
i.1, 2-bis (2-methyl-6-chloroquinazolin-4-yl) diselenide,
j.1, 2-bis (2-methyl-6, 8-dichloroquinazolin-4-yl) diselenide,
k.1, 2-bis (2-chloro-6-chloroquinazolin-4-yl) diselenide,
1, 2-bis (2-chloro-6, 8-dichloroquinazolin-4-yl) diselenide,
m, 1, 2-bis (6-bromoquinazolin-4-yl) diselenide,
n, 1, 2-bis (6, 8-dibromoquinazolin-4-yl) diselenide,
o, 1, 2-bis (2-methyl-6-bromoquinazolin-4-yl) diselenide,
p, 1, 2-bis (2-methyl-6, 8-dibromoquinazolin-4-yl) diselenide,
q, 1, 2-bis (2-chloro-6-bromoquinazolin-4-yl) diselenide,
r.1, 2-bis (2-chloro-6, 8-dibromoquinazolin-4-yl) diselenide.
The above-mentioned one for antitumor drugThe preparation method is characterized in that 4-chloroquinazoline, sodium diselenide or potassium diselenide or lithium diselenide are taken as raw materials, and water, ethanol, isopropanol, absolute ethanol, sodium diselenide, potassium diselenide, lithium diselenide, sodium diselen,N,N-dimethylformamide, dioxane, dimethylsulfoxide or a mixture thereof as a solvent, and reacting to synthesize: adding 4-chloroquinazoline in batches at 20-120 ℃ into the prepared solution of sodium diselenide, potassium diselenide or lithium diselenide, performing reflux reaction for 3-36h, cooling, performing suction filtration to obtain a brownish red solid, and using the brownish red solidN,NRecrystallizing dimethyl formamide and water to obtain orange to brownish red crystals, namely the product of the bis-quinazoline diselenide compound. The synthetic chemical reaction equation is as follows:
Figure DEST_PATH_IMAGE004
the method is suitable for synthesizing all the above bis-quinazoline diselenide compounds.
The anti-tumor drug can be a pharmaceutical composition, and is characterized by comprising an effective amount of a compound shown in formula (I) or a pharmaceutically acceptable salt thereof, and the application of the anti-tumor drug is to treat and prevent various benign or malignant tumors, wherein the tumors comprise prostate cancer, leukemia, skin cancer, gastric cancer, breast cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, lymph cancer, colorectal cancer, nasopharyngeal cancer and oral cancer, and particularly the prostate cancer and the breast cancer.
The pharmaceutical compositions comprise as active ingredient at least a compound of formula (I) as such or in admixture with one or more pharmaceutically acceptable inert non-toxic excipients or carriers.
Detailed Description
The following examples will better illustrate the invention, but it should be emphasized that the invention is in no way limited to what is shown in these examples.
The following examples show different aspects of the invention, and the data given include specific operating and reaction conditions and products whose purity confirms their structure by infrared spectroscopy, nuclear magnetic resonance hydrogen spectroscopy and mass spectrometry.
Example 1, Synthesis of 1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide (compound No. a).
0.3 g (3.8 mmol) of selenium, 0.1 g (2.6 mmol) of sodium borohydride and 15 mL of absolute ethyl alcohol are sequentially added into a 150 mL three-necked bottle provided with a reflux condenser tube, the temperature of an ice water bath is controlled to be below 3 ℃, the solution turns brown from black, the solution turns reddish brown after about 10min, the ice bath is removed, and the solution is heated, stirred and refluxed for 1.5 h and turns dark brown. Adding 2.5 mmol 6, 7-dimethoxy-4-chloroquinazoline in batches, adding for about 1 h, changing the solution into dark brick red, refluxing for 24h, cooling to room temperature, adjusting the pH of the reaction system to =5-6 with glacial acetic acid, performing desolventization under reduced pressure to obtain an earthy yellow solid, and recrystallizing with DMF and water (V)DMF/H2O= 5: 1) to obtain orange crystal, namely the product 1, 2-bis (6, 7-dimethoxyquinazoline-4-yl) diselenide, the yield is 53.8 percent, and the melting point is>300℃。IR (KBr) v: 3039.6 (vAr-H), 2945.3 (v as CH3), 2845.0 (v s CH3), 1602.9-1467.8 (quinazoline skeleton vibration), 1246.0 (v as Ar-O-C), 1136.1 (v s Ar-O-C), 786.9 (δAr-H) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.93 (s, 2H, quinazoline H-2), 7.60 (s, 2H, quinazoline H-8), 7.29 (s, 2H, quinazoline H-5), 4.06, 4.01 (2s, 12H, 4OCH3). EIMS: m/z 538 (M+ ·, 17.2)。
Example 2 synthesis of 1, 2-bis (6, 7-diethoxyquinazolin-4-yl) diselenide (compound No. b).
