CN113929591A - Inhibitors with antiproliferative activity - Google Patents
Inhibitors with antiproliferative activity Download PDFInfo
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- CN113929591A CN113929591A CN202111176671.XA CN202111176671A CN113929591A CN 113929591 A CN113929591 A CN 113929591A CN 202111176671 A CN202111176671 A CN 202111176671A CN 113929591 A CN113929591 A CN 113929591A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
- C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/02—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 two hetero rings
- C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses an inhibitor with antiproliferative activity, which comprises a compound shown as a formula (I) or a formula (II):
wherein R is1Including halogen or amide groups, R2Including hydrogen or hydroxy, R3IncludedHydrogen or halogen, R4Including hydrogen or halogen, R5Comprising hydrogen, R6Including any of the following: alkyl, phenyl, substituted benzyl, unsubstituted benzyl, R7Including pyridyl or nitrophenyl, and X includes an oxygen or imine group.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an AF9YEATS structural domain inhibitor with antiproliferative activity.
Background
Medically, cancer refers to malignant tumors originating in epithelial tissues, and correspondingly, malignant tumors originating in mesenchymal tissues are collectively referred to as sarcomas. Cancer generally refers to all malignant tumors. Under the action of various carcinogenic factors, the regulation and control of local tissue cells on the gene level are disordered, and abnormal proliferation is caused to form malignant tumors. Malignant tumor has high proliferation speed, is easy to generate bleeding ulcer and the like, often migrates to distant organs to cause emaciation, anemia, fever, serious organ function damage and the like of human body, and about 996 ten thousand of cases of cancer death worldwide in 2020.
The development of cancer is often accompanied by genomic disorders, in which the dynamic structure of chromatin and gene expression are regulated by histone post-translational modifications. Recent studies found that the YEATS domain is a reader for recognizing histone acylation modification, and four human proteins containing the YEATS domain are: constituent proteins AF9 and ENL which recognize chromatin in the super-extension complex, ATAC complex component YEATS2 and component GAS41 of histone acetyltransferase complex are important components of histone acetyltransferase or chromatin remodeling complex, and participate in the regulation and control of chromatin structure, gene transcription, stress signal and DNA damage response, so that the dysfunction of YEATS domain is closely related to the occurrence of various diseases. For example, mutations in AF9 have been associated with the development of lymphoid cancers and gliomas. In addition, fusion of AF9 with MLL protein, resulting in chromosomal translocation, is an oncogenic factor in acute leukemia. However, the current drugs for treating cancer still need to be further studied.
Disclosure of Invention
The present invention provides an inhibitor with antiproliferative activity, intended to solve at least partially the technical problems set out above.
To achieve the above objects, the present invention provides an inhibitor having antiproliferative activity, which comprises a compound represented by formula (I) or formula (ii):
wherein R is1Including halogen or amide groups, R2Including hydrogen or hydroxy, R3Including hydrogen or halogen, R4Including hydrogen or halogen, R5Comprising hydrogen, R6Including any of the following: alkyl, phenyl, substituted benzyl, unsubstituted benzyl, R7Including pyridyl or nitrophenyl, and X includes an oxygen or imine group.
According to an embodiment of the present invention, the substituent of the substituted benzyl group includes any one of: chlorine, fluorine, hydroxyl, dimethyl.
According to an embodiment of the present invention, the halogen includes any one of: fluorine, chlorine.
According to an embodiment of the present invention, the amide group includes any one of: n-methylaminoacetyl, N- (acetamide) methylene.
According to an embodiment of the present invention, the alkyl group includes any one of: methyl and ethyl.
According to an embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following specific compounds:
according to an embodiment of the present invention, the compound represented by formula (II) is selected from any one of the following specific compounds:
according to the embodiment of the invention, the method further comprises any one of the following steps: stereoisomers, geometric isomers, tautomers and racemates of the compound shown in the formula (I); stereoisomers, geometric isomers, tautomers and racemates of the compound shown in the formula (II).
