CN107602446B - 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound, preparation method thereof, pharmaceutical composition and application thereof - Google Patents
1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound, preparation method thereof, pharmaceutical composition and application thereof Download PDFInfo
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- CN107602446B CN107602446B CN201610545851.3A CN201610545851A CN107602446B CN 107602446 B CN107602446 B CN 107602446B CN 201610545851 A CN201610545851 A CN 201610545851A CN 107602446 B CN107602446 B CN 107602446B
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Abstract
本发明提供了一种通式I所示的1,4‑双取代‑1,2,3,6‑四氢吡啶类化合物、其制备方法、药物组合物及其应用。特别地，本发明所述化合物为一种全新结构的靶向menin‑MLL相互作用界面的小分子抑制剂，所述抑制剂用于多种肿瘤的干扰和治疗，更优选地，所述肿瘤为白血病、肝癌、脑瘤、骨髓瘤、胰腺癌、乳腺癌、结肠癌、前列腺癌、膀胱癌或多发性内分泌腺癌。 The present invention provides a 1,4-disubstituted-1,2,3,6-tetrahydropyridine compound represented by general formula I, a preparation method thereof, a pharmaceutical composition and applications thereof. In particular, the compound of the present invention is a novel small molecule inhibitor targeting the interaction interface of menin-MLL, and the inhibitor is used for the interference and treatment of various tumors. More preferably, the tumor is Leukemia, liver cancer, brain tumor, myeloma, pancreatic cancer, breast cancer, colon cancer, prostate cancer, bladder cancer, or multiple endocrine adenocarcinomas. 
Description
Technical Field
The invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular relates to 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines, a preparation method thereof, a pharmaceutical composition and application thereof. Particularly, the compound is a small molecule inhibitor with a brand-new structure and targeting a menin-MLL interaction interface, and the interaction of the menin and the MLL protein can be considered as a potential effective target for molecular therapy, so that the interaction interface is selectively targeted, and the compound is favorable for research and development of new drugs related to the interaction interface.
Background
The multiple endocrine oncoprotein (menin protein) is encoded by multiple endocrine adenocarcinoma type 1 (MEN1) gene, and MEN1 gene functions as a tumor suppressor gene in endocrine organs. Menin proteins interact with a variety of proteins to form a complex network of interactions. Such as menin, directly interact with the N-terminus of wild-type MLL1 and fused MLL1 proteins and simultaneously bind chromatin-associated protein LEDGF (lens-derived epithelial growth factor). LEDGF eventually brings the complex to the corresponding target gene, activating gene expression.
The MLL gene family includes five members of MLL1-5, and is closely related to the development and worsening of various tumors and metastasis (Grembecka et al, Future medical Chemistry, 2014, 6(4), 447 462). The MLL1 protein is used as an epigenetic regulation enzyme reported at the earliest in the family, mediates methylation modification of histone H3K4, regulates transcription of genes such as HOX and the like, has an important function in the development process of a normal hematopoietic system, and a fusion protein produced by gene ectopy is considered to be a root cause of the onset and the deterioration of MLL leukemia. Grembecka et al report a small-molecule inhibitor MI-2 of a menin-MLL interaction interface for the first time based on deep research on a menin gene and a menin-MLL interaction interface, and subsequently provide a series of structurally optimized inhibitors with stronger activity. This series of inhibitors showed good therapeutic effects in MLL fusion-type leukemia cells and mouse models in the first place (Grembecka et al, Nature Chemical Biology, 2012, 8, 227-284). Furthermore, MLL1 is considered to be closely related to liver cancer and brain tumors. Recent research shows that in liver cancer cells, MLL1-menin participates in regulating and controlling malignant proliferation of liver cancer cells by up-regulating Yap1 gene expression through transcription, and reduction of menin expression effectively inhibits tumorigenicity and malignant proliferation of liver cancer cells on a nude mouse tumorigenic model. The MLL1 protein is vital to maintaining self-renewal, growth and tumorigenicity of brain tumor stem cells by activating transcription of HOXA10 and other genes. MLL alterations cause elevated levels of H3K4me3 and thus high protein expression in GATA4 and EST1 and are believed to be associated with bladder cancer (Song et al, Oncotarget,2016,7(3), 2629-2645). In addition, MLL2 is reported to be up-regulated in pancreatic cancer, breast cancer and colon cancer, the expression of MLL2 gene is reduced, the tumor cell cycle process is inhibited, and apoptosis is induced, so that MLL2 protein is closely related to the occurrence, development and deterioration of tumor.
Research shows that the direct interaction of menin with MLL1 and MLL2 proteins is indispensable for the enzyme activity of complex histone methylation modification (H3K4), the transcriptional regulation of target genes and the corresponding functions thereof (Yali et al, Nature Structure & Molecular Biology, 2006, 13, 713-719). Given that MLL1 and MLL2 proteins are necessary for various tumor malignant proliferations, and MLL proteins alone have no enzyme activity, we speculate that the function of promoting tumor malignant proliferation is probably completed in a large epigenetic regulation complex. Indeed, the function of wild-type MLL has also been shown to be dependent on its interaction with menin protein in prostate and breast cancer at present. In Castration-resistant prostate cancer, an MLL epigenetic regulatory complex is identified as a cofactor for the AR androgen receptor, and a menin-MLL inhibitor can effectively inhibit the signaling pathway downstream of AR by disrupting the function of the MLL complex, inhibiting the growth of prostate cancer in nude mouse models (Malik et al, NatureMedicine, 2015, 21(4), 344-352). In breast cancer, functionally-acquired mutants of TP53 contribute to genome-wide abnormalities in histone methylation and acetylation modification by transcriptionally upregulating expression of epigenetically regulated methyltransferases MLL1, MLL2, the acetyltransferase MOZ (Zhu et al, Nature, 2015, 525, 206-211). In the tumor, an inhibitor MI2-2 targeting menin-MLL destroys an MLL1 methyltransferase complex to inhibit the enzyme activity of the MLL1 methyltransferase complex, and obviously inhibits the tumor growth of tumor cells on a nude mouse tumor forming model.
