CN109721603B - Hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor and preparation method and application thereof - Google Patents
Hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a hypoxia targeting tumor cell DNA repair enzyme MGMT inhibitor, a preparation method and application thereof. The structural formula of the compound is shown as the formula I:
in the formula I, R1、R2、R3H or C is an alkyl group of 1 to 4. The preparation method comprises the following steps: in an organic solvent, mixing a compound shown as a formula II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine for reaction, mixing the obtained reaction system with a compound shown as a formula III for amidation reaction, and obtaining the compound. The compound can be used as a hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor, has a hypoxia activation group, is used as a prodrug, and can be specifically activated and released to obtain an active MGMT inhibitor in a hypoxic solid tumor area, so that the compound can specifically overcome MGMT-mediated drug resistance in tumor cells, reduce toxic and side effects on normal cells during combined chemotherapy with an alkylating agent, and has a simple preparation method.
Description
Technical Field
The invention relates to a hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor, a preparation method and application thereof, and belongs to the field of tumor inhibitors.
Background
Among the numerous cancer treatments, chemotherapy remains an important role, with DNA alkylating agents being the most widely used class of antineoplastic chemotherapeutic drugs in clinical use today. The alkylating agent can decompose under physiological conditions to generate alkyl positive ions, further attack base sites of DNA, generate a series of DNA damage products, inhibit biochemical metabolic processes such as DNA replication and transcription, and further kill cancer cells. Clinically used alkylating agents are mainly methylating agents (such as temozolomide TMZ, dacarbazine DTIC, procarbazine PCB and streptozotocin STZ) and chloroethylating agents such as chloroethylnitrosourea (carmustine BCNU, nimustine)Monatin ACNU, monatin MeCCNU, and lomustine CCNU, etc.). These alkylating agents are mainly through O attack on DNA guanine6Bit, produce O6The site alkyl guanine DNA adduct inhibits the biochemical metabolic processes of DNA replication, transcription and the like, thereby playing an anticancer effect. However, O expressed in cancer cells6-alkylguanine-DNA alkyltransferase (AGT/MGMT) capable of converting guanine O6the damage is transferred to 145 cysteine residues (Cys145) in the self-activity center to repair the damaged DNA, so that the cancer cells generate drug resistance to the alkylating agent and the anticancer effect of the drug is reduced-Type p-guanine O6very sensitive as a site alkylating agent ② Mer)+Type p-guanine O6The site alkylating agent is drug resistant. Thus, Mer is suppressed+The activity of MGMT in cancer cells becomes a key factor for improving the anticancer effect of the alkylating agent, and a series of MGMT inhibitors are synthesized to be used as prodrug adjuvant chemotherapy.
Disclosure of Invention
The compound can be used as a hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor, has a hypoxia activation group, is used as a prodrug, and can be specifically activated and released in a hypoxic solid tumor area to prepare an active MGMT inhibitor, so that MGMT-mediated drug resistance in tumor cells can be specifically overcome, toxic and side effects on normal cells during combined chemotherapy with an alkylating agent are reduced, and the preparation method is simple.
The invention provides a compound, which has a structural formula shown in a formula I:
in the formula I, R1、R2、R3H or C is an alkyl group of 1 to 4.
In the invention, the alkyl with C being 1-4 is a straight chain or branched chain group.
The invention also provides a preparation method of the compound, which comprises the following steps: in an organic solvent, mixing a compound shown as a formula II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine for reaction, mixing an obtained reaction system with a compound shown as a formula III for amidation reaction, and obtaining a compound shown as a formula I;
in the formula II, R1、R2、R3H or C is an alkyl group of 1 to 4.
In the invention, the structural formula of the compound is shown as a formula I-1:
in the above preparation method, the molar ratio of the compound represented by the formula II to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 1-hydroxybenzotriazole and the triethylamine may be 1: 1-2: 0.9-1.2: 1.5-2.5; specifically 1:1.5:1: 2;
the molar ratio of the compound of formula ii to the compound of formula iii may be 1:1 to 1.5, specifically 1:1.
In the above preparation method, the organic solvent is at least one of dichloromethane, acetone and chloroform;
the temperature of the mixing reaction can be-10-5 ℃, specifically 0 ℃, and the time can be 0.5-2.5 hours, specifically 1 hour;
the temperature of the amidation reaction is room temperature, and the time can be 1.5-3 h, specifically 2 h.