Synthesized according to the method and conditions of example 1, except for 6, 7-dimethoxyThe base-4-chloroquinazoline is replaced by 6, 7-diethoxy-4-chloroquinazoline to obtain the product 1, 2-bis (6, 7-diethoxy-quinazolin-4-yl) diselenide which is orange crystal, the yield is 52.6 percent, and the melting point is high>300℃。IR (KBr) v: 3036.9 (vAr-H), 2946.7 (v as CH3), 2935.8 (v as CH2), 2847.4 (v s CH3), 2836.4 (v s CH2), 1608.2-1464.6 (quinazoline skeleton vibration), 1242.6 (v as Ar-O-C), 1134.8 (v s Ar-O-C), 787.6 (δAr-H) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.95 (s, 2H, quinazoline H-2), 7.64 (s, 2H, quinazoline H-8), 7.31 (s, 2H, quinazoline H-5), 4.09, 4.06 (2s, 8H, 4OCH2), 1.34, 1.31 (2s, 12H, 4CH3). EIMS: m/z 594 (M+ ·, 18.6)。
Example 3 synthesis of 1, 2-bis (2-methyl-6, 7-dimethoxyquinazolin-4-yl) diselenide (compound No. c).
Synthesis by the method and conditions of example 1, substituting only 6, 7-dimethoxy-4-chloroquinazoline for 2-methyl-6, 7-dimethoxy-4-chloroquinazoline gave the product 1, 2-bis (2-methyl-6, 7-dimethoxyquinazolin-4-yl) diselenide as an orange yellow crystal, 48.2% yield, melting point>300℃。IR (KBr) v: 3030.2 (vAr-H), 2954.2 (v as CH3), 2865.9 (v s CH3), 1614.8-1458.2 (quinazoline skeleton vibration), 1248.3 (v as Ar-O-C), 1139.4 (v s Ar-O-C), 779.8 (δAr-H) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 7.63 (s, 2H, quinazoline H-8), 7.39 (s, 2H, quinazoline H-5), 3.90, 3.85 (2s, 12H, 4OCH3), 2.46, 2.42 (2s, 6H, 2CH3). EIMS: m/z 566 (M+ ·, 15.2)。
Example 4 synthesis of 1, 2-bis (2-methyl-6, 7-diethoxyquinazolin-4-yl) diselenide (compound No. d).
Synthesized as in example 1, except for changing 6, 7-dimethoxy-4-chloroquinazoline to 2-methyl-6, 7-diethoxy-4-chloroquinazoline, the product 1, 2-bis (2-methyl-6, 7-diethoxyquinazolin-4-yl) diselenide was obtained as orange yellow crystals in 45.6% yield and melting point>300℃。IR (KBr) v: 3033.0 (vAr-H), 2956.3 (v as CH3), 2948.5 (v as CH2), 2869.7 (v s CH3), 2838.6 (v s CH2), 1618.8-1451.7 (quinazoline skeleton vibration), 1247.8 (v as Ar-O-C), 1132.4 (v s Ar-O-C), 781.7 (δAr-H) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 7.65 (s, 2H, quinazoline H-8), 7.41 (s, 2H, quinazoline H-5), 4.05, 4.02 (2s, 8H, 4OCH2), 2.47, 2.45 (2s, 6H, 2CH3), 1.36, 1.33 (2s, 12H, 4CH3). EIMS: m/z 622 (M+ ·, 13.7)。
Example 5 Synthesis of 1, 2-bis (2-chloro-6, 7-dimethoxyquinazolin-4-yl) diselenide (compound No. e).