In addition, menin, a nuclear protein expressed in a tissue broad spectrum, participates in the formation of various important transcription regulation complexes, and shows various important biological functions in the body. In addition to participating in the formation of MLL1, MLL2 epigenetic regulatory complexes, the menin protein has been reported to interact with a variety of transcription factors, including JunD, NFKB, SMAD3, to regulate the transcriptional activation or repression of target genes (Agarwal et al, Cell, 1999, 96(1), 143-. Menin is involved in cell division proliferation and cell cycle regulation by interacting with ASK (activator of S-phasekinase) (Schnepp et al, Cancer Research, 2004, 64(18), 6791-6796); menin affects the stability of the genome through the interaction of the DNA damage repair protein FANCD2 (Jin et al Cancer Research, 2003, 63(14), 4204-4210). Menin interaction with BMP-2 signaling pathway proteins and Runx2 is thought to be involved in skeletal development (Katalin et al, TRENDS in Endocrinology and Metabolism,2006,17(9), 357-. Interestingly, structural studies have shown that the larger central pocket possessed by the menin protein is the major interface mediating interactions with other proteins. The results of crystal structure analysis of the single crystals of menin protein, the co-crystals of menin-MLL complex, and the co-crystals of menin-JunD show that the binding of menin to MLL and JunD proteins is consistent with the pocket structure of menin at the binding interface, and is the same as the pocket structure of menin protein alone. From this, we conclude that this pocket mediates not only the interaction between menin and MLL1 and MLL2 proteins but also the interaction between it and other proteins such as JunD. Therefore, small molecule inhibition targeting Menin-MLL or different types of structural derivatives thereof will likely selectively destroy the interaction of Menin with other different types of transcription factors by competitively occupying the Menin pocket, regulating the corresponding transcription events and related biological functions, thereby further expanding the application range of the Menin-MLL inhibitor.
Therefore, the interaction of the menin and the MLL fusion protein can be considered as a potential effective molecular therapy target, and the menin-MLL inhibitor has a wide application prospect, selectively targets the action interface, and is beneficial to the research and development of new drugs related to the action interface.
Disclosure of Invention
The invention relates to a1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound with a brand-new structure and shown in a general formula I, and a preparation method thereof, and activity evaluation and related biological experiments are combined to confirm that the compound can effectively target a menin-MLL interaction interface and can be used for treating diseases related to the interaction of menin-MLL protein and developing new drugs.
The invention aims to provide 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compounds shown in a general formula I or pharmaceutically acceptable salts thereof.
The invention also aims to provide a preparation method of the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound shown in the general formula I.
The invention also aims to provide application of the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound shown in the general formula I or pharmaceutically acceptable salts thereof in preparing medicines used as small molecule inhibitors targeting the menin-MLL protein interaction interface, and the application can be used for interference and treatment of various tumors related to the menin-MLL interaction interface. The tumor is leukemia, liver cancer, brain tumor, myeloma, pancreatic cancer, breast cancer, colon cancer, prostatic cancer, bladder cancer or multiple endocrine adenocarcinoma.
According to one aspect of the present invention, there is provided a compound represented by the general formula I:
wherein n is an integer of 1 to 4, preferably 1,2,3 or 4;
R1、R2the same or different and each independently is: hydrogen atom, hydroxy group, halogen, C1-C10Straight or branched alkyl, C1-C10Linear or branched alkoxy, C2-C10Straight-chain or branched alkenyl, C3-C10Cycloalkyl radical, C1-C6Alkylcarbonyl group, C1-C6Alkoxycarbonyl, aminocarbonyl C1-C6Alkyl radical, C1-C6Alkylamido or C5-C20Aryl of (a); more preferably: hydrogen atom, hydroxy group, halogen, C1-C6Straight or branched alkyl, C1-C6Linear or branched alkoxy, C2-C6Straight-chain or branched alkenyl, C3-C8Cycloalkyl radical, C1-C6Alkylcarbonyl group, C1-C6Alkoxycarbonyl, aminocarbonyl C1-C3Alkyl radical, C1-C3Alkylamido or C5-C10Aryl of (a); more preferably H, Br, Cl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, ethenyl, propenyl, butenyl, pentenyl, hexenyl, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexylalkyl, cycloheptyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, t-butylcarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, or methylamide, ethylamido, aminocarbonylmethyl, aminocarbonylethyl, phenyl or naphthyl;
R3and R4The same or different and each independently is: hydrogen atom, C1-C10Straight or branched alkyl, C2-C10Straight-chain or branched alkenyl, C3-C10Cycloalkyl, substituted or unsubstituted C5-C20Aryl, or substituted or unsubstituted five-or six-membered heteroaryl, wherein C is substituted5-C20The substituents in the aryl or substituted five-or six-membered heteroaryl group are selected from halogen, hydroxy, amino, substituted by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Aryl carbonyl, trifluoromethyl, sulfoAcyl radical, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Linear or branched alkoxycarbonyl, C1-C6Straight or branched alkyl, or C1-C6One or more of linear or branched alkoxy groups; preferably a hydrogen atom, C1-C6Straight or branched alkyl, C2-C6Straight-chain or branched alkenyl, C3-C8Cycloalkyl, substituted or unsubstituted C5-C12Aryl, or substituted or unsubstituted five-or six-membered heteroaryl, wherein C is substituted5-C12The substituents in the aryl or substituted five-or six-membered heteroaryl group are selected