CN114591346B - Camptothecin prodrug, preparation method, application and salt thereof - Google Patents
Camptothecin prodrug, preparation method, application and salt thereof Download PDFInfo
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Abstract
The invention discloses a camptothecin prodrug, a preparation method, application and salts thereof, belonging to the field of anticancer drugs. The camptothecin prodrug provided by the invention is a camptothecin prodrug containing a (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment, has a novel structure, and can avoid the defect of unstable traditional borate prodrugs; the selenium atom is easily oxidized by hydrogen peroxide, so that the prodrug has good response to the hydrogen peroxide and can effectively release active drug CPT; the prodrug is specifically converted to CPT in tumor cells compared to normal cells with higher ROS content, and therefore exhibits a significant antiproliferative effect on three tumor cells and is significantly less toxic to normal cells than CPT. The compound provided by the invention can be used for preparing antitumor drugs, and provides more treatment options for patients and doctors.
Description
Technical Field
The invention belongs to the field of anticancer drugs, and in particular relates to a camptothecin prodrug, a preparation method, application and salts thereof.
Background
At present, the clinical treatment method of malignant tumors is basically surgical excision therapy, chemical drug therapy, radiation therapy and immunotherapy, wherein the chemical drug therapy is most widely applied. Camptothecin, a potent DNA topoisomerase I inhibitor, has broad spectrum antitumor activity, and since 1966, tens of thousands of camptothecin derivatives were synthesized for further enhancement of activity, stability enhancement, and pharmacokinetic properties improvement. Three camptothecin derivatives have been approved for clinical treatment abroad: topotecan, irinotecan, and belotimod. These drugs have potent anticancer activity, but are found to have significant systemic adverse effects during clinical use, including myelosuppression, gastrointestinal reactions, and granulocytopenia. These problems stem from their lack of tumor selectivity.
To address the above problems, some prodrugs have been designed to be synthesized by the unique microenvironment of the tumor. These prodrugs can be responsive to Gao Guguang Galanin (GSH), high Reactive Oxygen Species (ROS), low pH, and certain enzymes in tumor tissue, thereby releasing the active agent at the tumor site. In various cancer cells and tumor tissues, hydrogen peroxide, hydroxyl radicals, superoxide anions, etc. are produced in large amounts, so that the active oxygen levels thereof far exceed normal cells and tissues. ROS-induced oxidative stress also plays an important role in several pathological processes of tumor progression, such as metastasis, apoptosis, proliferation and angiogenesis. Hydrogen peroxide is one of the most prominent ROS in cells and readily reacts with boric acid and its esters. The reported hydrogen peroxide-responsive camptothecin prodrugs are conjugates of boric acid or boric acid ester fragments, and the structure of the boric acid and the boric acid ester has the defects of instability, difficult separation and the like.
Disclosure of Invention
The present invention aims to overcome the disadvantages of the prior art and provide a camptothecin prodrug, a preparation method, application and salts thereof.
In order to achieve the purpose, the invention is realized by adopting the following technical scheme:
a camptothecin prodrug containing a (4- ((3- (phenylsulfanyl or phenylselenyl) prop-1-en-1-yl) oxy) benzyl) carbonate fragment having the structural formula:
in the formula I, X is sulfur, selenium or tellurium;
R 1 ～R 9 is a hydrogen atom, a hydroxyl group, a cyano group or a nitro group.
Further, R 1 ～R 9 Is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyl, alkylamino, alkylaminoalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
A camptothecin prodrug containing a (4- ((3- (phenylsulfanyl or phenylselenyl) prop-1-en-1-yl) oxy) benzyl) carbonate fragment:
structural formula the enantiomers, diastereomers, tautomers or enantiomers of the structural formula of the compounds described above in the present invention.
Further: r is R 1 Is hydrogen or methyl, R 2 Is hydrogen or fluorine atom, R 3 Is methyl, fluorine, bromine or trifluoromethoxy, R 4 Is hydrogen or fluorine atom, R 5 Is hydrogen or methyl, R 6 ～R 9 Is a hydrogen atom.
