CN111317731A - FTO inhibitor prepared from 9- (2-carboxyphenyl) xanthene compound and treatment effect thereof - Google Patents
FTO inhibitor prepared from 9- (2-carboxyphenyl) xanthene compound and treatment effect thereof Download PDFInfo
- Publication number
- CN111317731A CN111317731A CN201811607418.3A CN201811607418A CN111317731A CN 111317731 A CN111317731 A CN 111317731A CN 201811607418 A CN201811607418 A CN 201811607418A CN 111317731 A CN111317731 A CN 111317731A
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- substituted
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- fto
- cyano
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- -1 2-carboxyphenyl Chemical group 0.000 title claims abstract description 77
- 239000003112 inhibitor Substances 0.000 title claims abstract description 21
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention relates to application of a 9- (2-carboxyphenyl) xanthene compound in preparation of an FTO inhibitor, and particularly discloses application of a 9- (2-carboxyphenyl) xanthene compound shown as a formula (I) and a derivative and pharmaceutically acceptable salts thereof in preparation of an FTO inhibitor or a pharmaceutical composition for treating diseases related to FTO.
Description
Technical Field
The invention relates to the field of pharmacology, in particular to application of a compound with a structure shown in a general formula I in an FTO inhibitor.
Background
FTO is also known as Obesity-Associated Protein (Fat Mass and Obesity-Associated Protein), which was first discovered to be a Protein having a close relationship with Obesity in 2007 (Science, 2007, 316 (5826): 889-94). Individuals with variation in the FTO gene in vivo, if both copies are variant, have a greater chance of obesity than those with no variant copies by as much as 70%. If there is only one copy of the FTO gene that is mutated, the chance of obesity is also 30% higher compared to people without the mutated copy.
With the intensive research on FTO, FTO is RNA demethylase and plays a very important role in the regulation of RNA methylation (Nat Chem biol.2011, 7 (12): 885-7). N is a radical of6Methyl adenosine (m)6A) Is the most abundant chemical modification in mRNA, widely found in viruses, most eukaryotic cells such as yeast, insect, occupational and mammalian cells (cell.2017, 169 (7): 1187-6A, thereby achieving mRNA specific demethylation in vitro and in vivo.
FTO-mediated oxidative de-m6The discovery of A methyl action may open up the extensive study of reversible chemical modification of RNA on biological regulation. Further research shows that FTO can regulate m6A affects the biological functions of mRNA such as transcription, splicing, nuclear translocation, translation, degradation and the like and is involved in the development of diseases (science.2016, 352 (6292): 1408-12). Studies have shown that viral RNA can pass through m6A modifies the detection of Host pattern recognition receptors that elicit antiviral innate immunity to enhance self-resistance (Cell Host microbe.2017, 22 (6):830) and regulates self-replication ability (Nat immunol.2017, 18 (10)): 1094-1103). As RNA demethylase, FTO can promote further leukemia exacerbation by regulating downstream genes such as ATRA (Cancer cell.2017, 31 (1): 127-141). The inhibition of the activity can effectively inhibit the malignant transformation and the in-vivo progression of the tumor (cell.2018, 172 (1-2): 90-105). The results indicate that the FTO has important regulation and control effects on important human diseases such as obesity, virus infection, tumorigenesis and development and the like.
FTO is closely related to human health, and very few FTO inhibitors have been reported. Therefore, the development and optimization of the inhibitor taking FTO as a target point can play a great promoting role in the research on the FTO function and the treatment of related diseases.
Disclosure of Invention
The invention provides an inhibitor for specifically and targetedly inhibiting FTO (fluorine-doped tin oxide) action.
In a first aspect of the present invention, there is provided a compound of the following formula (I), and the use of a pharmaceutically acceptable salt thereof:
wherein:
x ═ O or NH;
each R is1Each independently selected from the group consisting of halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde, ester, amide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted carbonyl C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-9 membered heterocyclyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde group, ester group, amide group, C1-C6 alkyl, C1-C6 alkoxy, carbonyl C1-C6 alkyl, C6-C12 aryl, 5-9 membered heterocyclic group;
each R is2Each independently selected from halogen, amino,Hydroxyl, nitro, cyano, carboxyl, aldehyde, ester, amide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted carbonyl C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-to 9-membered heterocyclic, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde group, ester group, amide group, C1-C6 alkyl, C1-C6 alkoxy, carbonyl C1-C6 alkyl, C6-C12 aryl, 5-9 membered heterocyclic group;
each R is3Each independently selected from the group consisting of halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde, ester, amide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted carbonyl C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-9 membered heterocyclyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde group, ester group, amide group, C1-C6 alkyl, C1-C6 alkoxy, carbonyl C1-C6 alkyl, C6-C12 aryl, 5-9 membered heterocyclic group;
n, m and t are each selected from the following integers: 0. 1, 2, 3, 4
The above compounds are all used for a use selected from the group consisting of: (1) compositions of FTO protein inhibitors; (2) preparing a pharmaceutical composition for treating FTO related diseases; (3) and in vitro use as FTO inhibitors.
