Phthalimide compound and preparation method and application thereof
阅读说明：本技术 一种邻苯二甲酰亚胺类化合物及其制备方法和应用 (Phthalimide compound and preparation method and application thereof ) 是由 陈宝泉 池春兰 徐路 栗俊婕 刘洋 于 2020-07-07 设计创作，主要内容包括：本发明公开了一种邻苯二甲酰亚胺类化合物及其制备方法和应用,该化合物以乙醇为溶剂,在缚酸剂存在下,通过含有巯基的邻苯二甲酰亚胺类化合物与巯基异硫脲盐酸盐类化合物进行反应,制备了一种新的邻苯二甲酰亚胺类化合物,本发明的优点是：按照新药设计理论和方法,首次制备了一种新的邻苯二甲酰亚胺类化合物,以CCK-8法,通过测试这类化合物对人体宫颈癌细胞Hela和肺癌A549细胞的增殖抑制活性,结果表明：这类化合物具有较好的抗肿瘤细胞增值抑制活性,用于制备包括抗宫颈癌Hela和肺癌A549细胞的药物,为研制新的抗癌药物开辟了新的途径。(The invention discloses a phthalimide compound and a preparation method and application thereof, the compound takes ethanol as a solvent, and the phthalimide compound containing sulfydryl reacts with sulfydryl isothiourea hydrochloride compounds in the presence of an acid-binding agent to prepare a novel phthalimide compound, and the invention has the advantages that: according to the new drug design theory and method, a new phthalimide compound is prepared for the first time, the CCK-8 method is used for testing the proliferation inhibition activity of the compound on human cervical cancer cells Hela and lung cancer cells A549, and the results show that: the compounds have good antitumor cell proliferation inhibition activity, are used for preparing medicaments for resisting cervical cancer Hela and lung cancer A549 cells, and open up a new way for developing new anticancer medicaments.)
1. A phthalimide compound is characterized by having a chemical structural formula as follows:
in the structural formula: r1Is one of a plurality of substituents of alkyl, amino, nitro, halogen atom and methoxyl, wherein the halogen atom is fluorine, chlorine, bromine or iodine atom; r2Is C1-6 alkyl, C3-8 cycloalkyl or C5-14 aromatic cyclic group, wherein the aromatic cyclic group may be substituted with 1 to 3 of hydroxy, nitro, halogen atom, cyano, C1-6 alkoxy or C1-6 alkyl group, or amino substituted with one or two of C1-6 alkyl, C1-6 alkylsulfonyl and C1-6 alkylcarbonyl.
2. The method for preparing phthalimide compound according to claim 1, which comprises reacting phthalimide compound containing mercapto group with mercapto group isothiourea hydrochloride compound in the presence of acid-binding agent in ethanol as solvent, and comprises the following steps:
1) mixing 5-substituted-2- (4-mercaptophenyl) isoindoline-1, 3-dione, mercaptoisothiourea hydrochloride compound, ethanol and dichloromethane mixed solvent, uniformly stirring, dripping acid-binding agent aqueous solution at 0-5 ℃, and stirring for reaction for 5-6h to obtain reaction liquid;
2) and (3) adding water and dichloromethane into the reaction solution for extraction to obtain an organic phase, then carrying out reduced pressure concentration and cooling to separate out a solid, and carrying out column chromatography to obtain the target product.
3. The method for producing a phthalimide compound according to claim 2, wherein: the acid-binding agent is sodium bicarbonate, anhydrous sodium acetate, pyridine or piperidine.
4. The method for producing a phthalimide compound according to claim 2, wherein: the molar ratio of the mercaptoisothiourea hydrochloride compound to the 5-substituted-2- (4-mercaptophenyl) isoindoline-1, 3-diketone is 1-1.1: 1; the dosage ratio of the 5-substituted-2- (4-mercapto phenyl) isoindoline-1, 3-diketone to the solvent is 1mmol:6-8 ml; the molar ratio of the acid-binding agent to the mercapto-isothiourea hydrochloride compound is 1.4-1.7: 1.
5. The use of a phthalimide compound according to claim 1, wherein: the compound is used for preparing medicaments for resisting cervical cancer Hela and lung cancer A549 cells.
Technical Field
The invention relates to the field of anti-cancer drugs, in particular to a phthalimide compound and a preparation method and application thereof.
Background
Cancer has been one of the major public health problems threatening human health, with millions of reported deaths each year. At present, the anti-tumor drugs are in various types, and particularly, compounds with phthalimide as a parent structure show better anti-cancer activity in previous researches and reports. Many documents report that phthalimide is an important pharmacodynamic fragment. Has wide bioactivity, and can be used in organic synthesis, medicinal chemistry, and material science.
The phthalimide compound has potential application values in multiple aspects of antibiosis, dementia resistance, tumor resistance, anti-inflammation, convulsion resistance, angiogenesis resistance, tuberculosis resistance, microorganism resistance, immunoregulation and the like due to the biological activity. In addition, the disulfide compound has various biological activities, such as antibacterial activity, antifungal activity, antitumor activity, anti-HIV activity and the like, and has good activity. Thus drawing attention in many fields. In recent years, a molecular hybridization method that combines two pharmacophores and produces a single molecule with additional biological properties has been favored by medicinal chemists. These hybrids combine two active molecules in a single molecule in order to create a more medically effective chemical entity than a single component. In this way, synergy and superposition of biological activity of the pharmacophores are achieved. Phthalimide with biological activity becomes an indispensable heterocyclic skeleton in drug development, and the synthesis and biological activity of phthalimide derivatives have attracted much attention.