According to the embodiment of the invention, the method further comprises any one of the following steps: a nitroxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound of formula (I); an oxynitride, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of the compound represented by the formula (II).
According to an embodiment of the present invention, the use of the above-mentioned inhibitor for the treatment of cancer.
The invention synthesizes a novel micromolecule inhibitor of AF9YEATS structural domain, achieves the technical effect of effectively inhibiting tumor proliferation by blocking the recognition of target point AF9 and histone and further regulating the technical means of gene transcription, and solves the technical problem of drug shortage in the current cancer treatment.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments.
The invention provides an inhibitor with antiproliferative activity, which comprises a compound shown as the following formula (I) or formula (II):
wherein R is1Including halogen or amide groups, R2Including hydrogen or hydroxy, R3Including hydrogen or halogen, R4Including hydrogen or halogen, R5Comprising hydrogen, R6Including any of the following: alkyl, phenylSubstituted benzyl, unsubstituted benzyl, R7Including pyridyl or nitrophenyl, and X includes an oxygen or imine group.
The compound of the novel micromolecule inhibitor of the AF9YEATS structural domain synthesized by the embodiment of the invention can block the recognition of a target point AF9 and histone, and further regulate gene transcription, thereby effectively inhibiting tumor proliferation and solving the technical problem of drug shortage in the current cancer treatment.
According to an embodiment of the present invention, the substituent of the substituted benzyl group includes any one of: chlorine, fluorine, hydroxyl, dimethyl.
According to an embodiment of the present invention, the halogen includes any one of: fluorine, chlorine.
According to an embodiment of the present invention, the amide group includes any one of: n-methylaminoacetyl, N- (acetamide) methylene.
According to an embodiment of the invention, the alkyl group comprises any one of: methyl and ethyl.
According to an embodiment of the present invention, the compound represented by formula (I) is selected from any one of the following specific compounds:
the present invention will be described in detail by taking the method for preparing KD1-KD11 as an example.
Preparation of KD1 using scheme 1 below:
step one, sequentially adding N, N-Dimethylformamide (DMF) and oxalyl chloride into a Dichloromethane (DCM) solution dissolved with methoxyacetic acid at the temperature of 0 ℃ under an ice bath condition, reacting for half an hour at room temperature, and performing rotary evaporation on the obtained solution to obtain an acyl chloride dichloromethane solution;
adding N, N-Diisopropylethylamine (DIPEA) into a Dichloromethane (DCM) solution dissolved with 4-chloroaniline;
step three, slowly dripping the acyl chloride dichloromethane solution obtained in the step one into the solution obtained in the step two under the condition of stirring at 0 ℃, after dripping is finished, stirring the mixture at room temperature for a night, and after the reaction is finished, adding water into a reaction system for quenching and stirring;
step four, extracting the reaction liquid obtained in the step three with dichloromethane for three times, and combining the obtained organic phases;
step five, washing the organic phase obtained in the step four with salt, then drying with anhydrous sodium sulfate, and then filtering;
and sixthly, carrying out rotary evaporation on the filtrate obtained in the fifth step, and separating the crude product by using silica gel column chromatography to obtain a compound KD 1.
And step seven, performing nuclear magnetic test on the amide compounds KD1 and KD2 obtained in the step six.
The nuclear magnetic test result of the compound KD1 is as follows:
1H NMR(500MHz,Chloroform-d)；δ＝8.3(s,1H),7.5(d,J＝8.8Hz,2H),7.3 (d,J＝8.8Hz,2H),4.0(s,2H),3.5(s,3H)。
13C NMR(126MHz,CDCl3) (ii) a δ 167.7,135.8,129.5,129.1,121.1,72.1, 59.4. Preparation of KD2 using scheme 2 below:
scheme 2 the experimental procedures are the same as those of scheme 1 except that "step two, N-Diisopropylethylamine (DIPEA) is added to a Dichloromethane (DCM) solution of 3-hydroxy-4-chloroaniline", and the rest of the experimental procedures are the same as those of scheme 1.
