CN117304092A - DNA methyltransferase 1 inhibitor and preparation method and application thereof - Google Patents

DNA methyltransferase 1 inhibitor and preparation method and application thereof Download PDF

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CN117304092A
CN117304092A CN202311177132.7A CN202311177132A CN117304092A CN 117304092 A CN117304092 A CN 117304092A CN 202311177132 A CN202311177132 A CN 202311177132A CN 117304092 A CN117304092 A CN 117304092A
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carbazol
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张倩
刘婧怡
阮敏丽
刘月琴
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Fudan University
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a compound with an inhibitory activity on DNA methyltransferase 1 (DNMT 1), and a preparation method and application thereof. In the invention, a DNMT1 small molecule inhibitor with a 2-isoindolyl-3-carbazolyl propionic acid skeleton is found and prepared, and is expected to be applied to the treatment of DNA hypermethylation related diseases, in particular to the treatment of tumors.

Description

DNA methyltransferase 1 inhibitor and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound with a DNA methyltransferase 1 inhibition effect, and a preparation method and application thereof.
Background
DNA methylation is an important epigenetic modification that plays an important role in maintaining chromosome structure, X-chromosome inactivation, gene imprinting, and the development and progression of many human genetic diseases (e.g., cancer, cardiovascular disease, diabetes, etc.). Among them, gene silencing by hypermethylation of the oncogene promoter is one of the important causes of tumor formation.
DNA methylation is mainly the process of converting cytosine on CpG islands of DNA into 5-methylcytosine by taking S-adenosylmethionine as a methyl donor under the catalysis of DNA methyltransferase (DNMTs) so as to silence and lose functions of the gene. The DNMTs family mainly includes DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L, etc. Among them, DNMT1 is the methyltransferase most studied at present, and studies indicate that there is a direct correlation between the amount of DNMT1 expressed and the degree of gene methylation. When the expression level or activity of DNMT1 is too high, the CpG island of the cancer suppressor gene promoter region is changed from a hypomethylation state to a hypermethylation state, so that the cancer suppressor gene is inactivated and the oncogene is activated, and the cancer also occurs. During the invasion process of cancer, DNMT1 can regulate cancer cell proliferation, matrix degradation, cancer cell metastasis and evade immune system to influence the development of tumor through DNA methylation.
Currently, DNMT1 inhibitors reported in the literature are largely classified into two types, nucleoside and non-nucleoside. Nucleoside inhibitors include decitabine, azacytidine, guadecitabine, and the like. Among them, azacitidine, decitabine, clofarabine have been approved for the treatment of myelodysplastic syndrome (MDS), acute Myeloid Leukemia (AML) and chronic myelomonocytic leukemia (CMML). Non-nucleoside small molecule inhibitors include procainamide, RG108, SGI-1027, MC3343, GSK3685032, etc., but no compound has been entered into clinical studies.
Disclosure of Invention
In order to solve the problems, the invention provides a DNA methyltransferase 1 inhibitor, the structural formula of which is shown as the formula I,
wherein R1-R4 are substituents on the isoindole ring selected from the group consisting of independent hydrogen, halogen, hydroxy, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1-4 carbon atoms, substituted or unsubstituted alkoxy containing 1-4 carbon atoms, acyloxy containing 1-4 carbon atoms, substituted or unsubstituted alkylamino containing 1-4 carbon atoms, substituted or unsubstituted amido containing 1-4 carbon atoms, or a combination thereof; r1, R2, R3, R4 may be the same or different groups; R5-R12 are substituents on the carbazole ring selected from the group consisting of independent hydrogen, halogen, hydroxy, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1-6 carbon atoms, substituted or unsubstituted alkoxy containing 1-6 carbon atoms, substituted or unsubstituted acyloxy containing 1-6 carbon atoms, substituted or unsubstituted acyl containing 1-6 carbon atoms, substituted or unsubstituted sulfonyl containing 1-6 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-6 carbon atoms, substituted or unsubstituted aryl containing 6-12 carbon atoms, substituted or unsubstituted aromatic hetero groups containing 3-12 carbon atoms, or combinations thereof; r5 to R12 may be the same or different groups, or may be adjacent groups to form a ring.