In a further preferred embodiment of the method,
each R is1Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, aldehyde, carbomethoxy, carboethoxy, carboxamide, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted propoxyA substituted or unsubstituted aryl group, a substituted or unsubstituted propionyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted indolyl group, or a substituted or unsubstituted quinolyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolinyl;
each R is2Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, aldehyde, carbomethoxy, carboethoxy, carboxamide, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted propoxy, substituted or unsubstituted acetyl, substituted or unsubstituted propionyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indolyl, or substituted or unsubstituted quinolyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolinyl;
each R is3Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, aldehyde group, carbomethoxy, carboethoxy, amido, substituted or unsubstituted methyl, and the likeSubstituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted propoxy, substituted or unsubstituted acetyl, substituted or unsubstituted propionyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indolyl, or substituted or unsubstituted quinolyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolinyl; (ii) a
n is an integer selected from the group consisting of: 0. 1, 2, 3, 4;
and/or m is an integer selected from the group consisting of: 0. 1, 2, 3, 4, 5;
and/or t is an integer selected from the group consisting of: 0. 1, 2, 3, 4 and 5.
In a further preferred embodiment of the method,
each R is1Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, carbomethoxy, carboethoxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, amido, aldehyde, alkenyl, alkynyl;
each R is2Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, carbomethoxy, carboethoxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, amido, aldehyde, alkenyl, alkynyl;
each R is3Each independently of the otherIs selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, carbomethoxy, carboethoxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, amido, aldehyde, alkenyl, alkynyl;
in another preferred embodiment, the compound is one compound selected from the following compounds:
in another preferred embodiment, the compound of formula (I) is selected from the group consisting of: FTO-01, FTO-02, FTO-03, FTO-04, FTO-05, FTO-06, FTO-07, FTO-09 and FTO-08.
In another preferred embodiment, the inhibitor composition is for use in non-therapeutically inhibiting the activity of an FTO protein in vitro.
In another preferred embodiment, the compound of formula (I) is used as an active ingredient in the inhibitor composition, and the active ingredient is used to selectively inhibit FTO protein activity.
In another preferred embodiment, the FTO protein inhibitor does not inhibit an ALKB family protein selected from the group consisting of: ALKBH2, ALKBH3, ALKBH5, or a combination thereof.
In another preferred embodiment, the FTO protein inhibitor does not inhibit other ALKB family proteins other than FTO proteins. In another preferred embodiment, said inhibition comprises inhibiting the activity of FTO on DNA substrates and/or the activity of FTO on RNA substrates.
In another preferred embodiment, the disease is selected from the group consisting of: obesity, bacterial or viral infections, cancer, Metabolic Syndrome (MS), Type 2 diabetes, T2D, cardiovascular disease (CVD), hypertension, and stroke, among others.
In a second aspect of the invention, there is provided an inhibitor composition for selectively inhibiting FTO protein, said inhibitor comprising (a) an inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) optionally a pharmaceutically acceptable carrier.
In another preferred embodiment, the carrier is a liquid and the concentration of the compound of formula (I) in the composition is 300. mu.M or less, preferably 100. mu.M or less, more preferably 25. mu.M or less.
In a third aspect of the invention, there is provided the use of a compound of formula (I),
wherein each group is as defined above;
characterized in that it is used for non-therapeutically inhibiting the activity of FTO protein in vitro.
In another preferred embodiment, the inhibition is selective inhibition of FTO protein activity.
In another preferred embodiment, said selective inhibition of the activity of the FTO protein is not inhibitory to an ALKB family protein selected from the group consisting of: ALKBH2, ALKBH3, ALKBH5, or a combination thereof; preferably, said selective inhibition of the activity of the FTO protein means that no inhibition is exerted on other proteins of the ALKB family than the FTO protein.