Nuclear magnetic test result of compound KD2
1H NMR(500MHz,DMSO-d6)δ＝10.2(s,1H),9.8(s,1H),7.6(d,J＝2.4Hz, 1H),7.2(d,J＝8.6Hz,1H),7.0(dd,J＝8.6,2.4Hz,1H),4.0(s,2H),3.4(s, 3H)。
13C NMR(126MHz,DMSO)δ＝168.1,152.9,138.2,129.5,114.0,111.6, 107.9,71.7,58.6。
The following scheme 3 was used to prepare KD 3:
step one, adding 4-aminophenylacetic acid and SOCl into methanol in sequence2After that, the mixture was heated under reflux for 1 hour, and then the solvent was removed in vacuo;
step two, performing column chromatography separation on the crude product obtained in the step one to obtain a white solid compound, namely 4-amino methyl phenylacetate;
step three, dissolving the methyl 4-aminophenylacetate obtained in the step two in 40% methylamine water solution, and stirring for 24 hours at room temperature;
step four, performing column chromatography separation on the reaction liquid obtained in the step three to obtain a light yellow oily product 4-amino-N-methylphenylacetamide;
step five, dissolving the 4-amino-N-methylphenylacetamide obtained in the step four in Dichloromethane (DCM), and adding Dicyclohexylcarbodiimide (DCC) into a reaction system at 10 ℃;
step six, dissolving methoxyacetic acid in Dichloromethane (DCM);
and step seven, dropwise adding the solution obtained in the step six into the reaction solution obtained in the step five, stirring at room temperature for 12 hours, and removing the organic solvent in vacuum, and performing column chromatography separation to obtain a product KD 3.
And step eight, performing nuclear magnetic test on the amide compound KD3 obtained in the step seven.
Nuclear magnetic test result of compound KD3
1H NMR(500MHz,DMSO-d6)；δ＝9.7(s,1H),7.9(s,1H),7.6(d,J＝8.5Hz, 2H),7.2(d,J＝8.2Hz,2H),3.4(s,3H),3.3(s,2H),2.6(d,J＝4.6Hz,3H)。13C NMR(126MHz,DMSO)；δ＝170.6,167.9,136.7,131.6,129.1,119.7, 71.7,58.6,41.8,25.6。
The following scheme 4 was used to prepare KD 4:
reacting lanthanum trifluoromethanesulfonate, 4-aminobenzylamine and ethyl acetate in a two-neck flask with a stirring rod at 50 ℃ for 24 hours under the protection of argon;
step two, after the reaction is finished, diluting the reaction liquid obtained in the step one by using dichloromethane, and purifying by using silica gel flash column chromatography to obtain an amide intermediate product;
step three, dissolving the amide intermediate product obtained in the step two and methoxyacetic acid in anhydrous Dichloromethane (DCM) at room temperature, and then sequentially adding dichloromethane solutions of N, N-Diisopropylethylamine (DIPEA) and a Kate condensing agent (BOP);
step four, stirring the mixture obtained in the step three for 12 hours at room temperature;
and step five, performing rotary evaporation on the reaction liquid obtained in the step four, and performing column chromatography purification on a silica gel column to obtain a final product KD 4.
And step six, performing nuclear magnetic test on the compound KD4 obtained in the step five.
Nuclear magnetic test result of compound KD4
1H NMR(500MHz,DMSO-d6)；δ＝9.7(s,1H),8.3(t,J＝6.0Hz,1H),7.6(d, J＝8.5Hz,2H),7.2(d,J＝8.4Hz,2H),4.2(d,J＝5.9Hz,2H),4.0(s,2H), 3.4(s,3H),1.9(s,3H).13C NMR(126MHz,DMSO)δ169.1,167.9,137.1, 134.7,127.6,119.7,71.7,58.6,41.7,22.6。
Preparation of KD5 using scheme 5 below:
scheme 5 is the same as scheme 4 except that "step three, the amide intermediate obtained in step two and methyl-substituted iminoacetic acid are dissolved in anhydrous Dichloromethane (DCM) at room temperature, followed by the addition of N, N-Diisopropylethylamine (DIPEA) and a dichloromethane solution of a carbine condensation agent (BOP)".