Further, the compound comprises:
the invention also provides a preparation method of the compound, which is characterized by comprising the following reactions:
dissolving differently substituted 2- (1, 3-dioxoisoindole-2-yl) methyl acrylate (A) and carbazole (B) substituted by different substituents in a solvent, and condensing under alkaline conditions to generate 3- (9H-carbazole-9-yl) -2- (1, 3-dioxoisoindole-2-yl) methyl propionate (C) with different substituents through Michael addition reaction; dissolving a compound C, and heating and stirring under the action of a catalyst to perform ester hydrolysis reaction to obtain a target product; wherein, in the differently substituted methyl 2- (1, 3-dioxoisoindol-2-yl) acrylate (A), R1 to R4 are selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1 to 4 carbon atoms, substituted or unsubstituted alkoxy containing 1 to 4 carbon atoms, acyloxy containing 1 to 4 carbon atoms, substituted or unsubstituted alkylamino containing 1 to 4 carbon atoms, substituted or unsubstituted amido containing 1 to 4 carbon atoms, or a combination of the above groups, R1, R2, R3 and R4 can be the same or different groups; r5 to R12 in carbazole (B) substituted by different substituents are selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1 to 6 carbon atoms, substituted or unsubstituted alkoxy containing 1 to 6 carbon atoms, substituted or unsubstituted acyloxy containing 1 to 6 carbon atoms, substituted or unsubstituted acyl containing 1 to 6 carbon atoms, substituted or unsubstituted sulfonyl containing 1 to 6 carbon atoms, substituted or unsubstituted cycloalkyl containing 3 to 6 carbon atoms, substituted or unsubstituted aryl containing 6 to 12 carbon atoms, substituted or unsubstituted aryl-heteroaryl containing 3 to 12 carbon atoms, or a combination of the above, and R5 to R12 can be the same or different groups or can form a ring by adjacent groups.
The invention also provides a preparation method of the compound, which comprises the following reactions: 2- (1, 3-dioxoisoindole-2-yl) methyl acrylate and carbazole are dissolved in a solvent, and 3- (9H-carbazole-9-yl) -2- (1, 3-dioxoisoindole-2-yl) methyl propionate is generated through Michael addition reaction and condensation under alkaline conditions; dissolving 3- (9H-carbazole-9-yl) -2- (1, 3-dioxoisoindole-2-yl) methyl propionate, and heating and stirring under the action of a catalyst to perform ester hydrolysis reaction to obtain a target product.
Further, the solvent in the condensation reaction is acetone, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, N-dimethylformamide, methanol, ethanol, isopropanol, or tert-butanol, preferably from acetone and acetonitrile; the alkali is at least one selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydrogen, sodium ethoxide, sodium methoxide, potassium tert-butoxide, diisopropylaminopotassium, pyridine, N-dimethylaminopyridine, triethylamine and diisopropylamine.
Preferably, the base is selected from potassium carbonate, sodium hydroxide and potassium hydroxide.
Further, in the ester hydrolysis reaction, the solvent in the dissolution of 3- (9H-carbazole-9-yl) -2- (1, 3-dioxoisoindol-2-yl) methyl propionate is selected from at least one of tetrahydrofuran, acetone, ethyl acetate and acetonitrile; the catalyst is at least one selected from lithium iodide, lithium hydroxide and lithium carbonate.
The invention also provides application of the compound and stereoisomers thereof, including R-configuration and S-configuration, or pharmaceutically acceptable salts thereof in preparing medicaments for inhibiting DNA methyltransferase 1.
The invention also provides a pharmaceutical composition for inhibiting DNA methyltransferase 1, which takes the compound as an active ingredient; the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
The invention has the following beneficial effects:
in the invention, a DNMT1 small molecule inhibitor with a 2-isoindolyl-3-carbazolyl propionic acid skeleton is found and prepared, and is expected to be applied to the treatment of DNA hypermethylation related diseases, in particular to the treatment of tumors.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 example 3 CD and ECD maps of two isomers;
FIG. 2 example 7 CD and ECD maps of two isomers;
FIG. 3 CD and ECD spectra of the two isomers of example 8.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
The technical scheme of the invention is conventional in the field, and the reagents or raw materials are purchased from commercial sources or are disclosed.
Example 1.3- (9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.06(d,J＝6.9Hz,2H),7.74(d,J＝3.0Hz,2H),7.34(dd,J＝5.1,3.0Hz,2H),7.37～7.27(m,4H),7.21～7.14(m,2H),4.81(dd,J＝5.0,5.2Hz,1H),4.65(d,J＝5.0Hz,1H),4.44(d,J＝5.2Hz,1H).ESI-MS m/z 385.7(M+H + ).
Example 2.3- (3, 6-dichloro-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.25(s,2H),7.74～7.71(m,4H),7.46(d,J＝8.8Hz,2H),7.39(d,J＝8.7,2H),5.16(dd,J＝3.3,3.7Hz,1H),4.71～4.66(m,2H).ESI-MS m/z 453.1(M+H + ).
Example 3.3- (3, 6-dibromo-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,2H),7.77～7.68(m,4H),7.51(d,J＝7.0Hz,2H),7.40(d,J＝6.8Hz,2H),5.13～5.07(m,2H),4.67(dd,J＝5.8,4.6Hz,1H).ESI-MS m/z 540.4(M+H + ).