In another preferred embodiment, said inhibition comprises inhibiting the activity of FTO on DNA substrates and/or the activity of FTO on RNA substrates.
In a fourth aspect of the invention, there is provided a use of a compound of formula I,
wherein each group is as defined above;
wherein the compound of formula I is used for treating diseases related to the expression amount of FTO protein; preferably, the disease is caused by excessive expression or activity of FTO protein.
Within the scope of the present invention, said technical features of the present invention and those specifically described in the following examples may be combined with each other to constitute new or preferred technical solutions.
Detailed Description
The research finds that the compounds with the structure shown as the general formula I can selectively inhibit the activity of FTO protein, and meanwhile, have no inhibiting effect on other members of an AlkB family which belongs to the same genus as FTO, which indicates that the compounds can selectively inhibit the FTO. Based on the above findings, the inventors have completed the present invention.
Specific examples
Exemplary embodiments of the present invention will be described below with reference to the accompanying drawings to assist understanding of the present invention.
Examples
Experimental example 1: high throughput virtual screening based on molecular dynamics simulation
The basic process of the virtual screening is to construct a pharmacophore model, molecular docking, molecular dynamics simulation, MM/PBSA energy calculation and activity test (figure 1). Because small molecule inhibitors have different binding sites in FTO protein, two pharmacophore models are constructed in the invention, and the used crystal structures are respectively PDB: 4CXW, 4CXX and 4 CXY; PDB No.: 4ZS 2. Using these two pharmacophore models, approximately 20 million compounds from SPECS (http:// www.specs.net) commercial database were individually prescreened, followed by molecular docking, and further screening by scoring functions and rationality of molecular conformation. Then, molecular dynamics simulation and MM/PBSA energy calculation were performed, and finally, 26 candidate compounds were selected and purchased by energy score, and 2 active compounds were obtained by activity test.
Experimental example 2: chemical preparation of 9- (2-carboxyphenyl) xanthene compounds.
Preparation of FTO-02
1.21g of resorcinol, 741mg of phthalic anhydride and 7.5mL of methanesulfonic acid were reacted at 100 ℃ for 24 hours while introducing nitrogen under stirring. Cooled to room temperature, the reaction mixture was poured into 30mL of ice water to precipitate a solid, which was then pumped outAnd (5) filtering. The wet residue was used directly in the next reaction without drying. The resulting solution was dissolved in 30mL of a 4M NaOH aqueous solution and stirred for 30 min. The solution was adjusted to pH < 5 with concentrated HCl and a large amount of solid precipitated, filtered off with suction, washed with water and purified on a column to give the title compound (1.35g, 81%).1H NMR(400MHz，MeOD)δ8.06(d，J＝7.6Hz，1H)，7.80 (t，J＝7.4Hz，1H)，7.73(t，J＝7.5Hz，1H)，7.25(d，J＝7.5Hz，1H)，6.77(d，J＝2.1Hz，2H)，6.69(d，J＝ 8.7Hz，2H)，6.62(dd，J＝8.7，2.1Hz，2H).13C NMR(101MHz，MeOD)δ169.80，153.42，134.86，129.79， 129.15，127.21，125.17，124.58，112.96，110.73，102.14.HRMS(ESI-TOF)m/z[M+H]+calcd for C20H12O5333.0758，found 333.0751。