The following scheme 6 was used to prepare KD 6:
step one, adding benzyl alcohol into Tetrahydrofuran (THF) solution dissolved with sodium hydride (NaH) under the condition of 0 ℃ under the protection of argon, and stirring for reaction for 30 min;
step two, adding a tetrahydrofuran solution of bromoacetic acid into the reaction solution obtained in the step one, and reacting for 12 hours under a reflux condition;
step three, adding water into the reaction liquid obtained in the step two for quenching, and then washing with ethyl acetate for three times;
step four, slowly dripping 1M dilute hydrochloric acid solution into the water phase obtained in the step three, adjusting the pH value of the solution to be 3-4, extracting for three times by using ethyl acetate, and combining organic phases;
step five, washing the organic phase obtained in the step four with salt, drying the organic phase with anhydrous sodium sulfate, and finally performing rotary evaporation to obtain an acid intermediate;
dissolving the acid intermediate obtained in the fifth step in Dichloromethane (DCM) as a solvent, and sequentially adding N, N-Dimethylformamide (DMF) and oxalyl chloride into the solvent at the temperature of 0 ℃ under the ice bath condition;
step seven, reacting the reaction solution obtained in the step six at room temperature for half an hour;
step eight, carrying out rotary evaporation on the reaction liquid obtained in the step seven to obtain an acyl chloride dichloromethane solution;
adding N, N-Diisopropylethylamine (DIPEA) into a Dichloromethane (DCM) solution dissolved with parachloroaniline;
step ten, slowly dropwise adding the acyl chloride dichloromethane solution obtained in the step eight into the solution obtained in the step nine under the stirring condition at 0 ℃, stirring overnight at room temperature, and after the reaction is finished, adding water into a reaction system for quenching and stirring;
step eleven, extracting the reaction liquid obtained in the step eleven with dichloromethane for three times, and combining the obtained organic phases;
step twelve, washing the organic phase obtained in the step eleven with salt, then drying with anhydrous sodium sulfate, and then filtering;
and thirteen, rotatably evaporating the filtrate obtained in the step twelve, and separating the crude product by using silica gel column chromatography to obtain the amide compound KD6-KD 11.
And step fourteen, carrying out nuclear magnetic test on the amide compound KD6-KD11 obtained in the step thirteen.
Nuclear magnetic test result of compound KD6
1H NMR(400MHz,Chloroform-d)；δ＝8.3(s,1H),7.5(d,J＝8.2Hz,2H), 7.4–7.3(m,5H),7.3(d,J＝8.9Hz,2H),4.6(s,2H),4.1(s,2H)。
13C NMR(101MHz,CDCl3)；δ＝167.7,136.6,135.9,129.6,129.2,128.9, 128.6,128.2,121.2,74.0,69.7。
The following scheme 7 was used to prepare KD 7:
in scheme 7, the experimental procedures are the same as those of scheme 6 except that "step one, phenol is added to a Tetrahydrofuran (THF) solution with sodium hydride (NaH) dissolved therein at 0 ℃ under argon shield, and the reaction is stirred for 30 min".
Nuclear magnetic test result of compound KD7
1H NMR(400MHz,Chloroform-d)；δ＝8.3(s,1H),7.5(d,J＝8.8Hz,2H), 7.4–7.3(m,4H),7.1(t,J＝7.4Hz,1H),7.0(d,J＝8.4Hz,2H),4.6(s,2H)。
13C NMR(101MHz,CDCl3)；δ＝157.0,135.5,130.0,129.9,129.2,122.6, 121.5,114.9,67.6。
Preparation of KD8 using scheme 8 below:
in scheme 8, the experimental procedures are the same as those in scheme 6 except that in the first step, p-fluorobenzyl alcohol is added to a Tetrahydrofuran (THF) solution with sodium hydride (NaH) dissolved therein under the protection of argon at 0 ℃ and stirred for reaction for 30 min.