Synthesized as in example 1, substituting only 6, 7-dimethoxy-4-chloroquinazoline for 6, 7-dimethoxy-2, 4-dichloroquinazoline, provided the product 1, 2-bis (2-chloro-6, 7-dimethoxyquinazolin-4-yl) diselenide as an orange-red crystal, 53.8% yield, melting point>300℃。IR (KBr) v: 3032.1 (vAr-H), 2958.1 (v as CH3), 2868.5 (v s CH3), 1618.2-1460.8 (quinazoline skeleton vibration), 1250.4 (v as Ar-O-C), 1140.6 (v s Ar-O-C), 787.1 (δAr-H) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 7.67 (s, 2H, quinazoline H-8), 7.43 (s, 2H, quinazoline H-5), 3.99, 3.89 (2s, 12H, 4OCH3). EIMS: m/z 606 (M+ ·, 28.5)。
Example 6 Synthesis of 1, 2-bis (6-chloroquinazolin-4-yl) diselenide (compound No. g).
Synthesized as in example 1, except for the change of 6, 7-dimethoxy-4-chloroquinazoline to 4, 6-dichloroquinazoline, to give the product 1, 2-bis (6-chloroquinazolin-4-yl) diselenide as an orange yellow crystal, 50.3% yield, melting point>300℃。IR (KBr) v: 3039.9 (vAr-H), 1496.4-1570.1 (quinazoline skeleton vibration) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.75 (s, 2H, quinazoline H-2), 8.31 (s, 2H, quinazoline H-5), 7.86 (d, J = 8.8 Hz, 2H, quinazoline H-8), 7.73 (d, J = 8.8 Hz, 2H, quinazoline H-7). EIMS: m/z 484 (M+ ·, 20.8)。
Example 7 synthesis of 1, 2-bis (6, 8-dichloroquinazolin-4-yl) diselenide (compound No. h).
Synthesized as in example 1, except for changing 6, 7-dimethoxy-4-chloroquinazoline to 4,6, 8-trichloroquinazoline, to give the product 1, 2-bis (6, 8-dichloroquinazolin-4-yl) diselenide as orange yellow crystals in 47.8% yield and melting point>300℃。IR (KBr) v: 3036.4 (vAr-H), 1477.5-1566.2 (quinazoline skeleton vibration) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.76 (s, 2H, quinazoline H-2), 8.63 (d, J = 2.0 Hz, 2H, quinazoline H-7), 8.20 (d, J = 2.0 Hz, 2H, quinazoline H-5). EIMS: m/z 554 (M+ ·, 24.5)。
Example 8 Synthesis of 1, 2-bis (2-methyl-6-chloroquinazolin-4-yl) diselenide (compound No. i).
Synthesized as in example 1, except for changing 6, 7-dimethoxy-4-chloroquinazoline to 2-methyl-4, 6-dichloroquinazoline, the product 1, 2-bis (2-methyl-6-chloroquinazolin-4-yl) diselenide was obtained as orange red crystals in 43.1% yield and melting point>300℃。IR (KBr) v: 3032.0 (vAr-H), 2974.4 (v as CH3), 2868.2 (v s CH3), 1490.6-1582.0 (quinazoline skeleton vibration) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.77 (s, 2H, quinazoline H-2), 8.33 (s, 2H, quinazoline H-5), 7.88 (d, J = 8.8 Hz, 2H, quinazoline H-8), 7.75 (d, J = 8.8 Hz, 2H, quinazoline H-7), 2.49, 2.47 (2s, 6H, 2CH3). EIMS: m/z 512 (M+ ·, 18.3)。
Example 9 Synthesis of 1, 2-bis (2-methyl-6, 8-dichloroquinazolin-4-yl) diselenide (compound No. j).
Synthesized as in example 1, except for changing 6, 7-dimethoxy-4-chloroquinazoline to 2-methyl-4, 6, 8-trichloroquinazoline, the product 1, 2-bis (2-methyl-6, 8-dichloroquinazolin-4-yl) diselenide was obtained as orange red crystals in 40.1% yield and melting point>300℃。IR (KBr) v: 3036.0 (vAr-H), 2971.1 (v as CH3), 2866.7 (v s CH3), 1465.7-1502.6 (quinazoline skeleton vibration) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.79 (s, 2H, quinazoline H-2), 8.76 (d, J = 2.0 Hz, 2H, quinazoline H-7), 8.23 (d, J = 2.0 Hz, 2H, quinazoline H-5), 2.44, 2.42 (2s, 6H, 2CH3). EIMS: m/z 582 (M+ ·, 15.4)。
Example 10 synthesis of 1, 2-bis (6-bromoquinazolin-4-yl) diselenide (compound No. m).