from halogen, hydroxy, amino, substituted by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, trifluoromethyl, sulfonyl, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Linear or branched alkoxycarbonyl, C1-C6Straight or branched alkyl, or C1-C6One or more of linear or branched alkoxy groups; further preferred is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, ethenyl, propenyl, butenyl, pentenyl, hexenyl, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexyl, cycloheptyl, substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl, wherein the substituents in said substituted phenyl or substituted pyridyl are selected from halogen, hydroxy, amino, trifluoromethyl, substituted with one or two C' s1-C6Linear or branched alkyl-substituted ammoniaBase, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Linear or branched alkoxycarbonyl, C1-C6Straight or branched alkyl, or C1-C6One or more of linear or branched alkoxy groups;
R5is substituted or unsubstituted C5-C12An aryl group, a substituted or unsubstituted five-or six-membered heteroaryl group, a substituted or unsubstituted benzo five-or six-membered heteroaryl group, or a substituted or unsubstituted dibenzothienyl group, wherein the substituted C is5-C12The substituent of aryl, substituted five-membered or six-membered heteroaryl, substituted benzo five-membered or six-membered heteroaryl or substituted dibenzothienyl is selected from halogen, hydroxyl, amino, substituted by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, trifluoromethyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Linear or branched alkoxycarbonyl, aminosulfonyl, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylsulfonamido, amino C1-C6Straight or branched alkyl, halogen-substituted phenylsulphonamide, halogen-substituted phenyl, C1-C6Straight or branched alkyl, or C1-C6One or more of linear or branched alkoxy groups; preferably, R5Is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstitutedUnsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl or substituted or unsubstituted oxazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzothiazolyl, or substituted or unsubstituted dibenzothienyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, amino, substituted or two C, or C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, trifluoromethyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Linear or branched alkoxycarbonyl, aminosulfonyl, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylsulfonamido, amino C1-C6Straight or branched alkyl, halogen-substituted phenylsulphonamide, halogen-substituted phenyl, C1-C6Straight or branched alkyl, or C1-C6One or more of linear or branched alkoxy groups; most preferably, R5Is unsubstituted or selected from halogen, trifluoromethyl, C1-C6Alkoxy, amino, by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6A linear or branched alkoxycarbonyl group,Amino group C1-C6Alkyl, halophenyl, halophenylsulphonamido, aminosulphonyl or C1-C6A phenyl group substituted with at least one substituent in the alkylsulfonamide group; unsubstituted or substituted by halogen, trifluoromethyl, C1-C6Alkoxy, amino, by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Straight or branched alkoxycarbonyl, amino C1-C6Alkyl, halophenyl, halophenylsulphonamido or C1-C6Pyridyl substituted with at least one substituent in the alkylsulfonamide group; unsubstituted or substituted by halogen, trifluoromethyl, C1-C6Alkoxy, amino, by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Straight or branched alkoxycarbonyl, amino C1-C6Alkyl, halophenyl, halophenylsulphonamido or C1-C6An indolyl group substituted with at least one substituent group of the alkylsulfonamide group; unsubstituted or substituted by halogen, trifluoromethyl, C1-C6Alkoxy, amino, by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Straight or branched alkoxycarbonyl, amino C1-C6Alkyl, halophenyl, halophenylsulphonamido or C1-C6A quinolyl group substituted with at least one substituent group of the alkylsulfonamide group; unsubstituted or substituted by halogen, trifluoromethyl, C1-C6Alkoxy, amino, by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Straight or branched alkoxycarbonyl, amino C1-C6Alkyl, halophenyl, halophenylsulphonamido or C1-C6A thioindenyl group substituted with at least one substituent of the alkylsulfonamide group.
Preferably, R3And R4Is a substituted or unsubstituted phenyl group, the substituents in said substituted phenyl group being selected from halogen, hydroxy, amino, substituted by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, trifluoromethyl, sulfonyl, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Linear or branched alkoxycarbonyl, C1-C6Straight or branched alkyl, or C1-C6One or more of linear or branched alkoxy groups.
Further preferably, the compounds of the present invention have a structure represented by formula II:
wherein R is1、R4And R5The definition is as described above in the above,
R6is hydrogen atom, halogen, C1-C6Alkyl, trifluoromethyl, hydroxy, amino, by one or two C1-C6Straight or branched alkyl-substituted amino, C1-C6Acyl-substituted amino, sulfonylamino, C1-C6Straight-chain or branched alkylsulfonylamino group, C5-C12Arylcarbonyl, sulfonyl, C1-C6Straight-chain or branched alkylsulfonyl, C1-C6Straight or branched alkylcarbonyl, C1-C6Straight-chain or branched alkyl carbonyl oxygen, C1-C6Straight or branched alkoxycarbonyl, or C1-C6Linear or branched alkoxy.
In the present invention, terms are defined as follows, unless otherwise indicated:
halogen represents fluorine, chlorine, bromine or iodine;
the five-or six-membered heteroaryl group represents a five-or six-membered aryl group having at least one heteroatom selected from N, O or S in the ring, and examples thereof include, but are not limited to, thienyl, furyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl or oxazolyl;
the benzo five-or six-membered heteroaromatic ring group means a ring formed by fusing benzene with a five-or six-membered aromatic group having at least one heteroatom selected from N, O or S in the ring, and examples thereof include, but are not limited to, indazolyl, indolyl, quinolyl, naphthyl, isoquinolyl, benzofuranyl, benzothienyl, or benzothiazolyl.