Nuclear magnetic test result of compound KD8
1H NMR(500MHz,DMSO-d6)；δ＝9.9(s,1H),7.7(d,J＝8.6Hz,2H),7.5 (dd,J＝8.4,5.6Hz,2H),7.4(d,J＝8.5Hz,2H),7.2(t,J＝8.8Hz,2H),4.6(s, 2H),4.1(s,2H)。
13C NMR(126MHz,DMSO)；δ＝168.2,161.7(d,J＝243.5Hz),137.4,133.9 (d,J＝3.4Hz),130.0(d,J＝8.2Hz),128.5,127.2,121.3,115.1(d,J＝21.2 Hz),71.7,69.4。
The following scheme 9 was used to prepare KD 9:
in scheme 9, the experimental procedures are the same as those in scheme 6, except that in "step one, ortho-hydroxybenzyl alcohol is added to a Tetrahydrofuran (THF) solution in which sodium hydride (NaH) is dissolved under argon protection at 0 ℃, and the reaction is stirred for 30 min".
Nuclear magnetic test result of compound KD9
1H NMR(500MHz,DMSO-d6)；δ＝9.9(s,1H),9.7(s,1H),7.7(d,J＝8.6Hz, 2H),7.4(d,J＝8.6Hz,2H),7.3(d,J＝7.5Hz,1H),7.2(t,J＝7.7Hz,1H),6.9 (d,J＝8.0Hz,1H),6.8(t,J＝7.4Hz,1H),4.6(s,2H),4.1(s,2H)。
13C NMR(126MHz,DMSO)；δ＝169.2,155.9,137.7,130.3,129.6,129.0, 127.7,124.0,121.7,119.3,115.6,69.7,69.0。
The following scheme 10 was used to prepare KD 10:
in the synthetic route 10, except for the step one, benzyl alcohol is added into Tetrahydrofuran (THF) solution dissolved with sodium hydride (NaH) under the protection of argon at the temperature of 0 ℃, and the mixture is stirred and reacted for 30 min; step nine, N-Diisopropylethylamine (DIPEA) was added to a Dichloromethane (DCM) solution dissolved with 1, 5-difluoro-3-chloroaniline ", and the remaining experimental steps were the same as those of scheme 6. Nuclear magnetic test result of compound KD10
1H NMR(500MHz,DMSO-d6)；δ＝9.7(s,1H),7.5–7.4(m,4H),7.4(t,J＝ 7.4Hz,2H),7.3(t,J＝7.2Hz,1H),4.6(s,2H),4.2(s,2H)。
13C NMR(126MHz,DMSO)；δ＝168.6,157.9(dd,J＝251.2,6.6Hz),137.5, 131.7(t,J＝13.1Hz),128.3,127.9,127.7,113.7(t,J＝17.2Hz),113.0(dd,J ＝21.2,5.8Hz),72.5,69.0。
The following scheme 11 was used to prepare KD 11:
in scheme 11, the experimental procedures are the same as those in scheme 6, except that "step one, 2, 6-dimethylbenzyl alcohol is added to a Tetrahydrofuran (THF) solution in which sodium hydride (NaH) is dissolved under argon protection at 0 ℃, and the reaction is stirred for 30 min".