Synthesized as in example 1, except for changing 6, 7-dimethoxy-4-chloroquinazoline to 6-bromo-4-chloroquinazoline, the product 1, 2-bis (6-bromoquinazolin-4-yl) diselenide was obtained as orange-red crystals with a yield of 47.5% and a melting point of 47.5%>300℃。IR (KBr) v: 3030.8 (vAr-H), 1458.6-1599.1 (quinazoline skeleton vibration) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.81 (s, 2H, quinazoline H-2), 8.46 (s, 2H, quinazoline H-5), 7.92 (d, J = 8.8 Hz, 2H, quinazoline H-8), 7.84 (d, J = 8.8 Hz, 2H, quinazoline H-7). EIMS: m/z 576 (M+ ·, 21.6)。
Example 11 synthesis of 1, 2-bis (6, 8-dibromoquinazolin-4-yl) diselenide (compound No. n).
Synthesized as in example 1, except for changing 6, 7-dimethoxy-4-chloroquinazoline to 6, 8-dibromo-4-chloroquinazoline, the product 1, 2-bis (6, 8-dibromoquinazolin-4-yl) diselenide was obtained as orange-red crystals in 40.7% yield and melting point>300℃。IR (KBr) v: 3030.7 (vAr-H), 1457.7 -1652.6 (quinazoline skeleton vibration) cm-1. 1H NMR (DMSO- 6d, 600 MHz) δ: 8.85 (s, 2H, quinazoline H-2), 8.71 (d, J = 2.0 Hz, 2H, quinazoline H-7), 8.38 (d, J = 2.0 Hz, 2H, quinazoline H-5). EIMS: m/z 732 (M+ ·, 19.2)。
Example 12 Synthesis of 1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide (compound No. a).
Synthesized as in example 1, except that the solvent absolute ethanol was changed to 50% aqueous ethanol to give the product 1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide as orange crystals in 38.6% yield and melting point >300 ℃.
Example 13 Synthesis of 1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide (compound No. a).
Synthesized as in example 1, except that the solvent absolute ethanol was changed toN,NDimethyl formamide, the reaction temperature is maintained in a water bath at 80 ℃, and the product 1, 2-bis (6, 7-dimethoxy quinazoline-4-yl) diselenide is obtained in orange crystal with the yield of 56.1 percent and the melting point>300℃。
Example 14 Synthesis of 1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide (compound No. a).
Synthesized as in example 1, except that the solvent absolute ethanol was changed to dimethyl sulfoxide and the reaction temperature was maintained in a water bath at 80 ℃ to obtain 1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide as a product in orange crystals with a yield of 53.7% and a melting point of >300 ℃.
Example 15 proliferation inhibition assay of Compound a on breast cancer cells MDA-MB-435.
The test method comprises the following steps: dissolving the medicine in DMSO to prepare each concentration, and repeating each concentration for three times; MDA-MB-435 cells were digested and made into a suspension of 4X 104Adding 10ml of the powder into a large culture dish, and adding medicine after 24hr of adherence; taking 2 dishes at random after 24hr, and recording cell state; sucking out original culture medium, and processing with medicinal culture medium (10% FBS 1640) for 72 hr; adding 1.5ml pancreatin, digesting for 4min, adding the original drug-containing culture medium to stop digestion, stirring uniformly, counting the number of cells, taking an average value, and calculating the inhibition rate.
And (3) test results: tested, the compoundaThe inhibition rate of the medicament concentration of 10mmol/L on MDA-MB-435 cell proliferation reaches 99.69 +/-0.18%, the effect is much better than that of oxaliplatin which is a positive control medicament, and the medicament shows extremely high anticancer activity.
Example 16, measurement of proliferation inhibition of Breast cancer cell MDA-MB-435 by Compound h.
The test method was the same as in example 15.