Example 4.3- (3, 6-diiodo-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.53(s,2H),7.76～7.69(m,4H),7.63(d,J＝8.6Hz,2H),7.28(d,J＝8.6Hz,2H),5.17～5.05(m,2H),4.67(dd,J＝5.6,4.5Hz,1H).ESI-MS m/z 636.7(M+H + ).
Example 5.3- (2, 7-dibromo-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.05(d,J＝8.3Hz,2H),7.77～7.71(m,4H),7.60(s,2H),7.28～7.24(m,2H),5.18(dd,J＝4.0,3.3Hz,1H),5.04(d,3.8Hz,1H),4.63(d,3.4Hz,1H).ESI-MS m/z 540.3(M+H + ).
Example 6.3- (3, 6-dimethyl-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.80(s,2H),7.74～7.68(m,4H),7.28(d,J＝8.3Hz,2H),7.13(d,J＝8.4Hz,2H),5.15～5.10(m,2H),4.73(dd,J＝5.6,5.5Hz,1H),2.39(s,6H).ESI-MS m/z 413.1(M+H + ).
Example 7.3- (3, 6-Di-tert-butyl-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.98(s,2H),7.68～7.62(m,4H),7.34(d,J＝8.9Hz,2H),7.27(d,J＝8.9Hz,2H),5.41(dd,J＝6.5,5.2Hz,1H),5.13～5.08(m,2H),1.36(s,18H).ESI-MS m/z 497.5(M+H + ).
Example 8.3- (1, 3, 6-trichloro-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.34(s,1H),8.23(s,1H),7.77～7.72(m,4H),7.62(s,1H),7.37(d,J＝7.7Hz,1H),7.28(d,J＝7.5Hz,1H),5.56(dd,J＝5.5,4.5Hz,1H),5.14～5.10(m,2H).ESI-MS m/z 487.3(M+H + ).
Example 9.3- (3-bromo-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.14(s,1H),7.96(d,J＝7.7Hz,1H),7.54(dd,J＝8.7,7.8Hz,2H),7.32～7.17(m,4H),7.06(d,J＝8.5Hz,1H),6.95(d,J＝7.2Hz,2H),4.66(dd,J＝6.5,5.5Hz,1H),4.54～4.37(m,2H).ESI-MS m/z 463.4(M+H + ).
EXAMPLE 10.3- (3-iodo-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.47(s,1H),8.11(d,J＝7.8Hz,1H),7.73～7.69(m,4H),7.61(d,J＝9.5Hz,1H),7.41(d,J＝9.2Hz,1H),7.38～7.28(m,2H),7.12(d,J＝7.4Hz,1H),5.16～5.12(m,2H),4.71(dd,J＝6.8,5.5Hz,1H).ESI-MS m/z 511.0(M+H + ).
Example 11.2- (1, 3-Dioxoisoindolin-2-yl) -3- (4- (oxiran-2-ylmethoxy) -9H-carbazol-9-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.10(d,J＝7.5Hz,1H),7.77～7.67(m,4H),7.47(d,J＝8.3Hz,2H),7.30～7.20(m,2H),7.11(dd,J＝7.6,7.1Hz,1H),6.67(d,J＝7.3Hz,1H),5.51(dd,J＝7.6,3.8Hz,1H),5.02(d,J＝7.6Hz,1H),4.52(d,J＝3.8Hz,1H),4.07～3.99(m,2H),3.30(d,J＝3.1Hz,1H),2.92(d,J＝2.8Hz,1H),2.82(d,J＝2.4Hz,1H).ESI-MS m/z 457.1(M+H + ).
Example 12.3- (3, 6-dinitro-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ9.43(s,2H),8.31(d,J＝7.46Hz,2H),7.98～7.87(m,4H),7.33(d,J＝7.46Hz,2H),4.95(dd,J＝5.91,5.27Hz,1H),4.79(d,J＝5.37Hz,1H),4.51(d,J＝5.91Hz,1H).ESI-MS m/z 475.1(M+H + ).
Example 13.3- (3, 6-diacetyl-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.96(s,2H),7.99(d,J＝8.6Hz,2H),7.70～7.65(m,4H),7.55(d,J＝8.7Hz,2H),5.32～5.14(m,2H),4.75(dd,J＝5.2,3.4Hz,1H),2.65(s,6H).ESI-MS m/z 469.2(M+H + ).