A pharmaceutically acceptable salt thereof, which is characterized by being obtained by the reaction of the free base of the camptothecin prodrug containing the (4- ((3- (phenylthio or phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment with an inorganic acid or an organic acid;
the inorganic acid is hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid or perchloric acid;
the organic acid is acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, p-toluenesulfonic acid or salicylic acid.
A pharmaceutically acceptable salt formed by substituting an acidic proton of a camptothecin prodrug containing a (4- ((3- (phenylsulfanyl or phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment described in the present invention with a metal ion or complexing with an organic base;
the metal ions are alkali metal ions, alkaline earth metal ions or aluminum ions;
organic bases such as ethanolamine, diethanolamine or triethanolamine.
A method of preparing a camptothecin prodrug containing a (4- ((3- (phenylsulfanyl or phenylselenyl) prop-1-en-1-yl) oxy) benzyl) carbonate fragment, comprising the steps of:
reacting camptothecin with 4-nitro-phenyl chloroformate to obtain an activated camptothecin intermediate (1-a);
para-hydroxybenzaldehyde is sequentially subjected to NaBH 4 Reducing and TBSCl to form a protecting group, and then carrying out addition reaction with methyl propiolate to form a second intermediate (1-d), wherein the second intermediate is subjected to DIBAL-H reduction, thiocyanate or selenocyanate substitution and TBS protecting group removal under the action of TBAF to form a third intermediate (1-f);
the activated camptothecin intermediate (1-a) and the third intermediate (1-f) are subjected to alcoholysis reaction of the ester to generate the camptothecin prodrug containing the (4- ((3- (phenylthio or phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment.
The invention relates to application of a camptothecine prodrug containing (4- ((3- (phenylthio or phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment in preparation of an anticancer drug preparation.
Compared with the prior art, the invention has the following beneficial effects:
the camptothecin prodrug provided by the invention is a camptothecin prodrug containing a (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment, has a novel structure, and can avoid the defect of unstable traditional borate prodrugs; the selenium atom is easily oxidized by hydrogen peroxide, so that the prodrug has good response to the hydrogen peroxide and can effectively release active drug CPT; the prodrug is specifically converted to CPT in tumor cells compared to normal cells with higher ROS content, and therefore exhibits a significant antiproliferative effect on three tumor cells and is significantly less toxic to normal cells than CPT. The compound provided by the invention can be used for preparing antitumor drugs, and provides more treatment options for patients and doctors.
The preparation method of the camptothecin prodrug provided by the invention is simple to operate, controllable in process and capable of mass production.
The application of the camptothecin prodrug provided by the invention is used for an anti-tumor drug, can be specifically converted into CPT in tumor cells, has obvious anti-proliferation effect on three tumor cells, and has low toxicity on normal cells.
Drawings
FIG. 1 is a synthetic reaction scheme for Compound 1;
FIG. 2 shows compounds 1-8 at different equivalent weights (eq) H 2 O 2 The proportion of CPT released after 10h of action;
FIG. 3 shows that compounds 1-8 are present at 10 equivalents H 2 O 2 The proportion of CPT released after various times of action.
Detailed Description
In order that those skilled in the art will better understand the present invention, a technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in which it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
It should be noted that the terms "first," "second," and the like in the description and the claims of the present invention and the above figures are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used may be interchanged where appropriate such that the embodiments of the invention described herein may be implemented in sequences other than those illustrated or otherwise described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention is described in further detail below with reference to the attached drawing figures:
alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain groups of 1 to 12 carbon atoms. Medium-sized alkyl groups containing 1 to 10 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, etc.
Cycloalkyl refers to a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 membered fused ring or polycyclic fused ring group (fused ring means that each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system), wherein one or more rings have a fully attached pi electron system, examples of cycloalkyl include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene.
Alkoxy represents-O- (unsubstituted alkyl) and-O (unsubstituted cycloalkyl), representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.