Among them, compounds containing o-phenylenediamine subunits are described as bioscaffolds (biophoros) for designing novel drug prototypes with different biological activities and for different diseases such as leprosy, aids, tumors, diabetes, multiple myeloma, convulsions, inflammation, pain, bacterial infection, etc. See: reference 1) Siegel RL, Miller KD, JemalA, et al.CA,2016,66: 7-30; document 2) Jemal A, Center MM, DeSantis C, et al, cancer epidemic Biomark Prev,2010,19, 1893-; document 3) Zahran M A H, Abdin Y G, Osman AM A, et al, Archiv der Pharmazie,2014,347(9) 642-; document 4) Fadda a, Soliman NN, baulomy N m.j Heterocyclic Chem,2019,4, 2369; document 5) Sang Z, Wang K, Wang H, et.j.bioor.med.chem.let, 2017,27, 5053-5059; document 6) s.h.l.kok, r.gambari, c.h.chui, et al.bioorg med.chem.2008,16, 3626-; document 7) s.h.chan, k.h.lam, c.h.chui, et al eur.j.med.chem.2009,44, 2736-; document 8) Lima LM, Castro P, machado. al, et. bioorg. med. chem.2002,10, 3067-; literature 9) Bailleux v., valley l., Nuyts jp., et al.j.biomed pharmacother.1994,48, 95-101; document 10) T.Noguchi, H.Fujimoto, H.Sano, et al.Bioorg.Med.chem.Lett.2005,15, 5509-.
In order to find a new anticancer drug, the invention further researches a phthalimide compound. The splicing of disulfide and phthalimide structures is realized through chemical reaction, the number of active groups in organic molecules is increased, and then the proliferation inhibition activity of the compounds on tumor cells is measured by adopting a CCK-8 method, so that the synergy and the superposition of biological activity of the pharmacodynamic groups are realized.
Disclosure of Invention
The invention aims to provide a phthalimide compound, and also provides a preparation method and application of the compound aiming at the technical analysis. The compounds have anticancer activity, and open up a new way for developing new anticancer drugs and enriching clinical drug varieties.
The technical scheme of the invention is as follows:
the phthalimide compound has the following chemical structural formula:
in the structural formula: r1The substituent group can be one of various substituent groups such as alkyl, amino, nitro, halogen atom, methoxy and the like, wherein the halogen atom is fluorine, chlorine, bromine or iodine atom; r2Is C1-6 alkyl, C3-8 cycloalkyl or C5-14 aromatic cyclic group, wherein the aromatic cyclic group may be substituted with 1 to 3 of hydroxy, nitro, halogen atom, cyano, C1-6 alkoxy or C1-6 alkyl group, or with one or two of C1-6 alkyl, C1-6 alkylsulfonyl and C1-6 alkylcarbonyl groupSubstituted with an amino group of (a).
The preparation method of the phthalimide compound takes ethanol and dichloromethane as solvents and is prepared by reacting the phthalimide compound containing sulfydryl with a sulfydryl isothiourea hydrochloride compound in the presence of an acid-binding agent, and comprises the following steps:
1) mixing 5-substituted-2- (4-mercaptophenyl) isoindoline-1, 3-dione, mercaptoisothiourea hydrochloride compound, ethanol and dichloromethane mixed solvent, uniformly stirring, dripping acid-binding agent aqueous solution at 0-5 ℃, and stirring for reaction for 5-6h to obtain reaction liquid;
2) and (3) adding water and dichloromethane into the reaction solution for extraction to obtain an organic phase, then carrying out reduced pressure concentration and cooling to separate out a solid, and carrying out column chromatography to obtain the target product.
The acid-binding agent is sodium bicarbonate, anhydrous sodium acetate, pyridine or piperidine.
The molar ratio of the mercaptoisothiourea hydrochloride compound to the 5-substituted-2- (4-mercaptophenyl) isoindoline-1, 3-diketone is 1-1.1: 1; the dosage ratio of the 5-substituted-2- (4-mercapto phenyl) isoindoline-1, 3-diketone to the solvent is 1mmol:6-8 ml; the molar ratio of the acid-binding agent to the mercapto-isothiourea hydrochloride compound is 1.4-1.7: 1.
The synthetic route of the preparation method is shown as follows:
the phthalimide compound is used for preparing anti-tumor pharmaceutical compositions, including anti-liver cancer, anti-gastric cancer, anti-lung cancer, anti-breast cancer, anti-prostate cancer, anti-ovarian cancer, anti-cervical cancer, anti-pancreatic cancer, anti-rectal cancer, anti-lymph cancer, anti-esophageal cancer, anti-oral cancer, anti-nasopharyngeal cancer or anti-skin cancer pharmaceutical compositions.
The invention has the advantages that: the invention prepares a new phthalimide compound for the first time according to the new drug design theory and method, and the result shows that the compound has the proliferation inhibition activity on the human lung cancer cell A549 and the human cervical carcinoma cell Hela by testing the compound by a CCK-8 method: the compound has stronger anticancer activity, and opens up a new way for developing new anticancer drugs and enriching clinical drug varieties.
Detailed Description
In order to search for an anticancer drug with good curative effect and inhibitory activity on various cancer cells, and combine the knowledge of the anticancer drug, a plurality of compounds are synthesized according to literature reports and years of research work results of the laboratory of the applicant, and an in vitro anticancer activity preliminary screening pharmacological test is carried out on the obtained target compound. The phthalimide compound is found to have stronger anticancer activity and has a prospect of being developed into a new anticancer drug.