And (3) test results: tested, the compoundhThe inhibition rate of the medicament concentration of 10mmol/L on MDA-MB-435 cell proliferation reaches 59.07 +/-3.95%, and the medicament has better effect than a positive control medicament oxaliplatin and shows higher anticancer activity.

Claims (11)

1. An antitumor agent characterized by being a compound represented by the following general formula (I):
（I）
wherein,
R1is hydrogen, R2、R3、R4And R5Each is hydrogen, halogen atom, C1-6 alkyl, C1-6An alkoxy group; but does not include R1、R2、R3、R4And R5Are all hydrogen.
2. The antitumor drug according to claim 1, wherein R in the general formula (I) of the compound is1、R4And R5Are each hydrogen, R2And R3Selected from C1-6 alkyl and C1-6 alkoxy.
3. The antitumor drug according to claim 1, wherein R in the general formula (I) of the compound is1、R3And R5Are each hydrogen, R2And R4Selected from halogen atoms.
4. The antitumor agent according to claim 1, wherein R5 is methyl group and R is represented by the general formula (I)2、R3And R4Selected from halogen atom, C1-6 alkyl, C1-6 alkoxy.
5. The antitumor agent according to claim 2, wherein R is represented by the general formula (I)2And R3Selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, neopentoxy.
6. The antitumor agent according to claim 3, wherein R is represented by the general formula (I)2And R4Selected from fluorine, chlorine, bromine, iodine atoms.
7. The antitumor agent according to claim 4, wherein R is represented by the general formula (I)2And R3Selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-butoxyPentoxy, neopentoxy.
8. A medicament according to claim 1 for use against tumors, characterized in that the partially synthesized compound is as follows:
1, 2-bis (6, 7-dimethoxyquinazolin-4-yl) diselenide,
1, 2-bis (6, 7-diethoxyquinazolin-4-yl) diselenide,
c.1, 2-bis (2-methyl-6, 7-dimethoxyquinazolin-4-yl) diselenide,
1, 2-bis (2-methyl-6, 7-diethoxyquinazolin-4-yl) diselenide,
e.g. 1, 2-bis (2-chloro-6, 7-dimethoxyquinazolin-4-yl) diselenide,
f.1, 2-bis (2-chloro-6, 7-diethoxyquinazolin-4-yl) diselenide,
g of 1, 2-bis (6-chloroquinazolin-4-yl) diselenide,
h.1, 2-bis (6, 8-dichloroquinazolin-4-yl) diselenide,
1, 2-bis (2-methyl-6-chloroquinazolin-4-yl) diselenide,
j.1, 2-bis (2-methyl-6, 8-dichloroquinazolin-4-yl) diselenide,
k.1, 2-bis (2, 6-dichloroquinazolin-4-yl) diselenide,
l.1, 2-bis (2,6, 8-trichloroquinazolin-4-yl) diselenide,
m.1, 2-bis (6-bromoquinazolin-4-yl) diselenide,
n.1, 2-bis (6, 8-dibromoquinazolin-4-yl) diselenide,
o.1, 2-bis (2-methyl-6-bromoquinazolin-4-yl) diselenide,
p.1, 2-bis (2-methyl-6, 8-dibromoquinazolin-4-yl) diselenide,
q.1, 2-bis (2-chloro-6-bromoquinazolin-4-yl) diselenide,
r.1, 2-bis (2-chloro-6, 8-dibromoquinazolin-4-yl) diselenide.
9. The preparation method of an antitumor drug according to claim 1, characterized in that the compound is synthesized by using substituted 4-chloroquinazoline, sodium diselenide, potassium diselenide or lithium diselenide as a raw material and water, ethanol, isopropanol, N-dimethylformamide, dioxane, dimethylsulfoxide or a mixture thereof as a solvent: adding substituted 4-chloroquinazoline in batches at the temperature of 20-120 ℃ into the prepared solution of sodium diselenide, potassium diselenide or lithium diselenide, carrying out reflux reaction for 3-36h, cooling, carrying out suction filtration to obtain a brownish red solid, and recrystallizing with N, N-dimethylformamide and water to obtain an orange-to-brownish red crystal, namely the product.
10. Use of the antitumor agent for treating and preventing various benign or malignant tumors according to claim 1.
11. A pharmaceutical composition comprising an effective amount of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1.
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