More specifically, the compound represented by the general formula I may be any one of the following compounds:
TABLE 1
The pharmaceutically acceptable salts of the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compounds comprise: salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, and the like; and salts with organic acids such as maleates, methanesulfonates, p-toluenesulfonates, trifluoroacetates, acetates, tartrates, malonates, and the like.
According to another aspect of the present invention, there is provided a method for preparing a1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound, comprising the steps of:
wherein, n, R1、R2、R3、R4And R5The definition of (a) is the same as above,
a) carrying out substitution reaction on the compound 1 and the compound 2 to obtain a compound 3;
b) carrying out reduction reaction on the compound 3 to obtain a compound 4;
c) substitution of compound 4 on the amino N atom gives compound 5, including N-methylation, acetylation, methylformate, alkylation and arylation.
Preferably, the reaction condition of the step a) is that under the action of alkali, the bromide 1 and the 4-aryl-1, 2,3, 6-tetrahydropyridine compound 2 are subjected to substitution reaction; the alkali is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, preferably sodium carbonate, the used solvent is acetonitrile, 1, 4-dioxane, tetrahydrofuran, 2-methyl-tetrahydrofuran, toluene and the like, preferably acetonitrile, the reaction temperature is the reflux temperature of the used solvent, preferably the reflux temperature of the acetonitrile is 80 ℃, and the reaction time is 3-8 hours, preferably 4 hours;
the reaction condition of the step b) is that under the action of a reducing agent, cyano is reduced to amino, the reducing agent is lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), borane and borane/dimethyl sulfide compound, the additive is anhydrous aluminum trichloride, preferably lithium aluminum hydride-anhydrous aluminum trichloride combination (molar ratio is 1:1), the solvent comprises diethyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1, 4-dioxane and the like, preferably tetrahydrofuran;
the reaction conditions for step c) are determined by the particular reaction and are generally well known in the art. According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
According to another aspect of the invention, the invention provides a use of the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines shown in the general formula I or pharmaceutically acceptable salts thereof in preparing a medicament serving as a small molecule inhibitor targeting a menin-MLL protein interaction interface. The inhibitor can be used for the interference and treatment of various tumors, such as leukemia, liver cancer, brain tumor, myeloma, pancreatic cancer, breast cancer, colon cancer, prostatic cancer, bladder cancer or multiple endocrine adenocarcinoma.
According to a further aspect of the present invention, there is provided a method for treating a tumor, which comprises administering to a patient an effective amount of a1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound according to the present invention or a pharmaceutically acceptable salt thereof.
The invention has the beneficial effects that: the invention provides a series of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compounds with brand-new structures and a preparation method thereof, wherein the compounds effectively act on a menin-MLL mutual interface and can be used for developing new drugs of small molecule inhibitors targeting the menin-MLL protein mutual interface. The series of compounds can be synthesized by a conventional method, and the activity of the series of compounds is obvious through test evaluation at a molecular level and a cell level.
Drawings
FIG. 1 shows that protein thermomigration experiment confirms compound D28A graph of binding to menin protein;
FIG. 2 shows that the surface plasmon resonance experiment confirms compound D28A graph of binding to menin protein;
FIG. 3 shows that the competitive NMR saturation transfer difference spectrum experiment confirms compound D28A graph of binding to menin protein;
FIG. 4 shows that the co-immunoprecipitation experiment confirms compound D28A map of disruption of the interaction of menin protein with MLL protein at the cellular level;
FIG. 5 is Compound D28And D37Schematic representation of binding pattern analysis with menin protein;
FIG. 6 shows Compound D28A graph of selective inhibition of proliferation of MLL fused leukemia cells;
FIG. 7 is Compound D28Subjecting leukemia cells MV 4; 11 block at stage G0/G1;
FIG. 8 is Compound D28Inducing leukemia cells MV 4; 11 map of differentiation;
FIG. 9 is Compound D28Graph of induction of leukemia cell KOPN-8 differentiation;
FIG. 10 is Compound D28A graph of downregulating expression of HOXA9, HOXA10, MEIS1 and DLX2 genes in leukemia cells.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Example 1: representative compounds of the 4-aryl-2 ', 2' -diaryl (alk) yl-1-tetrahydropyridinamines derivatives of the invention are prepared as follows: compound D1Synthesis of (2)
1) Adding raw material A into a reaction bottle1-20(257mg,0.86mmol, commercially available from carbofuran technologies, Ltd.), Compound B1(174mg,0.9mmol, commercially available from Energy Chemical), sodium carbonate (339mg,3.2mmol), acetonitrile (15mL), reacted at 80 ℃ for 4 hours, extracted with ethyl acetate after completion of the reaction, dried and concentrated in the organic layer, and chromatographed to give Compound C1(283mg，80％)。
2) An anhydrous reaction flask was charged with a THF solution of lithium aluminum hydride (2.4M,2.76mL), a THF solution of aluminum trichloride (153mg) (10mL) was slowly added dropwise at 0 deg.C, followed by addition of Compound C1THF solution (95mg,0.23mmol) is transferred to room temperature for reaction for 1 hour, then reflux heating is carried out for 7 hours, water is added for quenching after cooling to room temperature, ether and saturated potassium sodium tartrate solution are used for extraction, organic layer is dried and concentrated for column chromatography to obtain compound D1(43mg,45％)。
Spectral data:1H NMR(300MHz,CDCl3)δ7.32-7.18(m,14H),6.00(s,1H),3.35(s,2H),3.11-3.03(m,2H),2.61(t,J＝5.4Hz,2H),2.53-2.38(m,4H),2.23-2.14(m,2H)；13C NMR(125MHz,CDCl3) δ 146.3,139.2,133.9,132.6,128.4,128.2,128.2,126.2,122.3,53.9,53.4,50.9,50.6,49.1,33.5, 28.1; HRMS (EI) calculation C27H29ClN2[M]+416.2019, measurement 416.2025.