Preparation of FTO-04
Synthesis methods such as compound FTO-02, 1.59g of 2-chloro-1, 3-benzenediol, 741mg of phthalic anhydride and 7.5mL of methanesulfonic acid, purification by column chromatography gave the title compound (1.70g, 85%).1H NMR(400MHz，MeOD)δ8.03(d，J＝7.5Hz，1H)，7.80 (t，J＝7.4Hz，1H)，7.72(t，J＝7.5Hz，1H)，7.26(d，J＝7.6Hz，1H)，6.73(d，J＝8.8Hz，2H)，6.57(d，J＝ 8.8Hz，2H).13C NMR(126MHz，MeOD)δ169.68，148.19，135.36，130.01，126.54，125.96，124.64，124.00， 112.36，111.15，108.33.HRMS(ESI-TOF)m/z[M+H]+calcd for C20H10O5Cl2400.9978，found 400.9974。
Preparation of FTO-06
Synthesis procedures such as compound FTO-02, 4-fluororesorcinol 1.41g, phthalic anhydride 741mg and methanesulfonic acid 7.5mL were performed and column-purified to give the title compound (1.38g, 75%).1H NMR(400MHz，MeOD)δ8.08(d，J＝7.7Hz，1H)，7.83(t， J＝7.0Hz，1H)，7.76(t，J＝7.2Hz，1H)，7.27(d，J＝7.6Hz，1H)，6.86(d，J＝7.5Hz，2H)，6.42(d，J＝11.1 Hz，2H).13C NMR(101MHz，DMSO)δ168.75，152.15，149.51，148.11，147.98，147.82，136.17，130.83， 126.38，125.50，124.32，114.30，114.09，108.86，105.30.HRMS(ESI-TOF)m/z[M+H]+calcd for C20H10O5F2369.0569，found369.0568。
Preparation of FTO-07
Synthesis methods such as compound FTO-02, 4-chlororesorcinol 1.59g, phthalic anhydride 741mg and methanesulfonic acid 7.5mL, purification on a column afforded the title compound (1.83g, 91%).1H NMR(400MHz，DMSO)δ11.10(s，2H)，8.02(d，J＝7.6Hz， 1H)，7.83(td，J＝7.5，1.1Hz，1H)，7.76(td，J＝7.5，0.9Hz，1H)，7.34(d，J＝7.6Hz，1H)，6.92(s，2H)，6.66 (s，2H).13C NMR(101MHz，DMSO)δ168.74，155.59，151.97，150.56，136.38，131.00，128.64，126.37， 125.55，124.41，116.72，110.94，104.18.
Preparation of FTO-11
Synthesis procedures such as compound FTO-02, 4-methoxyresorcinol 154mg, phthalic anhydride 74mg and methanesulfonic acid 1mL, purification on a column afforded the title compound (155mg, 79%).1H NMR(500MHz，MeOD)δ8.22(d，J＝7.6Hz，1H)，7.81 (t，J＝7.5Hz，1H)，7.75(t，J＝7.4Hz，1H)，7.39(d，J＝7.3H2，1H)，6.81(s，2H)，6.33(s，2H)，3.62(s，6H).13C NMR(101MHz，MeOD)δ168.57，149.16，147.79，145.40，132.57，131.75，129.67，129.58，129.04， 113.88，105.21，102.66，54.88.
Preparation of FTO-15
Synthesis procedures such as compound FTO-02, 4-fluororesorcinol 159mg, 4, 5-dichlorophthalic anhydride 109mg and methanesulfonic acid 1mL, purification on a column afforded the title compound (157mg, 72%).1H NMR(500MHz，MeOD)δ8.24(s，1H)，7.53(s，1H)，6.86 (d，J＝7.2Hz，2H)，6.60(d，J＝10.6Hz，2H).13C NMR(126MHz，DMSO)δ166.65，149.57，148.10，147.67，138.95，134.12，127.78，127.52，126.97，114.68，114.51，108.12，105.17.
Preparation of FTO-16
Synthesis procedures such as compound FTO-02, 4-fluororesorcinol 159mg, 3, 6-difluorophthalic anhydride 92mg and methanesulfonic acid 1mL, purification on a column afforded the title compound (156mg, 77%).1H NMR(500MHz，MeOD)δ7.57-7.44(m，2H)，6.85(d， J＝7.3Hz，2H)，6.71(d，J＝11.0Hz，2H).13CNMR(101MHz，MeOD)δ164.28，156.42，156.39，153.82， 151.43，150.01，148.28，147.60，123.99，123.79，119.74，119.45，112.69，112.48，104.87，104.84.
Experimental example 3: the non-denaturing polyacrylamide gel electrophoresis detection structure is the inhibition effect of the compound with the general formula I on FTO.