EXAMPLE 14.2- (1, 3-Dioxoisoindolin-2-yl) -3- (1, 2,3, 4-tetrahydro-11H-benzo [ a ] carbazol-11-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.19～8.11(m,1H),7.87(dd,J＝5.0,3.1Hz,2H),7.78～7.59(m,4H),7.37～7.29(m,2H),6.90(d,J＝7.8Hz,1H),4.70(dd,J＝3.4,3.4Hz,1H),4.59(d,3.4Hz,1H),4.53(d,3.4Hz,1H),3.01～2.87(m,2H),2.78(dd,J＝6.9,6.2Hz,2H),1.83～1.68(m,4H).ESI-MS m/z 439.2(M+H + ).
EXAMPLE 15.3- (11H-benzo [ a ] carbazol-11-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.31(d,J＝8.4Hz,1H),8.11～8.09(m,3H),7.87(dd,J＝7.6,5.0Hz,2H),7.84～7.89(m,4H),7.54(d,J＝7.6Hz,1H),7.39(d,J＝7.5Hz,1H),7.33(d,J＝7.6,1H),7.17(d,J＝5.0,1H),4.96(dd,J＝5.2,3.4Hz,1H),4.58～4.44(m,2H).ESI-MS m/z 435.1(M+H + ).
EXAMPLE 16.3- (3, 6-diacetoxy-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.84(s,2H),7.74～7.70(m,4H),7.45(d,J＝8.9Hz,2H),7.30(d,J＝8.6Hz,2H),5.25～5.11(m,2H),4.80(dd,J＝5.4,3.5Hz,1H),2.27(s,6H).ESI-MS m/z 501.1(M+H + ).
EXAMPLE 17.3- (3, 6-diacetoxy-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ10.11(s,2H),7.85,(s,2H),7.78～7.71(m,4H),7.56(d,J＝9.0,2H),7.38(d,J＝9.0,2H),5.13～4.96(m,2H),4.77(dd,J＝6.1,5.2Hz,1H),2.04(s,6H).ESI-MS m/z 499.1(M+H + ).
EXAMPLE 18.2- (1, 3-Dioxoisoindolin-2-yl) -3- (7, 8,9, 10-tetrahydro-5H-benzo [ b ] carbazol-5-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.19(s,1H),7.87(dd,J＝5.0,3.1Hz,2H),7.74～7.67(m,4H),7.60(d,J＝3.1Hz,1H),7.37(d,J＝3.1Hz,1H),7.26(s,1H),4.75(dd,J＝3.4,3.3Hz,1H),4.61(d,J＝3.5Hz,1H),4.52(d,J＝3.3Hz,1H),2.78～2.65(m,4H),1.79～1.70(m,4H).ESI-MS m/z 439.1(M+H + ).
EXAMPLE 19.2- (1, 3-Dioxoisoindolin-2-yl) -3- (1, 2,3, 4-tetrahydro-7H-benzo [ c ] carbazol-7-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.15(d,J＝3.1Hz,1H),7.78～7.73(m,4H),7.70(dd,J＝5.1,3.1Hz,1H),7.55(dd,J＝5.4,3.1Hz,1H),7.33(d,J＝3.1Hz,2H),7.27(d,J＝3.1Hz,1H),4.75(dd,J＝3.5,3.4Hz,1H),4.61(d,J＝3.5Hz,1H),4.52(d,J＝3.3Hz,1H),2.90(d,J＝3.8Hz,2H),2.86(d,J＝3.8Hz,2H),2.81～2.72(m,2H),1.74～1.70(m,2H).ESI-MS m/z 386.1(M+H + ).
EXAMPLE 20.2- (1, 3-Dioxoisoindolin-2-yl) -3- (1-formyl-9H-carbazol-9-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.00(d,J＝7.7Hz,1H),7.68～7.61(m,4H),7.39(dd,J＝8.2,7.4Hz,2H),7.32(dd,J＝7.6,7.4Hz,1H),7.32(d,J＝7.4Hz,1H),7.15(d,J＝7.4Hz,2H),5.49(dd,J＝5.8,4.6Hz,1H),5.18～5.15(m,2H).ESI-MS m/z 413.1(M+H + ).
EXAMPLE 21.3- (2, 7-Di-tert-butyl-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.86(d,J＝8.2Hz,2H),7.72～7.61(m,4H),7.33(s,2H),7.19(d,J＝8.2Hz,2H),5.40(dd,J＝5.5,4.6Hz,1H),5.21(d,J＝5.6Hz,1H),5.14(d,J＝4.6Hz,1H),1.33(s,18H).ESI-MS m/z 497.2(M+H + ).
EXAMPLE 22.3- (3-bromo-6-methoxy-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.91(d,J＝5.1Hz,1H),7.73(s,1H),7.56～7.53(m,4H),7.35(s,1H),7.20(d,J＝5.1Hz,1H),6.88(d,J＝8.3Hz,1H),6.69(d,J＝8.3Hz,1H),5.18～5.01(m,2H),4.63(dd,J＝4.6,3.5Hz,1H),3.72(s,3H).ESI-MS m/z 493.0(M+H + ).