Pharmaceutically acceptable salts refer to salts that retain the biological effectiveness and properties of the parent compound. Such salts include: (1) The acid salt is obtained by reacting the free base of the parent compound with an inorganic acid including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or an organic acid including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, p-toluenesulfonic acid, salicylic acid, and the like. (2) The acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions, or salts formed by complexation with organic bases, such as ethanolamine, diethanolamine, triethanolamine, and the like.
Pharmaceutical compositions refer to the mixing of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
Pharmaceutically acceptable carrier refers to inactive ingredients in the pharmaceutical composition that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the compound being administered, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
The aforementioned pharmaceutical compositions may include, in addition to pharmaceutically acceptable carriers, pharmaceutically acceptable adjuvants such as, for example: antibacterial, antifungal, antimicrobial, shelf-life agent, toner, solubilizing agent, thickener, surfactant, complexing agent, protein, amino acid, fat, saccharide, vitamin, mineral, trace element, sweetener, pigment, essence or combinations thereof, etc.
1. Specific examples of Synthesis of Compounds 1-8
Example 1:
(S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (phenylsulfanyl) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 1), the synthetic reaction formula for Compound 1 is shown in FIG. 1:
step one: (S) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4-nitrobenzyl) carbonate (1-a)
CPT (0.50 g,1.4 mmol) and DMAP (1.05 g,8.6 mmol) were dissolved in DCM (40 mL), and a solution of 4-nitrophenyl chloroformate (1.00 g,5.0 mmol) in DCM (20 mL) was added dropwise thereto under ice-water bath conditions, and after the completion of the dropwise addition, the mixture was stirred at room temperature overnight to give a reaction solution. The reaction mixture was sequentially subjected to 1 mol.L -1 HCl solution (60 mL. Times.3), concentrated brine (30 mL. Times.2), the resulting organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, and the filtrate was distilled off to remove the solvent and then chromatographed on silica gel (DCM: meOH=60:1) to give the product 1-a as a pale yellow solid in 90% yield. 1 H NMR(400MHz,CDCl 3 )δ8.43(s,1H),8.28–8.16(m,3H),7.97(dd,J＝8.3,1.5Hz,1H),7.87(ddd,J＝8.4,6.8,1.5Hz,1H),7.70(ddd,J＝8.2,6.8,1.1Hz,1H),7.40(d,J＝9.8Hz,3H),5.72(d,J＝17.3Hz,1H),5.43(d,J＝17.4Hz,1H),5.31(t,J＝3.4Hz,2H),2.31(ddq,J＝51.6,14.8,7.4Hz,2H),1.07(t,J＝7.5Hz,3H)。
Step two: synthesis of 4-hydroxymethylphenol (1-b)
To a stirred solution of 4-nitrobenzaldehyde (0.50 g,4.1 mmol) in methanol (20 mL) was added NaBH in portions 4 (0.31 g,8.2 mmol) and the reaction liquid stirred at room temperature for about 6h, the solvent was directly evaporated to dryness and the residue was chromatographed on silica gel (PE: ea=3:1) to give the product 1-b as a white solid in 93% yield. 1 H NMR(400MHz,d-DMSO)δ9.26(s,1H),7.10(d,J＝8.4Hz,2H),6.70(d,J＝8.4Hz,2H),4.97(t,J＝5.7Hz,1H),4.36(d,J＝5.6Hz,2H)。
Step three: synthesis of 4- (((tert-butyldimethylsilyl) oxy) methyl) phenol (1-c)
Intermediate 1-b (1.00 g,8.1 mmol) was dissolved in DMF (20 mL), and imidazole (0.55 g,8.1 mmol) and TBSCl (1.20 g,8.1 mmol) were added under ice-water bath, and the reaction was stirred at room temperature for 1h. The reaction mixture was diluted with diethyl ether (35 mL) and sequentially saturated NH 4 Cl solution (50 mL) and brine (25 mL), the resulting organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the filtrate was distilled off the solvent and separated by silica gel column chromatography (PE: EA=2:1) to give yellow oil 1-c in 98% yield. 1 H NMR(400MHz,CDCl 3 )δ7.18(d,J＝8.4Hz,2H),6.76(d,J＝8.4Hz,2H),4.67(s,2H),0.94(s,9H),0.11(s,6H)。