The pET-28a-FTO prokaryotic expression vector plasmid is transformed into a BL21(DE3) prokaryotic expression strain, the strain is shaken at the temperature of 37 ℃ and 200rpm until the OD600 is 0.2-0.6, and then IPTG (isopropyl-beta-thiogalactopyranoside) is added for 0.5mM and 16 ℃ for 16 hours. After the thalli are taken and ultrasonically crushed, the supernatant is taken at 13000rpm for 30 min. The purity of FTO is more than 90 percent after NI-NTA and Sephadex-200 purification. Synthesis of a compound containing m6A49 bp ssDNA strand of sequence (' 5-TAGACATTGCCATTCTCGATAGG (M6A) -TCCGGTCAAACCTAGACGAATTCCA-3 ') containing 50mM Tris (hydroxymethyl) aminomethane-HCl buffer (Tris-HCl, pH 7.5) 300. mu.M α -ketoglutaric acid (2OG), 280. mu.M ferrous sulfate ((NH. sub.6. sup.3532) -TCCGGTCAAACCTAGACGAATTCCA-3 ') in a 100. mu.l reaction4)2Fe(SO4)2) 2mM L-ascorbic acid, 1 mu M ssDNA, 1 mu MFTO and 100 mu M compound are reacted for 2h at 25 ℃, then the single strand is annealed, then the single strand is cut by DPNII, after the single strand is cut, the band intensity is detected by 20% non-denatured polyacrylamide gel electrophoresis, if the single strand can be cut, the compound has no inhibition effect on FTO, if the cut band intensity is reduced, the compound has inhibition effect on FTO, and the preliminary screening is carried out according to the principle. Partial plots with inhibitory effect were used for concentration gradient inhibition as shown in FIG. 2. According to the compound obtained by primary screening, the two compounds are found to be similar in structure, and the parent nucleus structure is shown as a general formula I, so that structural modification is carried out.
Shown in this text "
"means n, m or t R1、R2And R3Substituted at any position on the phenyl ring, X ═ O or NH.
Specific compounds having the structure shown in formula I are shown below, and show activity inhibition to FTO to different degrees.
Experimental example 4: high performance liquid chromatography verifies that the compound with the structure as the general formula I selectively inhibits the demethylation activity of FTO.
Then, the active compound screened in the experimental example 2 is added with 10 mu MsRNA 1 mu M FTO in 100 mu l of reaction system, the compound to be detected with different concentrations is added to react for 30min at 25 ℃, the reaction system is inactivated at 5min at 95 ℃, P1 enzyme and alkaline phosphatase are added to carry out enzyme digestion, and then the liquid phase mass spectrometer is used for detecting M6Ratio of A to G. The concentration of the inhibitor when the inhibition rate of the enzyme activity reaches 50% is defined as IC50(FIG. 3). The calculation method of the inhibition rate is as follows: inhibition { (experimental group m)6A/Experimental group G/control group G)/(Control group m6A)}*100％
Table 1 shows the inhibition of FTO activity of some of the engineered compounds.
Table 1: inhibition of FTO demethylation activity of some compounds of formula I.
Experimental example 5: compounds of formula I and derivatives thereof inhibit FTO activity by non-chelating Fe (II)
Because FTO is a 2OG/Fe (II) -dependent oxygenase, addition of EDTA can chelate with Fe (II) to prevent the reaction. It must therefore be excluded that the compounds interfere by chelating iron ions, so experiments were designed to add different concentrations of excess fe (ii) over the compound, with 100 μ M compound FTO-03 added to each group, to ensure that FTO activity was not interfered with, and the results show that the compound was not dependent on fe (ii) to effect a change, indicating that the compound did not effect inhibition by chelating fe (ii) (fig. 4).
Experimental example 6: the compound of the general formula I and the derivative thereof have the function of killing tumor cells
MTT detection compound FTO-06 was used to detect the effect of activity on HL-60 and NB4 cells, cells were treated with different concentrations of compounds for 48h, incubated for 4h with MTT, solubilized formazan with DMSO, and then cell viability was calculated by measuring OD at 490 nm. The results show that FTO-06 has a certain killing effect on tumor cells HL-60 and NB4 (figure 5).
Experimental example 7: inhibition of FTO activity in cells by compounds of formula I and derivatives thereof
The compounds FTO-01, FTO-02 and FTO-09 have the effect of inhibiting FTO in human cervical carcinoma cells Hela. In the experiment, Hela cells are respectively treated by compounds with different concentrations, and m6A/A (‰) in mRNA is detected by a liquid phase mass spectrometer, and the result shows that m of the cells after being treated by the compounds is m6The level of A is obviously increased (figure 6), which shows that the 9- (2-carboxyphenyl) xanthene compound can obviously inhibit the activity of FTO in cells.