According to an embodiment of the present invention, the compound represented by formula (II) is selected from any one of the following specific compounds:
the following scheme 12 was used to prepare KD 12:
step one, 5-bromofuroic acid, 2-piperidinylaniline, 1-hydroxybenzotriazole Hydrate (HOBT) and triethylamine (Et) at room temperature3N) dissolved in Dichloromethane (DCM) and stirred to react for 10 min;
step two, adding l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) into the reaction solution obtained in the step one, and stirring the obtained orange solution overnight;
step three, quenching the reaction solution obtained in the step two by using a saturated sodium bicarbonate solution, then extracting by using dichloromethane, and finally combining the obtained organic phases;
step four, washing the organic phase obtained in the step three with halogen water, then drying the organic phase with magnesium sulfate, and then concentrating the organic phase under reduced pressure to obtain a crude product with the property of orange solid;
step five, purifying the crude product obtained in the step four by silica gel column chromatography to obtain an intermediate product 5-bromo-N- (4-chlorophenyl) furan-2-formamide;
step six, the intermediate product 5-bromo-N- (4-chlorphenyl) furan-2-formamide, 4-pyridine-B (OH) obtained in the step five2[1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride [ Pd (DPPF)2Cl2]And sodium carbonate (Na)2CO3) Placing the mixture into a two-neck flask;
step seven, under the condition of argon protection, tetrahydrofuran/water (THF/H)2Adding the mixed solution of O) into the reaction solution obtained in the sixth step;
step eight, heating the reaction liquid obtained in the step seven to 80 ℃, stirring for reaction for 5 hours, and cooling to room temperature;
step nine, carrying out reduced pressure concentration on the reaction liquid obtained in the step eight;
and step ten, purifying the substance obtained in the step nine by silica gel column chromatography to obtain pure products KD12 and KD 13.
Step eleven, performing nuclear magnetic test on the compound KD12 obtained in the step ten.
Nuclear magnetic detection result of compound KD12
1H NMR(500MHz,DMSO-d6)；δ＝10.4(s,1H),8.9–8.6(m,2H),8.0–7.9(m, 2H),7.9–7.7(m,2H),7.5–7.3(m,4H)。
13C NMR(126MHz,DMSO)；δ＝155.8,152.6,150.4,147.8,137.2,135.8, 128.6,127.8,122.3,118.4,117.2,111.5。
The following scheme 13 was used to prepare KD 13:
in scheme 13, in addition to "step six", the intermediate obtained in step five, 5-bromo-N- (4-chlorophenyl) furan-2-carboxamide, nitrobenzeneboronic acid, [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride [ Pd (DPPF)2Cl2]And sodium carbonate (Na)2CO3) The experimental procedure was the same as that of scheme 12 except that it was placed in a two-necked flask ".
Nuclear magnetic detection result of compound KD13
1H NMR(500MHz,DMSO-d6)；δ＝10.4(s,1H),8.8(t,J＝2.0Hz,1H),8.4(d, J＝7.9,1H),8.2(dd,J＝8.0,2.3Hz,1H),7.8(m,7.8–7.8,3H),7.45(m,7.5– 7.4,4H)。
13C NMR(126MHz,DMSO)；δ＝155.9,152.9,148.6,147.4,137.2,130.8, 130.7,130.6,128.6,127.7,123.1,122.3,118.8,117.3,110.3。
According to the embodiment of the invention, the method further comprises any one of the following steps: stereoisomers, geometric isomers, tautomers and racemates of the compound shown in the formula (I); stereoisomers, geometric isomers, tautomers and racemates of the compound shown in the formula (II).
The stereochemical definitions and rules used herein follow S.P. Parker, ED., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds', John Wiley & Sons, Inc., New York,1994, et al.
In one embodiment, any asymmetric atom (e.g., carbon atom) of a compound disclosed in embodiments of the present invention can exist in racemic or enantiomerically enriched forms. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography/fractional crystallization, and the like, depending on the differences in physicochemical properties.