In the above preparation method, the steps for preparing the compound represented by the formula II are as follows:
1) in methanesulfonic acid, mixing a compound shown as a formula IV and 3, 3-dimethyl methyl acrylate for reaction to obtain a compound shown as a formula V;
2) reacting the compound shown in the formula V with N-bromosuccinimide in a polar solvent to obtain a compound shown in a formula II;
in the formulae IV and V, R1、R2、R3H or C is an alkyl group of 1 to 4.
In the step 1) of the preparation method, the reaction temperature may be 50-90 ℃, specifically 70 ℃, 50-70 ℃, 70-90 ℃ or 60-80 ℃, and the reaction time may be 2-5 hours, specifically 3 hours, 3-5 hours, 2-3 hours or 2-4 hours;
the molar ratio of the compound shown in the formula IV to the 3, 3-dimethyl methyl acrylate can be 1: 1-2;
in the step 2), the reaction temperature is room temperature, and the reaction time can be 1-3 h, specifically 2.5h, 1-2.5 h or 2.5-3 h;
the polar solvent is a mixture of acetonitrile and water;
the molar ratio of the compound shown in the formula V to the N-bromosuccinimide can be 1: 1-3.
In the invention, the room temperature is common knowledge in the field and refers to 10-30 ℃.
In the above preparation method, the steps for preparing the compound represented by the formula III are as follows:
a) in an organic solvent 1, mixing a compound shown as a formula VI with N-methyl pyrrolidine for reaction to obtain a compound shown as a formula VII;
b) in an organic solvent 2, 3-aminomethyl benzyl alcohol and ethyl trifluoroacetate are mixed and react to obtain a compound shown as a formula VIII;
c) mixing the compound shown in the formula VII and the compound shown in the formula VIII for reaction in an inert atmosphere to obtain a compound shown in the formula IX;
d) and (2) reacting the compound shown in the formula IX in a polar solvent 1 under the condition of base catalysis to obtain the compound shown in the formula III.
In the step a) of the preparation method, the molar ratio of the compound shown in the formula VI to the N-methylpyrrolidine is 1: 1-2, specifically 1: 1; the reaction temperature can be 15-40 ℃, specifically 25 ℃, and the reaction time can be 18-24 hours, specifically 20 hours, 18-20 hours or 20-24 hours;
the organic solvent 1 is N, N-dimethylformamide or dimethyl sulfoxide;
in the step b), the molar ratio of the 3-aminomethyl benzyl alcohol to the ethyl trifluoroacetate can be 1: 0.5-1.5, specifically 1: 1; the reaction temperature can be room temperature, and the reaction time can be 1-3 h, specifically 2h, 1-2 h, 2-3 h or 1.5-2.5 h; the reaction is carried out in the presence of triethylamine;
the organic solvent 2 is dry methanol or dry acetonitrile;
in the step c), the molar ratio of the compound shown as the formula VII to the compound shown as the formula VIII can be 1: 1-2, and specifically can be 1: 1; the reaction temperature is room temperature, and the reaction time can be 1-4 h, specifically 2.5h, 1-2.5 h, 2.5-4 h or 2-3 h; the reaction solvent is N, N-dimethylformamide or dimethyl sulfoxide, and the reaction is carried out under the catalysis of potassium tert-butoxide;
the inert atmosphere is nitrogen, argon or helium;
in the step d), the polar solvent 1 is a mixed solution of methanol and water with a volume ratio of 17: 1; the reaction is carried out in the presence of potassium carbonate or sodium carbonate.
The invention also provides a targeting tumor cell DNA repair enzyme MGMT inhibitor which is a compound shown in the formula I;
preferably, the tumor cell targeted DNA repair enzyme MGMT inhibitor is a tumor cell targeted under hypoxic condition.
The invention also provides a hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor which is a compound shown in the formula I.
The compound shown in the formula I is applied to preparing the medicine for treating tumors. The tumor is solid tumor, including nervous system tumor, digestive system tumor, and reproductive system tumor; the nervous system tumor specifically comprises human brain glioma, the digestive system tumor specifically comprises colon cancer, and the reproductive system tumor specifically comprises breast cancer or cervical cancer.
The mechanism flow of the compound shown in the formula I as the hypoxia targeting tumor cell DNA repair enzyme MGMT inhibitor is as follows:
from the above reaction mechanism, it can be seen that the hypoxia-activating group in the compound of formula I is a group of the compound of formula ii, which is easily removed, yielding the MGMT inhibitor compound of formula iii.