EXAMPLE 23.3- (7H-benzo [ c ] carbazol-7-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.73(d,J＝8.3Hz,1H),8.56(d,J＝7.6Hz,2H),8.03(dd,J＝8.3,6.0Hz,2H),7.76～7.64(m,4H),7.48(d,J＝7.6Hz,1H)7.31(d,J＝6.0Hz,1H),7.29～7.10(m,3H),5.46～4.94(m,2H),4.86(dd,J＝5.9,4.3Hz,1H).ESI-MS m/z 435.1(M+H + ).
EXAMPLE 24.2- (1, 3-Dioxoisoindolin-2-yl) -3- (3, 6-dipropyl-9H-carbazol-9-yl) propionic acid
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1 H NMR(400MHz,DMSO-d 6 )δ8.50(d,J＝1.8Hz,2H),8.44(s,2H),7.90～7.81(m,4H),7.81(d,J＝1.5Hz,2H),4.75(dd,J＝3.4,3.3Hz,1H),4.58(d,J＝3.4Hz,1H),4.46(d,J＝3.3Hz,1H),2.95(q,J＝7.6Hz,4H),1.20(t,J＝7.6Hz,6H).ESI-MS m/z 497.2(M+H + ).
EXAMPLE 25.3- (2, 7-Diethoxy-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.90～7.83(m,4H),7.81(d,J＝7.8Hz
,2H),7.74(s,2H),7.18(d,J＝7.8Hz,2H),4.75(dd,J＝5.1,3.4Hz,1H),4.62(d,J＝3.5Hz,1H),4.51(d,J＝5.1Hz,1H),4.03(q,J＝6.7Hz,4H),1.43(t,J＝6.7Hz,6H).ESI-MS m/z 473.1(M+H + ).
EXAMPLE 26.3- (2-cyclopropyl-7-methyl-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.94(d,J＝4.9Hz,1H),7.87～7.74(m,4H),7.37(d,J＝2.1,Hz,1H),7.27(s,2H),7.20(d,J＝4.9Hz,1H),7.17(d,J＝2.1Hz,1H),4.75(dd,J＝3.4,3.3Hz,1H),4.64(d,J＝3.5Hz,1H),4.54(d,J＝3.3Hz,1H),2.46(s,3H),1.04–0.92(m,2H),0.85–0.73(m,2H).ESI-MS m/z 439.1(M+H + ).
EXAMPLE 27.3- (2-allyl-6-bromo-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.94(d,J＝8.2Hz,1H),7.87～7.74(m,4H),7.69(s,1H),7.49(dd,J＝8.2,1.8Hz,1H),7.39(d,J＝8.2Hz,1H),7.34(s,1H),7.17(dd,J＝7.9,2.0Hz,1H),5.94～5.92(m,1H),5.09(d,J＝9.6Hz,1H),4.96(d,J＝9.6Hz,1H),4.75(dd,J＝3.4,3.3Hz,1H),4.63(d,J＝3.5Hz,1H),4.49(d,J＝3.3Hz,1H),3.35～3.23(m,2H).ESI-MS m/z 503.1(M+H + ).
EXAMPLE 28.3- (1, 6-dibromo-3- (methylcarbamoyl) -9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ8.53(s,1H),7.99(s,1H),7.93(d,J＝2.2Hz,1H),7.87～7.74(m,4H),7.70(s,1H),7.49(d,J＝2.0Hz,1H),4.70(dd,J＝3.4,3.2Hz,1H),4.59～4.48(m,2H),2.93(s,3H).ESI-MS m/z 598.1(M+H + ).
Example 29.3- (3-butyl-1, 5, 7-trichloro-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.87～7.74(m,4H),7.61(s,1H),7.41(s,1H),7.07(s,1H),6.95(s,1H),4.70(dd,J＝3.4,3.3Hz,1H),4.61～4.59(m,2H),2.62(t,J＝8.3,2.7Hz,2H),1.58～1.50(m,2H),1.33～1.28(m,2H),0.95(t,J＝7.2Hz,3H).ESI-MS m/z543.1(M+H + ).
EXAMPLE 30.2- (5-acetamido-1, 3-dioxoisoindolin-2-yl) -3- (3, 6-di-tert-butyl-9H-carbazol-9-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ9.47(s,1H),8.05(d,J＝2.2Hz,1H),7.97(d,J＝2.1Hz,1H),7.44(d,J＝2.6Hz,2H),7.33(d,J＝2.6Hz,2H),7.24(s,2H),4.75(dd,J＝3.4,3.3Hz,1H),4.58(d,J＝3.3Hz,1H),4.46(d,J＝3.3Hz,1H),2.0(s,3H),1.35(s,18H).ESI-MS m/z 554.2(M+H + ).