Experimental example 8: the compound of the general formula I and the derivatives thereof have no inhibition effect on ALKBH5
The plasmid of the pET-28a-ALKBH5 prokaryotic expression vector is transformed into a BL21(DE3) prokaryotic expression strain, the strain is shaken at the temperature of 37 ℃ and the rpm of 200 until the OD600 is 0.2-0.6, and then IPTG is added into the strain for 0.5mM and the temperature of 16 ℃ for 16 hours. After the thalli are taken and ultrasonically crushed, the supernatant is taken at 13000rpm for 30 min. The purity of FTO is more than 90 percent after NI-NTA and Sephadex-200 purification. Synthesis of a compound containing m6A49 bp ssDNA strand of sequence (' 5-TAGACATTGCCATTCTCGATAGG (M6A) -TCCGGTCAAACCTAGACGAATTCCA-3 ') containing 50mM Tris (hydroxymethyl) aminomethane-HCl buffer (Tris-HCl, pH 7.5) 300. mu.M α -ketoglutaric acid (2OG), 280. mu.M ferrous sulfate ((NH. sub.6. sup.3532) -TCCGGTCAAACCTAGACGAATTCCA-3 ') in a 100. mu.l reaction4)2Fe(SO4)2) 2mM L-ascorbic acid, 1 mu M ssDNA, 1 mu MFTO and 100 mu M compound react for 2h at 25 ℃, then the single strand is annealed, then the single strand is cut by DPNII, after the single strand is cut, the band intensity is detected by 20% non-denatured polyacrylamide gel electrophoresis, if the single strand can be cut, the compound has no inhibition effect on ALKBH5, if the cut band intensity is reduced, the compound has inhibition effect on ALKBH5, and the activity inhibition effect of the compound on ALKBH5 is detected according to the principle. The structure shows that the compound has no obvious activity inhibition effect on ALKBH5 (figure 7).
Experimental example 9: effect of Compounds of formula I and derivatives thereof on lipid droplet formation
Fat drop formation experiments are further carried out by inducing the differentiation of 3T3-L1 preadipocytes, and the results show that FTO-06 can inhibit the formation of fat drops of 3T3-L1 preadipocytes and obviously reduce the expression of a transcription factor CEBP α related to fat formation (figure 8).
Drawings
FIG. 1 is a schematic diagram of high throughput virtual screening of compounds based on protein structure and FTO-06 docking with enzyme;
FIG. 2 shows the selective activity inhibition of FTO by the compound of formula I and its derivatives as shown by the results of native polyacrylamide gel electrophoresis;
FIG. 3 shows the effect of selective inhibition of FTO by compounds of general formula I and their derivatives;
compounds of general formula I and derivatives thereof, shown in figure 4, inhibit FTO activity by non-chelating fe (ii) means.
FIG. 5 shows the effect of compounds of formula I and their derivatives on the viability of different tumor cells;
the compound with the structure shown in the general formula I in figure 6 and the derivative thereof have the effect of inhibiting the activity of FTO at the cellular level.
The compound with the structure shown in the general formula I in figure 7 has no inhibition effect on ALKBH 5.
FIG. 8 shows the inhibition of lipid droplet formation by compounds of formula I.
FIG. 9FTO inhibitors of general formula I.
Claims (9)
1. The 9- (2-carboxyphenyl) xanthene compound shown in the following general formula I and the salt thereof can be used as the medicine for treating diseases taking FTO as a target point:
wherein:
x ═ O or NH;
each R is1Each independently selected from the group consisting of halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde, ester, amide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted carbonyl C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-9 membered heterocyclyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde group, ester group, amide group, C1-C6 alkyl, C1-C6 alkoxy, carbonyl C1-C6 alkyl, C6-C12 aryl, 5-9 membered heterocyclic group;
each R is2Each independently selected fromHalogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde, ester, amide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted carbonyl C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-9 membered heterocyclic group, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde group, ester group, amide group, C1-C6 alkyl, C1-C6 alkoxy, carbonyl C1-C6 alkyl, C6-C12 aryl, 5-9 membered heterocyclic group;
each R is3Each independently selected from the group consisting of halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde, ester, amide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted carbonyl C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-9 membered heterocyclyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: halogen, amino, hydroxyl, nitro, cyano, carboxyl, aldehyde group, ester group, amide group, C1-C6 alkyl, C1-C6 alkoxy, carbonyl C1-C6 alkyl, C6-C12 aryl, 5-9 membered heterocyclic group;
n, m and t are each selected from the following integers: 0. 1, 2, 3, 4
The above compounds are all used for a use selected from the group consisting of: (1) compositions of FTO protein inhibitors; (2) preparing a pharmaceutical composition for treating FTO related diseases; (3) and in vitro use as FTO inhibitors.