Example 2: compound D2-D20The preparation of the compound has the following general formula
Preparation is analogous to example 1, but starting from B2-B20(substituted phenyl boric acid and 3, 6-dihydro-4- [ [ (trifluoromethyl) sulfonyl group)]Oxy radical]-1(2H) -Picolinic acid tert-butyl ester was prepared by Suzuki coupling, commercially available from Profenox scientific LimitedSi) to obtain the target compound D2-D20Specifically, as shown in the following table, table 2:
example 3: compound D21-D27The preparation of the compound has the following general formula
The preparation is analogous to example 2, but starting from A21-A27To obtain the target compound D21-D27Specifically, as shown in the following table, table 3:
example 4: compound D28Synthesis of (2)
Adding the compound A into a reaction flask28(397mg), Compound B1(229mg), sodium carbonate (318mg) acetonitrile (5mL), and extraction with ethyl acetate after completion of the reaction at 80 ℃ for 4 hoursTaking, drying, concentrating and column-chromatographing an organic layer to obtain a compound C28(301mg，72％)。1H NMR(300MHz,CDCl3)δ7.43-7.33(m,9H),6.00(s,1H),3.45(t,J＝6.3Hz,2H),3.00(s,2H),2.59-2.50(m,2H),2.41-2.29(m,4H),2.06-1.93(m,4H),1.83-1.71(m,3H),1.51-1.35(m,4H).
An anhydrous reaction flask was charged with a THF solution of lithium aluminum hydride (2.4M,0.15mL), a THF solution of aluminum trichloride (49mg) (5mL) was slowly added dropwise at 0 deg.C, followed by addition of Compound C28THF solution (52mg) (5mL) was added to room temperature and reacted for 1 hour, then refluxed and heated for 7 hours, cooled to room temperature and quenched with water, extracted with ether and saturated sodium potassium tartrate solution, the organic layer was dried and concentrated and column chromatographed to give compound D28(22mg,42％)。
Spectral data:1H NMR(300MHz,CDCl3)δ7.40-7.20(m,9H),6.02(s,1H),3.60-3.44(m,2H),3.20-3.00(m,2H),2.90-2.60(m,8H),2.56-2.28(m,4H),1.93-1.75(m,2H),1.68-1.40(m,4H),1.16-0.90(m,3H)；13C NMR(125MHz,CDCl3)δ141.9,138.8,133.5,132.2,127.9,127.7,127.4,125.7,125.2,121.9,61.9,58.7,53.6,49.9,46.5,46.2,42.9,32.3,31.2,27.6,26.6,25.9,23.9,22.5,21.3；HRMS(EI)calcd.for C27H35ClN2[M]+,422.2489.Found,422.2487.
example 5: compound D29-D41The preparation of the compound has the following general formula
The preparation is analogous to example 2, but starting from A29-A35Or B3，B7，B15-B17And B36To obtain the target compound D29-D39Specifically, as shown in the following table, table 4:
example 6: compound D42Synthesis of (2)
The reaction flask is filled with compound D28(70mg) was dissolved in acetonitrile (5mL), followed by addition of formaldehyde solution (37%, 26mg), sodium cyanoborohydride (32mg), 1 drop of acetic acid, stirring at room temperature for 40 minutes, extraction with ethyl acetate and saturated sodium bicarbonate solution, drying of the organic layer, concentration of the organic layer, and column chromatography to give Compound D42(75mg, 86%). Spectral data:1H NMR(300MHz,CDCl3)δ7.43-7.15(m,9H),6.06(s,1H),3.26(s,2H),2.88-2.72(m,4H),2.65-2.47(m,4H),2.32-2.12(m,8H),1.74-1.56(m,2H),1.49-1.31(m,5H),1.17-1.03(m,2H)；13C NMR(125MHz,CDCl3)δ138.9,134.2,132.8,128.5,128.0,127.6,126.2,125.8,65.3,53.7,53.3,50.4,48.1,46.4,31.5,27.8,27.4,27.0,24.7,24.5；HRMS(EI)calcd.forC28H37ClN2[M]+,436.2645.Found,436.2649.
example 7: compound D43Synthesis of (2)
After sodium hydrogen (20mg) was added to the reaction flask and dissolved in DMF (2mL), the mixture was stirred at room temperature for 30 minutes, and Compound D was added28(70mg), adding one equivalent of methyl iodide, stirring at room temperature for 1h, extracting with ethyl acetate and saturated sodium bicarbonate solution, drying the organic layer, concentrating, and performing column chromatography to obtain compound D43(75mg, 41%). Spectral data:1H NMR(300MHz,CDCl3)δ7.26-7.13(m,9H),6.02(s,1H),3.31(m,2H),2.88(m,4H),2.45(m,4H),2.26-2.12(m,7H),1.67-1.58(m,2H),1.31(m,3H),1.17-1.02(m,2H)；HRMS(EI)calcd.for C27H35ClN2[M]+,422.2489.Found,422.2482.