The invention has the following advantages:
the compound can be used as a hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor, has a hypoxia activating group, is used as a prodrug, can be decomposed in a hypoxia area of solid tumor to obtain a high-activity MGMT inhibitor, can specifically overcome drug resistance mediated by the DNA repair enzyme MGMT in the tumor cell, and simultaneously reduces toxic and side effects on normal tissues, and has the advantages of simple preparation method and easy synthesis of raw materials.
Drawings
FIG. 1 is a flow chart of the mechanism of hypoxia activation of the compounds of the present invention.
FIG. 2 is a HPLC-UV and MS chart of Compound 2 in example 1 of the present invention.
FIG. 3 is a mass spectrum of Compound 2 of example 1 of the present invention.
FIG. 4 is a HPLC-UV and MS chart of Compound 3 in example 1 of the present invention.
FIG. 5 is a mass spectrum of Compound 3 of example 1 of the present invention.
FIG. 6 is a HPLC-UV and MS plot of the target compound in example 1 of the present invention.
FIG. 7 is a mass spectrum of a target compound in example 1 of the present invention.
FIG. 8 is a hydrogen spectrum of a target compound in example 1 of the present invention.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Examples 1,
1. Synthesis of Compound of formula V, R1、R2、R3Compound 2 which is methyl:
20.0mL of methanesulfonic acid are taken in a 100mL measuring flask, after heating to 70 ℃ 2.0g of trimethylhydroquinone (13.14mmol) and 1.7g of methyl 3, 3-dimethacrylate (14.9mmol) are added and the reaction is continued at 70 ℃ for 3h, after which 250mL of water and 75mL of ethyl acetate are added to the reaction mixture and the extraction is continued (3 times), the organic phase is combined with water and saturated NaHCO3Washed once with saturated NaCl, anhydrous MgSO4Drying and concentrating under reduced pressure to obtain a crude product as a yellow-white solid. Recrystallization from ethyl acetate gave 22.5 g (10.67mmol, 81.2% yield) of white crystals. TLC monitoring reaction: cyclohexane: ethyl acetate 1:1.
The structure of compound 2 was confirmed: as shown in fig. 2 and 3.
2. Synthesis of Compound of formula II R according to Compound 2 of the following reaction scheme1、R2、R3Compound 3 which is methyl:
2.5g of Compound 2(10.67mmol) was weighed out and suspended in a 15% acetonitrile solution (130 mL). Subsequently, 40mL (v/v, 40%) of an acetonitrile solution containing 2.6g N-bromosuccinimide (14.6mmol) was added dropwise to the solution, and the reaction was stirred dropwise>1h (specifically room temperature 25 ℃, reaction time 2.5 h). After the addition, the reaction is continued to be stirred for 30min, and then 330mL of water is added for dilutionThe reaction solution was released and extracted with ether 3 times with 75mL each time. The combined organic phases were washed 2 times with water (100 mL each) anhydrous MgSO4Drying and concentrating under reduced pressure to obtain a crude product which is a yellow solid. Recrystallization from ethyl acetate gave 2.15g of yellow crystals 3(8.59mmol, yield 80.5%). TLC monitored the reaction product: cyclohexane: ethyl acetate 1:1.
The structure of compound 3 was confirmed: as shown in fig. 4 and 5.
3. Preparation of a Compound of formula III:
a) in N, N-dimethylformamide, the molar ratio of the compound shown in the formula VI to N-methylpyrrolidine is 1: 1; the reaction temperature can be 25 ℃ at room temperature, and the mixture is stirred and reacted for 20h to obtain a compound shown in a formula VII;
b) in dry methanol, the mol ratio of 3-aminomethyl benzyl alcohol to ethyl trifluoroacetate is 1:1, and triethylamine is added for stirring and mixing reaction; the reaction time is 2 hours at the room temperature of 25 ℃; obtaining a compound shown as a formula VIII;
c) mixing a compound shown as a formula VII and a compound shown as a formula VIII in a molar ratio of 1:1 in a nitrogen atmosphere, adding potassium tert-butoxide, and stirring at room temperature of 25 ℃ for reaction for 2.5h to obtain a compound shown as a formula IX;
d) and (2) reacting the compound shown as the formula IX in a mixed solution of methanol and water in a volume ratio of 17:1 under the condition of potassium carbonate to obtain the compound shown as the formula III.