Step four: (E) Synthesis of methyl 3- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenoxy) acrylate (1-d)
To a solution of 1-c (1.78 g,7.5 mmol) in DCM (30 mL) under inert gas was added N-methylmorpholine (908. Mu.L, 8.2 mmol) and methyl propiolate (730. Mu.L, 8.2 mmol). After stirring the reaction at room temperature for 24h, it was diluted with DCM (30 mL) and washed with brine (50 mL), the resulting organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the filtrate was evaporated to remove the solvent and chromatographed on silica gel (PE: ea=40:1) to give 1-d as a colourless oil in 91% yield. 1 H NMR(400MHz,CDCl 3 )δ7.79(d,J＝12.2Hz,1H),7.32(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),5.54(d,J＝12.2Hz,1H),4.72(s,2H),3.73(s,3H),0.94(s,9H),0.10(s,6H)。
Step five: (E) Synthesis of 3- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenoxy) allyl alcohol (1-e)
1-d (0.30 g,0.9 mmol) was dissolved in anhydrous toluene (10 mL), and 1 mol.L was added dropwise thereto at-78deg.C under an inert gas atmosphere -1 The toluene solution of DIBAL-H was stirred for 6 hours after the completion of the dropwise addition. The reaction solution was poured into a mixture of saturated aqueous potassium sodium tartrate (20 mL) and EA (20 mL) under ice-water bath conditions, and stirred until delamination occurred. The organic phase was washed with brine (30 mL)Washing, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, evaporating the filtrate to remove the solvent, and separating by silica gel column chromatography (PE: EA=40:1-10:1) to obtain white oily liquid 1-e with the yield of 73%. 1 H NMR(400MHz,CDCl 3 )δ7.28(d,J＝8.6Hz,2H),6.97(d,J＝8.5Hz,2H),6.72(d,J＝12.1Hz,1H),5.53(dt,J＝12.2,7.2Hz,1H),4.70(s,2H),4.16(d,J＝7.2Hz,2H),0.93(s,9H),0.09(s,6H)。
Step six: (E) Synthesis of- (4- ((3- (phenylsulfanyl) -1-propenoyl) oxy) phenyl) methanol (1-f)
To a solution of 1-e (50.0 mg,0.17 mmol) in anhydrous THF (1 mL) in an inert gas atmosphere under ice-water bath conditions was added in this order n Bu 3 P (51. Mu.L, 0.20 mmol) and thiocyanate (22.9 mg,0.17 mmol). After the reaction system is continuously stirred for 30min, 1 mol.L of the catalyst is added -1 TBAF (190. Mu.L, 0.19 mmol) in THF. After stirring for 30min, saturated NH was added to the reaction solution 4 Aqueous Cl (10 mL) and EA (10 mL), the organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered off the sodium sulfate, and the filtrate was distilled off the solvent and separated by column chromatography on silica gel (PE: ea=10:1 to 2:1) to give white oily liquid 1-f in 52% yield. 1 H NMR(400MHz,CDCl 3 )δ7.56(dd,J＝13.4,9.9Hz,2H),7.35–7.29(m,3H),7.23(d,J＝8.4Hz,2H),6.68(d,J＝8.4Hz,2H),6.25(d,J＝12.0Hz,1H),5.50(dt,J＝11.9,8.4Hz,1H),4.61(s,2H),3.52(d,J＝8.3Hz,2H)。
Step seven: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (phenylsulfanyl) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 1)
1-a (0.50 g,0.97 mmol), 1-f (0.34 g,1.07 mmol), DMAP (0.71 g,5.82 mmol) and DCM (30 mL) were added to a round-bottomed flask and the resulting mixture was heated under reflux for 14h. After the reaction solution had cooled to room temperature, it was cooled to 1 mol.L - 1 HCl (30 ml×3) and brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the filtrate was distilled off the solvent and separated by column chromatography on silica gel (DCM: ea=5:1) to give product 1 as an off-white solid in 77% yield. HRMS (ESI): calculated values: 647.18465[ M+H ]] + Measurement value:647.18492。
embodiment two: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 2)
embodiment III: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (p-tolylsueleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 3)
Compound 3 was prepared as in example one. And D, replacing phenyl thiocyanate in the step six with 4-methyl phenyl selenocyanate. HRMS (ESI): calculated values: 709.14475[ M+H ]] + Measurement value: 709.14606.