example 8: compound D44Synthesis of (2)
The reaction flask is filled with compound D28(82mg) was dissolved in dioxane (5mL), acetic anhydride (106mg) and 4-dimethylaminopyridine DMAP (3.2mg) were added thereto, the mixture was stirred at room temperature for 4 hours, and then extracted with ethyl acetate and a saturated sodium bicarbonate solution, and the organic layer was dried and concentrated by column chromatography to obtain Compound D43(116mg,77％)。
Spectral data:1H NMR(300MHz,CDCl3)δ7.48-7.20(m,9H),6.11(s,1H),3.32(s,2H),2.77-2.65(m,4H),2.56-2.41(m,4H),2.34(s,3H),2.29-2.12(m,8H),1.78-1.62(m,2H),1.51-1.35(m,5H),1.21-1.08(m,2H)；HRMS(EI)calcd.for C28H35ClN2O[M]+,436.2645.Found,436.2649.
example 9: compound D45Synthesis of (2)
The reaction flask is filled with compound D28(81mg) was dissolved in methylene chloride (5mL), triethylamine and methyl chloroformate (38mg) were added, the mixture was stirred at room temperature for 2 hours, and then extracted with ethyl acetate and a saturated sodium bicarbonate solution, and the organic layer was dried and concentrated to give compound D after column chromatography45(52mg, 34%). Spectral data:1H NMR(300MHz,CDCl3)δ7.81-7.22(m,9H),6.06(s,1H),3.78(s,3H),3.61(s,2H),3.21(s,2H),2.88-2.59(m,4H),2.57(m,4H),2.43(m,7H),1.99-1.62(m,2H),1.23(m,5H),1.18-1.06(m,2H)；HRMS(EI)calcd.For C28H35ClN2O2[M]+,466.2387.Found,466.2388.
example 10: compound D46Synthesis of (2)
The reaction flask is filled with compound D28(81mg) was dissolved in methylene chloride (5mL), chloroacetamide (38mg) was added, 1M KOH (2mL) solution was added and the mixture was stirred at room temperature for 2 to 3 hours, followed by extraction with ethyl acetate and saturated sodium bicarbonate solution, and the organic layer was dried and concentrated to give compound D after column chromatography44(52mg, 56%). Spectral data:1H NMR(300MHz,CDCl3)δ7.93-7.18(m,9H),6.08(s,1H),3.61(s,2H),3.21(s,2H),2.97-2.68(m,4H),2.56-2.45(m,4H),2.41-2.33(m,8H),1.99-1.62(m,2H),1.59-1.23(m,5H),1.18-1.06(m,2H)；HRMS(EI)calcd.For C28H36ClN3O[M]+,465.2547.Found,465.2542.
example 11: compound D47Synthesis of (2)
The reaction flask is filled with compound D28(1mmol), dissolving in DMSO (5mL), adding cuprous iodide 10%, L-proline 20%, potassium carbonate 1.5 eq, iodobenzene 1.2 eq, reacting at 80 deg.C overnight, extracting with ethyl acetate and saturated sodium bicarbonate solution, drying organic layer, concentrating, and performing column chromatography to obtain compound D47(37%). Spectral data:1H NMR(300MHz,CDCl3)δ7.44(s,5H),7.38(m,6H),7.31–7.07(m,8H),7.07–7.02(m,1H),6.69(s,1H),6.58(s,4H),6.45(s,2H),6.08(s,1H),3.61(s,2H),3.21(s,2H),2.97-2.68(m,4H),2.56-2.45(m,4H),2.41-2.33(m,8H),1.99-1.62(m,2H),1.59-1.23(m,5H),1.18-1.06(m,2H)；HRMS(EI)calcd.For C32H37ClN2[M]+,484.2645.Found,484.2641.
example 12: compound D48Synthesis of (2)
Adding the compound A into a reaction flask48(380mg), Compound (I)Object B1(229mg), sodium carbonate (320mg) and acetonitrile (5mL) at 80 deg.C for 4 hours, extracting with ethyl acetate after the reaction is completed, drying the organic layer, concentrating and column-chromatographing to obtain compound C48。
An anhydrous reaction flask was charged with a THF solution of lithium aluminum hydride (2.4M,0.15mL), a THF solution of aluminum trichloride (49mg) (5mL) was slowly added dropwise at 0 deg.C, followed by addition of Compound C48THF solution (52mg) (5mL) was added to room temperature and reacted for 1 hour, then refluxed and heated for 7 hours, cooled to room temperature and quenched with water, extracted with ether and saturated sodium potassium tartrate solution, the organic layer was dried and concentrated and column chromatographed to give compound D48(22mg,27％)。
Product spectral data:1H NMR(400MHz,CDCl3)δ8.41(m,4H),7.44(m,5H),7.17(d,J＝20.0Hz,5H),6.17(s,1H),3.53(s,2H),3.24–2.60(m,7H),2.58(s,1H),2.55(s,1H),2.44(d,J＝10.5Hz,6H),2.16–1.81(m,11H),1.69(dd,J＝34.9,20.0Hz,12H)；HRMS(EI)calcd.for C25H32ClN3[M]+,409.2285.Found,409.2282.
example 13: fluorescence Polarization assay (FP) for determining the Activity of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines
In fluorescence polarization experiments, we used 600nM menin protein and 30nM fluorescein isothiocyanate labeled MBM1 polypeptide (FITC-MBM1, Qiang Biotech, Suzhou) mixed in FP buffer, while adding the indicated final concentration of compound, and incubated at 4 ℃ in the dark for 2 h. The same volume of DMSO, unlabeled MBM1 polypeptide was used as negative and positive controls, respectively. The fluorescence intensity and fluorescence polarization value of each sample well after incubation were measured using an Envision multi-label microplate detector from PerkinElmer corporation to determine the inhibition rate of the compound, IC50Values and Ki values were obtained by fitting fluorescence polarization values with GraphPad Prism 5.0 software.