4. Synthesis of Compound I R with Compound III according to the following reaction scheme Compound 31、R2、R3A compound represented by the formula I-1 (target compound) which is a methyl group:
exactly 100mg of compound 3 (Mr. 250.29g/mol,0.4mmol) was weighed out and dissolved in 5mL of CH2Cl2115.02mg of EDC & HCl (Chinese name 1- (3-dimethylaminopropyl) were added-3-ethylcarbodiimide hydrochloride, Mr. 191.7g/mol,0.6mmol), 54mg HOBT (chinese name 1-hydroxybenzotriazole, Mr. 135.1mg/mol,0.4mmol), 110 μ lta (chinese name triethylamine, Mr. 101.19g/mol, ρ. 0.73g/cm30.8mmol) was added and the reaction was allowed to proceed at 0 deg.C for 1h, followed by addition of 100mg of compound 15(270g/mol,0.37mmol) and return to room temperature, and the reaction was stopped by TLC monitoring until the starting material spot disappeared. Adding 30mL of water and 30mL of ethyl acetate for extraction, washing the organic phase once with water and saturated NaCl, and removing anhydrous Na2SO4Dry overnight. (raw material ratio: acid: EDC. HCl: HOBT: TEA: amine: 1:1.5:1:2: 1). The mixture was filtered, and the residue was purified by column chromatography (methanol: dichloromethane: 1:50 to 1:10) to obtain 60mg (Mr: 502.56g/mol, 0.12mmol, yield 30%) of the desired compound.
The structure of the target compound is confirmed: as shown in fig. 6, 7 and 8.
For the compound represented by the formula I-1 synthesized by the present invention, in order to demonstrate the difference in the inhibitory activity against MGMT of the compound represented by the formula I-1 synthesized by the present invention under the hypoxic and normoxic conditions, the MGMT activity in the cells after the drug treatment was measured by the HPLC-ESI-MS/MS method (J.Chromatogr.B 2016,1033, 138-146.). The method is based on O6-benzylguanine (O)6-BG) as a substrate for MGMT, has a high affinity for MGMT. The specific determination steps are as follows: SF767 and SF763 cells (SF767 and SF763 are MGMT high expression human brain glioma cells) are treated with 100 μ M of the compound (abbreviated as drug) of formula I-1 synthesized by the invention under the condition of normal oxygen or hypoxia for 1h, then the culture medium containing the drug is discarded, PBS (NaCl137mmol/L, KCl 2.7mM, Na) is used2HPO410mM，KH2PO42mM, no calcium or magnesium) 3 times, 0.25% pancreatin was added for digestion, and the cells were collected by centrifugation. Then, 0.7mL of buffer (50mM Tris pH 8.0, 0.1mM EDTA-2Na, 1mM DTT, 5% glycerol, 0.1mM PMSF) was added thereto, and the mixture was washed 2 times, centrifuged, and the supernatant was discarded for use or stored at-80 ℃. Subsequently resuspending the cells in the above buffer until they are sonicated 5 times on ice for 30s each with 1min intervals, followed by 13000rpm centrifugation for 15min to remove cell debris, collecting the protein-containing supernatant on ice for use or rapid freezing in liquid nitrogen-Storing at 80 ℃ for later use. The protein concentration in the cellular protein extract was determined by the Bradford method.
Take 1.0 μ L of 200nM O6BG (200fmol) was added to 99. mu.L of buffer containing 100. mu.g of cell protein extract (50mM Tris-HCl, pH 7.5, 0.1mM EDTApH 8.0, 1mM dithiothreitol, 5% by volume glycerol, 0.1mM phenylmethylsulfonyl fluoride) and reacted at 37 ℃ for 1 h. After the reaction, half volume of cold acetonitrile was added to precipitate the protein, which was centrifuged at 12000rpm at 4 ℃ for 5min to obtain the supernatant. This procedure was repeated 1 time, and 2 supernatants were pooled. Subsequently, 1.0. mu.L of 1000nM D was added to the supernatant6-O6-BG as an isotope internal standard (final concentration of 5nM) was filtered through Microcon YM-10 millipore centrifuge filter tubes and the filtrate collected for HPLC-ESI-MS/MS analysis. A blank of cell-free protein extract was also set. O in the reaction system6The amount of-BG is 200 fmol.
The MGMT activity of human brain glioma cells SF767 and SF763 is changed after being treated by the compound shown in the formula I-1 synthesized by the invention under the hypoxia and normoxic conditions, and the experimental results are shown in the table 1:
TABLE 1 change in MGMT activity after SF767 and SF763 cell treatment (fmol/mg protein extract)
The results in table 1 show that the MGMT activity of the compound of formula I-1 of the present invention in the hypoxia-treated group is significantly lower than that of the normoxic control group, which indicates that the compound of the present invention has hypoxia activation and can effectively inhibit MGMT-mediated drug resistance in tumor cells, and thus can be used as a hypoxia-targeted tumor cell DNA repair enzyme MGMT inhibitor and for preparing drugs for treating tumors.