embodiment four: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (2, 6-dimethylphenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 4)
fifth embodiment: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (p-fluorophenyl seleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 5)
Compound 5 was prepared as in example one. And D, replacing phenyl thiocyanate in the step six with 4-fluoro-selenocyanate. HRMS (ESI): calculated values: 713.11968[ M+H ]] + Measurement value: 713.12234.
example six: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (3, 5-difluorophenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 6)
embodiment seven: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6,7] indolizine [1,2-b ] quinolin-4-yl (4- ((3- (p-bromophenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 7)
Compound 7 was prepared as in example one. And D, replacing phenyl thiocyanate in the step six with 4-bromoselenocyanate. HRMS (ESI): calculated values: 773.03961[ M+H ]] + Measurement value: 773.04043.
example eight: (S, E) -4-ethyl-3, 14-dioxo-3, 4, 12, 14-tetrahydro-1H-pyrano [3',4': synthesis of 6, 7-indolizine [1,2-b ] quinolin-4-yl (4- ((3- (p-trifluoromethoxyphenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate (Compound 8)
2. dose-effect aging measurements of the Hydrogen peroxide response of the products of examples 1-8
Determination of the inventive Compounds at different equivalent weights H by High Performance Liquid Chromatography (HPLC) 2 O 2 By action for 10H or at 10 equivalent H 2 O 2 The proportion of CPT released after various times of action. The specific operation is as follows: test compound was prepared as a mother solution at a concentration of 200mM in DMSO, 30% H 2 O 2 The aqueous solution was diluted with water to a concentration of 200 mM. After adding 5. Mu.L of DMSO stock solution to 8 1.5mL round bottom ep tubes, 195. Mu.L, 192.5. Mu.L, 190. Mu.L, 185. Mu.L, 175. Mu.L, 170. Mu.L, 155. Mu.L and 145. Mu.L PBS buffer were added, respectively, 0. Mu.L (0 eq), 2.5. Mu.L (0.5 eq), 5. Mu.L (1 eq), 10. Mu.L (2 eq), 20. Mu.L (4 eq), 25. Mu.L (5 eq), 40. Mu.L (8 eq) and 50. Mu.L (10 eq) dilutedH 2 O 2 The aqueous solution, each ep tube was stirred in a 37℃water bath. Adding 10eq H 2 O 2 20. Mu.L of the reaction system was sampled when the reaction time reached 0.5h, 1h, 2h, 4h, 8h, 10h and 12h, diluted 50-fold with acetonitrile of chromatographic purity, filtered through a 0.22 μm filter membrane, and then subjected to HPLC (Shimadzu corporation) measurement, and the mobile phase was acetonitrile and water at a flow rate of 0.3mL/min and a sample volume of 10. Mu.L.
The results of FIGS. 2 and 3 show that except compound 1 is not associated with H 2 O 2 Other compounds are reacted with H 2 O 2 And all showed concentration dependence and time dependence.