Example 31.3- (3, 6-Di-tert-butyl-9H-carbazol-9-yl) -2- (5-methoxy-1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.97(d,J＝2.2Hz,1H),7.91(s,1H),7.79(d,J＝2.5Hz,1H),7.40(d,J＝2.6Hz,2H),7.29(d,J＝2.6Hz,2H),7.24(s,2H),4.75(dd,J＝3.4,3.3Hz,1H),4.58(d,J＝3.3Hz,1H),4.46(d,J＝3.3Hz,1H),2.8(s,3H),1.35(s,18H).ESI-MS m/z 527.2(M+H + ).
Example 32.2- (5-Acetyloxy-4-bromo-1, 3-dioxoisoindolin-2-yl) -3- (3, 6-di-tert-butyl-9H-carbazol-9-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.93(d,J＝2.5Hz,1H),7.79(d,J＝2.5Hz,1H),7.44(d,J＝2.6Hz,2H),7.36(d,J＝2.6Hz,2H),7.25(s,2H),4.75(dd,J＝3.4,3.3Hz,1H),4.58(d,J＝3.3Hz,1H),4.46(d,J＝3.3Hz,1H),2.0(s,3H),1.35(s,18H).ESI-MS m/z633.2(M+H + ).
Example 33.3- (3, 6-dibromo-9H-carbazol-9-yl) -2- (5-methoxy-1, 3-dioxoisoindolin-2-yl) propionic acid
1 H NMR(400MHz,DMSO-d 6 )δ7.97(d,J＝2.2Hz,1H),7.91(s,1H),7.79(d,J＝2.5Hz,1H),7.45(d,J＝2.6Hz,2H),7.33(d,J＝2.6Hz,2H),7.27(s,2H),4.75(dd,J＝3.4,3.3Hz,1H),4.58(d,J＝3.3Hz,1H),4.46(d,J＝3.3Hz,1H),2.8(s,3H).ESI-MS m/z 633.2(M+H + ).
Example 34.
Preparation of example 2 (the compounds of examples 1,3-33 were obtained according to the following schemes, as represented by example 2)
Synthesis of methyl 3- (3, 6-dichloro-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionate (C2) A25 ml round bottom flask was charged with 3, 6-dichloro-9H-carbazole (118 mg,0.5mmol,1.15 eq) and 112mg KOH (3.5 eq) at 60℃for 1H, after which A1 (100 mg,0.7mmol,1 eq) was added and reacted overnight. PE: ea=4: the 1-dot plate found a new dot generation with a polarity slightly greater than 1a21. After stopping the reaction, insoluble materials were filtered off. Spin-drying acetonitrile, extracting with ethyl acetate, and performing column chromatography. (PE: ea=8:1) to give 140mg of a yellowish green solid. The yield thereof was found to be 69%. 1 H NMR(400MHz,CDCl 3 )δ8.22(s,2H),7.75～7.71(m,4H),7.47(d,J＝8.8Hz,2H),7.39(d,J＝8.7,2H),5.16(dd,J＝3.3,3.7Hz,1H),4.71～4.66(m,2H),3.82(s,3H).ESI-MS m/z 467.4(M+H + )
Synthesis of 3- (3, 6-dichloro-9H-carbazol-9-yl) -2- (1, 3-dioxoisoindolin-2-yl) propionic acid (example 2) A25 ml flask was charged with C2.sub.100 mg and 3eq LiI, dissolved in ethyl acetate, and heated at 80℃overnight with stirring. The reaction was carried out for 5 days. The precipitate was filtered and washed repeatedly with ethyl acetate. 45mg of a yellowish green solid was obtained. The yield thereof was found to be 45%. 1 H NMR(400MHz,DMSO-d6)δ8.25(s,2H),7.74～7.71(m,4H),7.46(d,J＝8.8Hz,2H),7.39(d,J＝8.7,2H),5.16(dd,J＝3.3,3.7Hz,1H),4.71～4.66(m,2H).
ESI-MS m/z 453.1(M+H + )
Example 35 resolution and Structure determination of examples 3,7 and 8
The preparation method comprises the following steps: the chiral isomers were separated using HPLC preparation equipment and chiral columns and the corresponding fractions were collected. The solvent was removed by rotary evaporation to give pure optical isomers.
Separation column specification: 0.46cm I.D. times.15 cm L; mobile phase: meOH/tfa=100/0.1 (V/V); flow rate: 1.0ml/min. The compound with the first peak was numbered 1, and the compound with the last peak was numbered 2.
Configuration determination: the configuration was determined using the method of superposition of the ECD spectra of predicted R-configuration compounds and S-configuration compounds with the measured CD spectra of compound-1 and compound-2.