2. The use according to claim 1,
each R is1Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, aldehyde, carbomethoxy, carboethoxy, amido, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, and the likeSubstituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted propoxy, substituted or unsubstituted acetyl, substituted or unsubstituted propionyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indolyl, or substituted or unsubstituted quinolyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolinyl;
each R is2Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, aldehyde, carbomethoxy, carboethoxy, carboxamide, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted propoxy, substituted or unsubstituted acetyl, substituted or unsubstituted propionyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indolyl, or substituted or unsubstituted quinolyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolinyl;
each R is3Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxylA group, an aldehyde group, a carbomethoxy group, an carbethoxy group, an amide group, a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted propoxy group, a substituted or unsubstituted acetyl group, a substituted or unsubstituted propionyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted indolyl group, or a substituted or unsubstituted quinolyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group; wherein, the substitution refers to that the hydrogen atom on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolinyl;
n is an integer selected from the group consisting of: 0. 1, 2, 3, 4;
and/or m is an integer selected from the group consisting of: 0. 1, 2, 3, 4, 5;
and/or t is an integer selected from the group consisting of: 0. 1, 2, 3, 4 and 5.
3. The use according to claim 1,
each R is1Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, carbomethoxy, carboethoxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, amido, aldehyde, alkenyl, alkynyl;
each R is2Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, carbomethoxy, carboethoxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyranylPyrrolyl, pyridyl, indolyl, quinolyl, amido, aldehyde, alkenyl and alkynyl;
each R is3Each independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, carboxyl, carbomethoxy, carboethoxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl, propionyl, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, indolyl, quinolyl, amido, aldehyde, alkenyl, alkynyl.
4. The use according to claim 1, wherein the compound is one compound selected from the group consisting of:
5. the use of claim 1, wherein the inhibitor composition is for non-therapeutically inhibiting the activity of an FTO protein in vitro.
6. The use according to claim 1, wherein in the inhibitor composition, the compound of formula (I) is used as an active ingredient and the active ingredient is used to selectively inhibit FTO protein activity.
7. The use according to claim 1, wherein the disease is selected from the group consisting of: obesity, bacterial or viral infections, cancer, Metabolic Syndrome (MS), Type 2 diabetes, T2D, cardiovascular disease (CVD), hypertension, and stroke, among others.
8. An inhibitor composition for selectively inhibiting FTO protein, said inhibitor comprising (a) an inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) optionally a pharmaceutically acceptable carrier.
9. Use of a compound of formula I for the treatment of a disease associated with FTO protein expression; the diseases are caused by excessive expression or high activity of FTO protein.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1331797A (en) * | 1998-12-21 | 2002-01-16 | 福托金公司 | High energy phototherapeutic agents |
| CN103087545A (en) * | 2012-12-13 | 2013-05-08 | 大连理工大学 | Fluorochrome taking fluorescein as matrix, as well as preparation method and application thereof |
| CN104069092A (en) * | 2014-07-14 | 2014-10-01 | 中国科学院上海药物研究所 | Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor |
| US20140343052A1 (en) * | 2013-03-12 | 2014-11-20 | Daiichi Sankyo Company, Limited | Phenylxanthene Derivatives |
| CN108853495A (en) * | 2018-06-01 | 2018-11-23 | 大连理工大学 | Composite nanoparticle, preparation method and application of the one kind based on fluorescein derivative dye |
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2018
- 2018-12-17 CN CN201811607418.3A patent/CN111317731A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1331797A (en) * | 1998-12-21 | 2002-01-16 | 福托金公司 | High energy phototherapeutic agents |
| CN103087545A (en) * | 2012-12-13 | 2013-05-08 | 大连理工大学 | Fluorochrome taking fluorescein as matrix, as well as preparation method and application thereof |
| US20140343052A1 (en) * | 2013-03-12 | 2014-11-20 | Daiichi Sankyo Company, Limited | Phenylxanthene Derivatives |
| CN104069092A (en) * | 2014-07-14 | 2014-10-01 | 中国科学院上海药物研究所 | Use of 2-(substituted phenylamino) benzoic acid and ester compound thereof in preparation of FTO (Fat Mass and Obesity-Associated Protein) inhibitor |
| CN108853495A (en) * | 2018-06-01 | 2018-11-23 | 大连理工大学 | Composite nanoparticle, preparation method and application of the one kind based on fluorescein derivative dye |
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