In one example, depending on the choice of starting synthesis materials and purification methods, the compounds of the examples of the invention may exist as one of the possible isomers or as mixtures thereof, such as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
In one example, the compounds of the present examples can be resolved into optical enantiomers by known methods using racemates of any of the resulting final products or intermediates, e.g., by separation of the diastereomeric salts thereof obtained, by methods familiar to those skilled in the art. Racemic products can also be separated by chiral chromatographic techniques, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis. Reference may be made to Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co, KGaA, Weinheim, Germany, 2007); principles of asymmetry Synthesis (2nd Ed. Robert E. Gawley, Jeffery Aube, Elsevier, Oxford, UK,2012), and the like.
In one embodiment, the term "tautomer" or "tautomeric form" refers to successive isomers that have different energies and are convertible to each other by a low energy barrier (low energy barrier). If tautomers are possible (e.g., in solution), the chemical equilibrium of the tautomers can be reached. For example, proton tautomers can interconvert by proton migration, such as keto-enol isomerization and imine-enamine isomerization, among others. Unless otherwise indicated, all tautomeric forms of all compounds of the invention are within the scope and the like of the invention.
According to the embodiment of the invention, the method further comprises any one of the following steps: a nitroxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound of formula (I); an oxynitride, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of the compound represented by the formula (II).
In one embodiment, a "solvate" of an embodiment of the present invention refers to an association of one or more solvent molecules with all compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol, and the like. The term "hydrate" refers to an association of a drug molecule with water.
In one embodiment, "metabolite" refers to a product resulting from the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized and verified by experimental methods as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the invention includes metabolites of the listed compounds, including metabolites produced by contacting the compounds of the invention with a mammal for a sufficient period of time.
In one embodiment, "pharmaceutically acceptable salts or prodrugs" as used in the embodiments of the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as is the literature: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,1977,66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic salts formed by reaction with amino groups such as hydrochloride, hydrobromide, sulfate, perchlorate, and organic salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or those salts described in the literature as being obtained by other methods such as ion exchange. Other pharmaceutically acceptable salts are adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, butyrates, camphorates, dodecylsulfates, ethanesulfonates, formates, fumarates, glycerophosphates, gluconates, hemisulfates, laurates, pectinates, malates, malonates, methanesulfonates, nitrates, oleates, palmitates, nicotinates, persulfates, pamoates, propionates, and the like. Salts obtained with suitable bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates and arylsulfonates.
According to an embodiment of the present invention, the use of the above-mentioned inhibitor for the treatment of cancer.
Activity test and cell survival rate test were carried out on the above compounds KD1-KD13, respectively.
Activity assay
NMR chemical shift perturbation test of affinity (K)D): the NMR HSQC titration method detects protein amino acid residues disturbed by small molecule compounds, and detects the affinity of the small molecules and proteins through signal disturbance related to dosage.15The concentration of the N-labeled AF9YEATS domain ranged from 0.05mM to 0.2mM, and the molar concentration ratio of the small molecule compound to the protein ranged from 0.0 to 4.0, which were titrated separately. HSQC spectra of each titration data point were collected for 18 min at 298K using 500MHz or 700MHz Agilent nuclear magnetic spectrometer, and the resultsAs shown in table 2.
Cell viability assay
Determination of cellular Activity We used the CCK8 kit for detection.
Firstly, dissolving an MCF-7 breast cancer cell line and an HGC-27 gastric cancer cell line frozen in a liquid nitrogen tank in a water bath kettle at 37 ℃; then directly sucking the cell suspension into a culture dish containing 6mL of fresh RPMI1640 culture medium, and uniformly dispersing the cells by adopting a blowing and beating mode. The next day, the cells were changed with fluid.
And step two, carrying out cell passage, wherein when the density of the cells in the culture medium reaches 80-90%, carrying out the passage. Firstly, absorbing and discarding a culture medium in a culture dish, and respectively washing twice by using 1mL of PBS solution; then adding 1mL of pancreatin to ensure that the pancreatin is paved on the bottom of the whole culture dish; then, the cells were digested in an incubator at 37 ℃ for about 1min, and the digested cells were observed under an inverted microscope.
(1) If the cells are normal and growing vigorously, the subsequent plating experiment can be performed.