The results are shown in Table 1:
table 1 results of partial compound isomer resolution and configuration determination
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Example 37 binding ability of compounds to DNMT1 (SPR Experimental results):
experimental operation: the binding capacity of 10mM sodium acetate buffer with pH of 5.5, 5.0, 4.5 and 4.0 respectively to DNMT1 protein with final concentration of 50.7 mug/mL was tested, the optimal coupling pH value was selected according to the result, DNMT1 protein was coupled to CM5 chip at this concentration, and then affinity measurement was performed on DNMT1 protein and 10 mug of small molecule inhibitor, with DNMT1 inhibitor RG108 as positive control, and the affinity measurement data was analyzed. The compound binding to DNMT1 protein was selected at a starting concentration of 5. Mu.M, diluted 2-fold, and at a total of 8 concentrations (containing 0 concentration). The corresponding solutions flowed into the Fc1 and Fc2 channels of the chip using conditions of 35s binding and 45s dissociation. The chip was then regenerated using HBS-EP+ at a flow rate of 30L/min for 30s. After binding assays, data analysis was performed using Biacore T200 evaluation software (blank concentration 0 nM). Finally, fitting analysis is performed using kinetics or affinity according to affinity patterns.
Experimental results: the results are shown in Table 2, and the optimal coupling pH of DNMT1 protein to CM5 chip was 4.5. And KD is performed for all examples 50 Testing of the values. Affinity with DNMT1 for all examplesThe force is significantly improved over RG 108.
TABLE 2 affinity assay results for small molecules with DNMT1
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Conclusion: the interaction force between the embodiment of the invention and DNMT1 is significantly higher than that between RG108 and DNMT1, mostly by nearly two orders of magnitude.
EXAMPLE 38 test of Compounds for DNMT1 enzyme inhibitory Activity and results
Experimental operation: preparing an enzyme solution: an enzyme solution was prepared in 1x detection buffer. Preparing a substrate solution: a substrate solution was prepared in 1x detection buffer. The compound was diluted to give a final DMSO-D6 concentration of 1%. A [3H ] -SAM solution is prepared. mu.L of enzyme solution was transferred to the assay plate and the lowest control group transferred 10. Mu.L of 1 Xassay buffer to the assay plate. Incubate for 15 minutes at room temperature.
To each well 10 μl of substrate solution was added. 10. Mu.L of [3H ] -SAM solution was added to each well to start the reaction. Incubate for 180 min at 37 ℃. To each well 10 μl of cold SAM solution was added to end the reaction.
The filter plates were pre-incubated with 0.5% PEI for 15 minutes and evacuated. The reaction system, 40. Mu.L, was transferred to a filter plate and the plate was vacuum washed 3 times with ddH 2O. Counts were read on MicroBeta.
Inhibition = (max-measure)/(max-min) ×100%.
The inhibition of DNMT1 enzyme by examples 1-11 at 250. Mu.M was tested, and several examples with better activity were selected and resolved and tested for inhibition of DNMT1 at 125. Mu.M.
The experimental results are shown in table 3:
TABLE 3 determination of inhibitory Activity of small molecule inhibitors on DNMT1
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Conclusion of experiment: the invention relates to a compound which has obvious inhibition effect on DNMT1 protease.
Example 39 inhibition of cancer cell proliferation Activity
Experimental operation: the a2780 cell line (ovarian cancer cells) and the Hela cell line (cervical cancer cells) were selected for testing for activity in inhibiting cell proliferation.
The log phase cells were collected, the cell suspension concentration was adjusted, 100ul was added to each well, and the cells to be tested were plated to adjust the density to 5000-8000 wells, (the marginal wells were filled with sterile PBS). 24h after cell inoculation, 100. Mu.L of inhibitor (D++ configuration) at a concentration of 400. Mu.M was added to the test wells, three wells per example. 5% CO2, incubated at 37℃for 48 hours and observed under an inverted microscope. 150ul MTT solution (0.5 mg/ml, i.e., 10-fold dilution of 0.5% MTT) was added to each well and incubation was continued for 4h. The culture was terminated and the in-well culture solution was carefully aspirated. 150ul of dimethyl sulfoxide was added to each well to dissolve the crystals thoroughly. Absorbance values for each well were measured at OD 570nm of the enzyme-linked immunosorbent assay.
The results are shown in Table 4, and the inhibition ratio% = [ (Ac-As)/(Ac-Ab) ]. Times.100%
As: assay well (cell-containing Medium, MTT, drug) readings
Ac: control well (cell-containing medium, MTT, no drug) readings
Ab: blank well (cell and drug free medium, DMSO) readings
TABLE 4 Effect of small molecule inhibitors on tumor cell proliferation
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The compound can effectively inhibit proliferation of cancer cells, and can be used for treating related diseases with higher DNMT1 expression, in particular to tumors such as cervical cancer, ovarian cancer and the like.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.