The activity of the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines was determined by the FP assay. NA-inactive, IC50<As indicated by the 10 μ M plus bold,
TABLE 5
Example 14: protein heat migration experiments prove that the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compounds are directly combined with menin protein
Protein thermomigration experiments were performed in a 20 μ l reaction system, 2.5 μ M menin protein was mixed with compound, 5 × SYPROOrange dye (Invitrogen) in buffer and then heated from 25 ℃ to 95 ℃ on a Quant Studio6Flex real-time PCR instrument (ABI) with a slope of 1 ℃/min. To reduce evaporation, the wells were sealed with a heat sealable film (Thermo scientific)). All samples contained three replicates. Fluorescence intensity was recorded and the Tm value of the menin protein was fitted with protein thermomigration Software ProteinThermal Shift Software Version 1.1 (ABI). The change in Tm value of menin protein in the compound group was calculated using DMSO group as a control. The results are shown in Table 6, wherein the concentration of the compound is 20. mu.M.
TABLE 6 protein thermomigration experiments to confirm the binding of various compounds to menin proteins
The results show that a plurality of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines can increase the melting temperature of the menin protein at the concentration of 20 mu M, and show that the compounds can be directly combined with the menin protein to make the protein more stable. FIG. 1 shows Compound D28The concentration-dependent increase in the melting temperature of the menin protein.
Example 15: surface Plasmon Resonance (SPR) experiments confirmed that Compound D28Binding to menin protein
SPR experiments were performed on a Biacore T200 instrument at 25 ℃ ((R))GE Healthcare). The Menin proteins were covalently coupled to CM5 chips with sodium acetate. HBS-EP for Compounds+The buffer was diluted in a series of concentrations and subjected to kinetic experiments. Equilibrium dissociation constant K of compound and menin proteinDValues were calculated by Biacore T200 data analysis software. As shown in FIG. 2, Compound D is shown28Can be directly combined with menin protein, and has equilibrium dissociation constant KD＝3.07μM。
Example 16: competitive saturation transfer difference Spectroscopy (STD) nuclear magnetic resonance experiments prove that the compound D28The region combined with the menin protein is MBM1 peptide fragment combination pocket
To illustrate that the binding region of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines to menin protein is indeed the binding pocket of the peptide MBM1 in menin, we used the saturation transfer difference Spectroscopy (STD) nuclear magnetic resonance assay to determine representative compound D28Competitive relationship with MBM 1. At a concentration of 5. mu.M, D containing menin protein28Different concentrations of MBM1 were added to 200. mu.M (5% DMSO-D6) in each case to compete for binding of the compound to the menin protein. The experiments were performed on a Bruker Avance III-600MHz NMR spectrometer at 25 ℃. As shown in FIG. 3, the menin protein is mixed with Compound D28Mixing, and collecting STD spectrogram to obtain compound peak with high signal value. With the addition of the competitive polypeptide MBM1, the peak value of the compound gradually decreases and shows a concentration-dependent relationship. Indicating that the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines compete with the MBM1 polypeptide for binding to the same pocket of the menin protein.
Example 17: co-immunoprecipitation experiments proved that Compound D28Disruption of the interaction between the menin protein and the MLL protein at the intracellular level
Will construct successfully expressed Flag-MLLNThe plasmids were transfected into 293T cells with PEI reagent (sigma), and the cells were treated 48h after transfection with a concentration of compound or an equal volume of DMSO. After 12h of administration, the cells were lysed (Cell Signaling technology), incubated with ANTI-FLAG M-2 (magnetic beads) at 4 ℃ for 2h, and enriched in FLAG-MLLNA protein. Washing the enriched sample with phosphate buffer solution to remove impure protein, and performing SDS-PAGE gel electrophoresisSeparating and immunoblotting to detect menin protein and Flag-MLLNA protein. The amount of menin protein obtained by co-immunoprecipitation was compared between the samples of the DMSO-treated group and the samples of the compound-treated group. If the compound is able to disrupt the interaction between the menin protein and the MLL protein, the amount of the menin protein will be less than in the DMSO group. As shown in FIG. 4, Compound D28The amount of the menin proteins immunoprecipitated at 40. mu.M and 20. mu.M in the treated cells was significantly less than that in the DMSO-treated group, and was also slightly decreased at 10. mu.M. Illustrative Compound D28It was indeed possible to disrupt the interaction between the menin protein and the MLL protein at the cellular level.
To this end, with a compound D28For representation, the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compounds are proved to be capable of destroying the interaction between menin and MLL protein in an in vitro experiment and an intracellular level and can be used as small molecule inhibitors of the menin-MLL interaction interface through a fluorescence polarization experiment, a protein thermal migration experiment, a surface plasmon resonance experiment, a competitive saturation difference spectrum nuclear magnetic resonance experiment and a co-immunoprecipitation experiment.