Claims (10)
1. A compound having a structural formula shown in formula I:
in the formula I, R1、R2、R3H or C is an alkyl group of 1 to 4.
2. A process for the preparation of a compound according to claim 1, comprising the steps of: in an organic solvent, mixing a compound shown as a formula II with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine for reaction, mixing an obtained reaction system with a compound shown as a formula III for amidation reaction, and obtaining a compound shown as a formula I;
in the formula II, R1、R2、R3H or C is an alkyl group of 1 to 4.
3. The method of claim 2, wherein: the molar ratio of the compound shown in the formula II to the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the 1-hydroxybenzotriazole and the triethylamine is 1: 1-2: 0.9-1.2: 1.5-2.5;
the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1:1 to 1.5.
4. The production method according to claim 2 or 3, characterized in that: the organic solvent is at least one of dichloromethane, acetone and chloroform;
the temperature of the mixing reaction is-10 to 5 ℃, and the time is 0.5 to 2.5 hours;
the temperature of the amidation reaction is room temperature, and the time is 1.5-3 h.
5. The production method according to claim 2 or 3, characterized in that: the preparation method of the compound shown in the formula II comprises the following steps:
1) in methanesulfonic acid, mixing a compound shown as a formula IV and 3, 3-dimethyl methyl acrylate for reaction to obtain a compound shown as a formula V;
2) reacting the compound shown in the formula V with N-bromosuccinimide in a polar solvent to obtain a compound shown in a formula II;
in the formulae IV and V, R1、R2、R3H or C is an alkyl group of 1 to 4.
6. The method of claim 5, wherein: in the step 1), the reaction temperature is 50-90 ℃ and the reaction time is 2-5 h;
the molar ratio of the compound shown in the formula IV to the 3, 3-dimethyl methyl acrylate is 1: 1-2;
in the step 2), the reaction temperature is room temperature, and the reaction time is 1-3 h;
the polar solvent is a mixture of acetonitrile and water;
the molar ratio of the compound shown in the formula V to the N-bromosuccinimide is 1: 1-3.
7. The production method according to claim 2 or 3, characterized in that: the preparation method of the compound shown in the formula III comprises the following steps:
a) in an organic solvent 1, mixing a compound shown as a formula VI with N-methyl pyrrolidine for reaction to obtain a compound shown as a formula VII;
b) in an organic solvent 2, 3-aminomethyl benzyl alcohol and ethyl trifluoroacetate are mixed and react to obtain a compound shown as a formula VIII;
c) mixing the compound shown in the formula VII and the compound shown in the formula VIII for reaction in an inert atmosphere to obtain a compound shown in the formula IX;
d) and (2) reacting the compound shown in the formula IX in a polar solvent 1 under the condition of base catalysis to obtain the compound shown in the formula III.
8. The method of claim 7, wherein: in the step a), the molar ratio of the compound shown in the formula VI to N-methylpyrrolidine is 1: 1-2; the reaction temperature is 15-40 ℃, and the reaction time is 18-24 h;
the organic solvent 1 is N, N-dimethylformamide or dimethyl sulfoxide;
in the step b), the molar ratio of the 3-aminomethyl benzyl alcohol to the ethyl trifluoroacetate is 1: 0.5-1.5; the reaction temperature is room temperature, and the reaction time is 1-3 h; the reaction is carried out in the presence of triethylamine;
the organic solvent 2 is dry methanol or dry acetonitrile;
in the step c), the molar ratio of the compound shown as the formula VII to the compound shown as the formula VIII is 1: 1-2; the reaction temperature is room temperature, and the reaction time is 1-4 h; the reaction solvent is N, N-dimethylformamide or dimethyl sulfoxide, and the reaction is carried out under the catalysis of potassium tert-butoxide;
the inert atmosphere is nitrogen, argon or helium;
in the step d), the polar solvent 1 is a mixed solution of methanol and water in a volume ratio of 17: 1; the reaction is carried out in the presence of potassium carbonate or sodium carbonate.
9. A tumor cell targeted DNA repair enzyme MGMT inhibitor which is a compound shown as the formula I in claim 1;
the targeted tumor cell DNA repair enzyme MGMT inhibitor is targeted to tumor cells under the condition of hypoxia.
10. The use of a compound of formula I as claimed in claim 1 for the preparation of a medicament for the treatment of tumors.
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