Claims (7)

1. A compound having an inhibitory effect on DNA methyltransferase 1 (DNMT 1), having the structural formula of formula i:
wherein R1-R4 are substituents on the isoindole ring selected from the group consisting of independent hydrogen, halogen, hydroxy, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1-4 carbon atoms, substituted or unsubstituted alkoxy containing 1-4 carbon atoms, acyloxy containing 1-4 carbon atoms, substituted or unsubstituted alkylamino containing 1-4 carbon atoms, substituted or unsubstituted amido containing 1-4 carbon atoms, or a combination thereof; r1, R2, R3, R4 may be the same or different groups; R5-R12 are substituents on the carbazole ring selected from the group consisting of independent hydrogen, halogen, hydroxy, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1-6 carbon atoms, substituted or unsubstituted alkoxy containing 1-6 carbon atoms, substituted or unsubstituted acyloxy containing 1-6 carbon atoms, substituted or unsubstituted acyl containing 1-6 carbon atoms, substituted or unsubstituted sulfonyl containing 1-6 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-6 carbon atoms, substituted or unsubstituted aryl containing 6-12 carbon atoms, substituted or unsubstituted aromatic hetero groups containing 3-12 carbon atoms, or combinations thereof; r5 to R12 may be the same or different groups, or may be adjacent groups to form a ring.
2. The compound of claim 1, wherein the compound comprises:
3. a process for the preparation of a compound according to claim 1 or 2, comprising the reaction of:
dissolving differently substituted 2- (1, 3-dioxoisoindole-2-yl) methyl acrylate (A) and carbazole (B) substituted by different substituents in a solvent, and condensing under alkaline conditions to generate 3- (9H-carbazole-9-yl) -2- (1, 3-dioxoisoindole-2-yl) methyl propionate (C) with different substituents through Michael addition reaction; dissolving a compound C in a solvent, and heating and stirring under the action of a catalyst to perform ester hydrolysis reaction to obtain a target product; wherein, in the differently substituted methyl 2- (1, 3-dioxoisoindol-2-yl) acrylate (A), R1 to R4 are selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1 to 4 carbon atoms, substituted or unsubstituted alkoxy containing 1 to 4 carbon atoms, acyloxy containing 1 to 4 carbon atoms, substituted or unsubstituted alkylamino containing 1 to 4 carbon atoms, substituted or unsubstituted amido containing 1 to 4 carbon atoms, or a combination of the above groups, R1, R2, R3 and R4 can be the same or different groups; r5 to R12 in carbazole (B) substituted by different substituents are selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, substituted or unsubstituted alkyl containing 1 to 6 carbon atoms, substituted or unsubstituted alkoxy containing 1 to 6 carbon atoms, substituted or unsubstituted acyloxy containing 1 to 6 carbon atoms, substituted or unsubstituted acyl containing 1 to 6 carbon atoms, substituted or unsubstituted sulfonyl containing 1 to 6 carbon atoms, substituted or unsubstituted cycloalkyl containing 3 to 6 carbon atoms, substituted or unsubstituted aryl containing 6 to 12 carbon atoms, substituted or unsubstituted aryl-heteroaryl containing 3 to 12 carbon atoms, or a combination of the above, and R5 to R12 can be the same or different groups or can form a ring by adjacent groups.
4. A process according to claim 3, wherein the solvent in the condensation reaction is acetone, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, N-dimethylformamide, methanol, ethanol, isopropanol, or tert-butanol, preferably from acetone and acetonitrile; the alkali is at least one selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydrogen, sodium ethoxide, sodium methoxide, potassium tert-butoxide, diisopropylaminopotassium, pyridine, N-dimethylaminopyridine, triethylamine and diisopropylamine.
5. The process according to claim 3, wherein the step of dissolving methyl 3- (9H-carbazol-9-yl) -2- (1, 3-dioxoisoindol-2-yl) propionate in a solvent selected from at least one of tetrahydrofuran, acetone, ethyl acetate and acetonitrile in the ester hydrolysis reaction; the catalyst is at least one selected from lithium iodide, lithium hydroxide and lithium carbonate.
6. The use of a compound as claimed in claim 1 or 2, and stereoisomers thereof, including the R-configuration and S-configuration, or in the preparation of a DNA methyltransferase 1 inhibitor, in a pharmaceutically acceptable salt.
7. A pharmaceutical composition of a DNA methyltransferase 1 inhibitor, which comprises the compound of claim 1 or 2 as an active ingredient; the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
CN202311177132.7A 2023-09-12 2023-09-12 DNA methyltransferase 1 inhibitor and preparation method and application thereof Pending CN117304092A (en)

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