Example 18: binding pattern analysis of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines with menin proteins
To better understand the detailed information on the interaction of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridines with the menin protein pocket, the present inventors selected representative compound D among them using GLIDE software28And D37The binding pattern of the protein was analyzed by molecular docking with the menin protein. The results of the analysis (FIG. 5) show that Compound D28And D37The F9(MLL protein amino acid phenylalanine at position 9) and P10(MLL protein amino acid proline at position 10) regions both occupying the binding pocket of menin and MBM1, well simulate the binding mode of MBM1 and menin protein. In addition, Compound D37The tail sulfonamide group may have hydrogen bond and hydrophobic interaction with the pocket formed by the menin M322, E326, W341, E363, and thus compare to D28Compound D37Shows better inhibitory activity in fluorescence polarization experiments.
Example 19: cell survival experiment determination of proliferation inhibition effect of 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compound on MLL fusion type leukemia cells
The inventor selects a mature MLL fusion type leukemia cell model to test the cell level function of the 1, 4-disubstituted-1, 2,3, 6-tetrahydropyridine compounds.
Selecting a leukemia cell strain MV4 with MLL fusion protein; 11(MLL-AF4), KOPN-8(MLL-ENL), and HL60 and Jurkat cells of a non-MLL fusion type, cells were treated with a plurality of key compounds and examined for inhibition of cell proliferation. The cells are all at 1 × 105mL-1The cells were incubated in 96-well transparent plates, treated with compound or the same volume of DMSO, and after 7 days of treatment, AlamarBlue was added for incubation, and the fluorescence intensity of each well was measured using the PHERAstar BMG multi-well microplate detector, indicating cell viability. Half proliferation inhibitory concentration GI50Values were determined by GraphPad Prism 5.0 software fitting. The results show that Compound D28Selectively inhibiting MLL fusion type leukemia cell MV 4; proliferation, specific inhibition and GI of 11 and KOPN-850See figure 6 and table 7 for values. In addition, a number of compounds are also disclosed at MV 4; 11 cells showed a better proliferation inhibitory effect, see table 7.
Table 7 cell viability experiments demonstrated that various compounds inhibited MLL fused leukemia cell MV 4; proliferation of 11
| Compound | GI50(μM) |
| D28 | 1.89 |
| D31 | 3.34 |
| D32 | 3.14 |
| D37 | 2.96 |
| D42 | 6.39 |
Example 20: cell cycle assay confirmation of Compound D28The cell cycle of the MLL fusion leukemia is blocked at the stage of G0/G1
For cell cycle experiments, 2X 105Perwell cell plates were plated in 12-well plates and treated with the corresponding concentrations of compound or 0.2% DMSO for 48 h. Centrifugation at 800g at 4 ℃ to collect 5X 104The cells were resuspended in 300. mu.l of precooled PBS, and 700. mu.l of precooled absolute ethanol was added dropwise with shaking and fixed overnight at 4 ℃. Then, ethanol was removed by centrifugation, washed with PBS, and finally resuspended by adding 300. mu. lPI/RNase solution (BD, cat # 550825), incubated at room temperature in the dark for 15min, and then detected on a flow cytometer. The results are shown in FIG. 7, comparing the cell samples from the DMSO-treated group with Compound D28At 15 μ M, the percentage of the cell population in the G0/G1 phase increased, while the percentage of the cell population in the S and G2 phases decreased. Thus, Compound D28The MLL fusion type leukemia cells are blocked at the G0/G1 stage, so that the proliferation of the cells is inhibited.
Example 21: flow detection CD11b and Giemsa reyi staining experiment confirm compound D28Induction of MLL fusion type leukemia cell differentiation
3×105Hole MV 4; 11 or KOPN-8 cells were plated in 12-well plates and treated with the corresponding concentration of compound or 0.2% DMSO for 7 or 10 days. To detect the cell surface differentiation marker CD11b, the cells were harvested 7 days after drug treatment, the medium was washed out with 1% BSA in PBS and the cells were resuspended. PE mouse anti-human CD11b Ab (BDPhamingen) was added, and the mixture was incubated at 4 ℃ for 30min in the absence of light for flow detection. To pairIn Giemsa reyi staining experiments, 10 days after drug treatment, cells were centrifuged onto slides using a Cytospin Shandon 3(Thermo Scientific Cytospin). After drying, the cell smears were stained with Giemsa Richardson stain (Baso).
FIG. 8 shows that Compound D28Processing the MV 4; after 11 cells, the proportion of cells positive to a cell surface differentiation marker CD11b is increased, and the Reishi Giemsa staining picture shows that the nuclear-cytoplasmic ratio of the cells can be reduced by drug treatment, and the change effect shows the concentration dependence of the drug. FIG. 9 shows Compound D28It also has differentiation inducing effect on KOPN-8 cells. Thus, this example illustrates Compound D28Can inhibit the proliferation of cells by inducing the differentiation of MLL fusion type leukemia cells.
Example 22: real-time quantitative PCR experiment confirms compound D28HOX gene group and genes MEIS1 and DLX2 capable of down-regulating high expression in MLL fusion type leukemia cells
Selecting MV 4; 11 cells, treated with the corresponding concentration of compound or 0.2% DMSO, were harvested at the indicated time points, total RNA was extracted using Trizol Kit (Invitrogen), and cDNA was synthesized by reverse transcription using the RevertAID First Strand cDNAsynthesis Kit (Thermo Scientific). Adding SYBR GreenRealtime PCR Master Mix (TOYOBO) into a sample, carrying out real-time quantitative PCR reaction on a Quant Studio6Flex real-time quantitative PCR instrument (ABI), and carrying out amplification quantification on a corresponding target gene. FIG. 10 shows Compound D compared to DMSO group28Processing the MV 4; 11 cells can down-regulate HOX genes such as HOXA9 and HOXA10, and genes MEIS1 and DLX2 which are highly expressed in MLL fusion type leukemia cells.
Claims (11)
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