(2) If the cytoplasm retracts and gaps appear between the cells, 3mL of culture medium is added to stop the digestion reaction, the cells are blown off by lightly blowing, and then the ratio of the cell fluid to the culture medium is 1: 3, diluting the mixture into a fresh culture medium, and after passage for 2-3 times, if the cell state is recovered to be normal, the subsequent plating experiment can be carried out if the cell grows vigorously.
Step three, when the density of the cells in the culture medium is 80% -90%, repeating the operation of the step two, terminating the reaction by the culture medium, and then, according to the cell sap and the culture medium of 1: 20% dilution of the cells, trying to ensure 10 per well4And (3) fully and uniformly blowing and stirring the diluted cell suspension, adding the cell suspension into a 96-well plate, adding 100 mu L of cell suspension into each corresponding well, and setting 6 control groups in each group of experiment.
And step four, after the cells adhere to the wall, slowly sucking out the original culture solution, adding the drug molecules with different concentrations diluted by a fresh culture medium, continuously culturing for 24 hours, adding 10 mu L of CCK8, reacting for more than 1 hour, and measuring the absorption value at the wavelength of 450nm by using an enzyme-labeling instrument, wherein the results are shown in Table 2.
TABLE 2 affinity and Activity data for compounds targeting the AF9YEATS Domain
aWherein + represents that the inhibition effect is not obvious, the percentage of the survival cells is more than 80%, + represents that the inhibition effect is certain, the percentage of the survival cells is more than 50%, and, + ++ represents that the inhibition effect is relatively obvious, and the percentage of the survival cells is less than 50%.bAnd (5) not testing.
As can be seen from Table 2, NMR chemical shift perturbation tests for affinity (K)D) The affinity of the antibody shows a gradually increasing trend in the order from compound KD1 to compound KD 13; the cell survival rate showed a decreasing trend in the order from compound KD1 to compound KD13, and the inhibitory effect showed an increasing trend.
In summary, NMR chemical shift perturbation was used to test affinity (K) in the order from compound KD1 to compound KD13D) Presenting a gradually decreasing trend; the cell survival rate shows a gradually decreasing trend; the inhibitory effect shows a tendency to be gradually enhanced.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An inhibitor of antiproliferative activity comprising a compound of formula (I) or formula (ii):
wherein R is1Including halogen or amide groups, R2Including hydrogen or hydroxy, R3Including hydrogen or halogen, R4Including hydrogen or halogen, R5Comprising hydrogen, R6Including any of the following: alkyl, phenyl, substituted benzyl, unsubstituted benzyl, R7Including pyridyl or nitrophenyl, and X includes an oxygen or imine group.
2. The inhibitor of claim 1, wherein the substituent of the substituted benzyl group comprises any one of: chlorine, fluorine, hydroxyl, dimethyl.
3. The inhibitor of claim 1, wherein the halogen comprises any one of: fluorine, chlorine.
4. The inhibitor of claim 1, wherein the amide group comprises any one of: n-methylaminoacetyl, N- (acetamide) methylene.
5. The inhibitor of claim 1, wherein the alkyl group comprises any one of: methyl and ethyl.
6. The inhibitor according to claim 1, wherein the compound represented by the formula (I) is selected from any one of the following specific compounds:
7. the inhibitor according to claim 1, wherein the compound represented by the formula (II) is selected from any one of the following specific compounds:
8. the inhibitor according to claim 1, further comprising any one of:
stereoisomers, geometric isomers, tautomers and racemates of the compound shown in the formula (I);
stereoisomers, geometric isomers, tautomers and racemates of the compound shown in the formula (II).
9. The inhibitor according to claim 1, further comprising any one of:
a nitroxide, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of a compound of formula (I);
an oxynitride, hydrate, solvate, metabolite, and pharmaceutically acceptable salt or prodrug of the compound represented by the formula (II).
10. Use of an inhibitor according to any one of claims 1 to 9 for the treatment of cancer.
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