3. In vitro antiproliferative activity assays of the Compounds of examples 1-8 on cells
The cell proliferation inhibitory activity of the compounds of the present invention against HCT-116 (human colon cancer cells), A549 (human lung cancer cells), hela (human cervical cancer cells)) and NIH-3T3 (mouse embryo cells) was determined. The cells were cultured in DMEM medium containing 10% fetal calf serum and containing penicillin 100 U.mL -1 Streptomycin 100. Mu.g.mL -1 At 37℃with 5% CO 2 Subculturing in an incubator. Cells in logarithmic growth phase were digested with pancreatin and prepared to a concentration of 1.5X10 with DMEM medium containing 10% fetal calf serum 4 ～2×10 4 Individual cells/ml of cell suspension. 200. Mu.L (about 3000-4000 tumor cells) was inoculated per well in a 96-well plate, and incubated at 37℃for 24 hours. Dissolving compound 1-8 and positive Camptothecine (CPT) in DMSO respectively to obtain a series of mother solutions (10mmol.L) -1 ，3.33mmol·L -1 ，1mmol·L -1 ，0.33mmol·L -1 ，0.1mmol·L -1 ，0.03mmol·L -1 ，0.01mmol·L -1 ，0.003mmol·L -1 ，0.001mmol·L -1 ，0.0003mmol·L -1 ) The drug mother solution prepared in DMSO was then diluted 10-fold with PBS, and 2. Mu.L of each well was administered to a 96-well plate dosing group, each group having 3 parallel wells. Adding the control group with the same volume of solvent as the medicine, standing at 37deg.C and 5% CO 2 Culturing in incubator for 72 hrmu.L of 5 mg/mL was added to each well -1 After incubation for 4h at 37 ℃, the supernatant was discarded, 150 μl of DMSO was added to each well, and after gentle shaking, the Optical Density (OD) was measured at 490nm with an enzyme-labeled instrument, and the proliferation inhibition of the tumor cells by the drug was calculated according to the following formula: cell inhibition = (1-mean OD value of dosing group/mean OD value of control group) x 100%,
calculating IC of different compounds for inhibiting proliferation of different cells by linear regression method according to inhibition rate 50 The values are shown in Table 1.
The data in Table 1 show that the compounds provided by the invention have significant inhibitory effects on the proliferation of Hela, A549 and HCT116 cells, wherein the compound 2 of example 2 has comparable proliferation activity against Hela and HCT116 cells as compared to the positive drug CPT, whereas in the normal cell NIH-3T3, the compound 2 exhibits lower cytotoxicity, indicating enhanced cell selectivity of the compound.
TABLE 1 growth inhibition of two human tumor cells by Compounds 1-8 (IC 50 ,μmol·L -1 )
The above is only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited by this, and any modification made on the basis of the technical scheme according to the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (3)
1. A camptothecin prodrug containing a (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment, characterized by the structural formula:
in the formula I, X is selenium;
R 1 is hydrogen or methyl, R 2 Is hydrogen or fluorine atom, R 3 Is methyl, fluorine, bromine or trifluoromethoxy, R 4 Is hydrogen or fluorine atom, R 5 Is hydrogen or methyl, R 6 ～R 9 Is a hydrogen atom.
2. A method of preparing a camptothecin prodrug containing a (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment according to claim 1, comprising the steps of:
reacting camptothecin with 4-nitro-phenyl chloroformate to obtain an activated camptothecin intermediate (1-a);
para-hydroxybenzaldehyde is sequentially subjected to NaBH 4 Reducing and TBSCl to form a protecting group, and then carrying out addition reaction with methyl propiolate to form a second intermediate (1-d), wherein the second intermediate is subjected to DIBAL-H reduction, selenocyanate substitution and TBS protecting group removal under the action of TBAF to form a third intermediate (1-f);
the activated camptothecin intermediate (1-a) and the third intermediate (1-f) are subjected to an alcoholysis reaction of the ester to generate a camptothecin prodrug containing a (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment.
3. Use of a camptothecin prodrug containing a (4- ((3- (phenylseleno) prop-1-en-1-yl) oxy) benzyl) carbonate fragment according to claim 1 in the preparation of an anticancer pharmaceutical formulation.
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