CN112023040B - Derivative of antineoplastic photosensitizer ALA hybrid 3-hydroxypyridine-4H-ketone and preparation method and application thereof - Google Patents
Derivative of antineoplastic photosensitizer ALA hybrid 3-hydroxypyridine-4H-ketone and preparation method and application thereof Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
The invention provides an anti-tumor photosensitizer ALA hybrid 3-hydroxypyridine-4H-ketone derivative, a preparation method thereof and application thereof in preparing photodynamic therapy medicaments, wherein the anti-tumor photosensitizer ALA hybrid 3-hydroxypyridine-4H-ketone derivative is a compound shown in a formula (I), a formula (II) or a formula (III) and a pharmaceutically acceptable salt thereof:
Description
Technical Field
The invention relates to a hydroxypyridone and 5-aminolevulinic acid (ALA) coupled derivative with iron ion chelating capacity, a preparation method thereof and application in the aspect of photodynamic.
Background
Traditional tumor treatment methods mainly comprise surgery, chemotherapy, radiotherapy and the like, but the treatment methods have some serious defects. In recent years, with the development of medical technology, photodynamic therapy (PDT) has gradually entered the visual field of people, PDT is a method of activating an exogenously applied or endogenously formed photosensitizing substance by using visible light in the presence of molecular oxygen, and photosensitizers after light activation cause the formation of singlet oxygen, which is a strong oxidizing agent and can cause the damage of various subcellular substrates and cell death. Through research on the action mechanism of the photosensitizer, the photosensitizer is found to be a key factor in the PDT treatment process, and the performance of the photosensitizer determines the treatment effect of PDT. Therefore, it is important to develop an ideal photosensitizer which has no dark toxicity, low skin photosensitivity and strong targeting property.
ALA is a second generation photosensitizer that has attracted considerable interest to researchers in the fields of PDT and photobiology. ALA is red bloodEarly intermediates of the biotin biosynthetic pathway are not themselves photosensitizers. It can generate protoporphyrin PpIX with photoactivity in vivo through a series of reactions. This process occurs more efficiently in rapidly dividing cancer cells and thus ALA is less toxic to normal tissue cells. The disadvantage of ALA arises primarily from ALA itself, which is a zwitterion at physiological pH conditions, whose hydrophilicity severely hampers its ability to pass through the cell membrane, limiting its uptake by the cell. In order to overcome the problem of low bioavailability associated with ALA, the development of ALA prodrugs has been the subject of most. Based on the mechanism of action of ALA in the body, it was found that PpIX production by ALA was associated with iron chelatase, which forms the basis of therapeutic approaches combining iron chelators with ALA-mediated PDT. In the final step of heme synthesis, the iron chelator chelates Fe with the action of ferrochelatase 2+ Leading to a massive accumulation of PpIX, suggesting that iron is critical for conversion of PpIX to hemoglobin in rapidly proliferating tumor cells. Therefore, iron chelation strategies in modern anticancer chemotherapy have attracted considerable interest, but cellular iron is always chelated by various molecules, which does not render it non-toxic, since the chelated iron is still capable of generating reactive oxygen species. Deferoxamine was found to be selective in increasing PpIX accumulation after its use as a heme synthesis inhibitor, but the pharmacokinetic profile was poor, which resulted in a longer duration of its distribution, and secondly, higher DFO concentrations may have a detrimental effect on PpIX formation due to the strong antioxidant activity of deferoxamine under these conditions.
A group of hydroxypyridone-based chelators, HPO, has recently been reported, which have a lower molecular weight and a higher lipophilicity than deferoxamine, and thus are particularly effective in chelating intracellular iron, thereby enhancing PpIX formation.
Disclosure of Invention
The invention designs and synthesizes a novel active compound with iron chelation and PDT activity based on the principles of reasonable drug design, drug-like property and the like. In particular to a 5-aminolevulinic acid-hydroxypyridone (ALA-HPO) conjugate capable of remarkably improving the drug effect of 5-aminolevulinic acid, and a preparation method and application thereof.
The technical scheme of the invention is as follows:
a derivative of ALA hybrid 3-hydroxypyridine-4H-ketone as an anti-tumor photosensitizer is a compound shown as a formula (I), a formula (II) or a formula (III) and a pharmaceutically acceptable salt thereof:
in the formula (II) or (III),
r is natural amino acid, R is benzyl, isobutyl, isopropyl, methyl, hydroxymethyl, sec-butyl, CH 3 SCH 2 CH 2 4-hydroxybenzyl or mercaptomethyl.
The invention also provides a preparation method of the compound shown in the formula (I), the formula (II) or the formula (III).
The preparation method of the compound shown in the formula (I) comprises the following steps:
(1) Dissolving the compound 1, benzyl bromide and an alkaline substance in an organic solvent, reacting for 2-12 h (preferably 3-8 h) at 25-90 ℃ (preferably 25-65 ℃), and then carrying out post-treatment on the reaction solution to obtain a compound 2;
the mass ratio of the compound 1, the benzyl bromide and the alkaline substance is 1:1 to 6:1 to 5, preferably 1:2 to 5:2 to 4;
the alkaline substance is one or a mixture of more than two of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate and triethylamine in any proportion, preferably potassium carbonate or potassium hydroxide;
the organic solvent is one or a mixed solvent of more than two of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, toluene, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide in any proportion, and preferably acetone or N, N-dimethylformamide;
the volume usage of the organic solvent is 1-5 mL/mmol based on the substance of the compound 1;
the post-treatment method comprises the following steps: after the reaction is finished, concentrating the reaction solution under reduced pressure, adding water, extracting with dichloromethane, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate to remove the solvent, and drying to obtain a compound 2;
(2) Reacting the compound 2 with NH 2 CH 2 COOH and alkaline substances are dissolved in an organic solvent and react for 1 to 12 hours (preferably 8 to 12 hours) at a temperature of between 40 and 100 ℃ (preferably between 60 and 85 ℃), and then the reaction solution is subjected to post-treatment to obtain a compound 3;
the compound 2, NH 2 CH 2 COOH, the amount of alkaline substances is 1:1 to 5:0.5 to 2, preferably 1: 1.5-2: 0.8 to 1.5;
the alkaline substance is one or a mixture of more than two of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate and triethylamine in any proportion, and preferably sodium hydroxide or potassium hydroxide;
the organic solvent is one or a mixed solvent of more than two of water, acetone, ethanol, methanol, dichloromethane, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide in any proportion, preferably ethanol or a mixed solvent of ethanol and water;
the volume usage of the organic solvent is 2-4 mL/mmol based on the substance of the compound 2;
the post-treatment method comprises the following steps: after the reaction, the reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography, and the reaction mixture was purified by dichloromethane: methanol: ammonia (25 to 28 wt%) =10:1:0.1 Separating to obtain a compound 3 by using the mixed solution (volume ratio) as an eluent;
(3) Dissolving a compound 3 in an organic solvent, sequentially adding 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), a compound 4 and N-methylmorpholine, reacting for 2-12 h at 10-50 ℃ (preferably 10-30 ℃), and then carrying out post-treatment on reaction liquid to obtain a compound 6;
the mass ratio of the compound 3 to the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate to the compound 4 to the N-methylmorpholine is 10:11:11:11;
the organic solvent is one or a mixed solvent of more than two of acetone, ethanol, methanol, acetic acid, dichloromethane, acetonitrile, dimethyl sulfoxide, dioxane, piperidine, N-dimethylformamide and N, N-dimethylacetamide in any proportion, preferably N, N-dimethylformamide;
the post-treatment method comprises the following steps: after completion of the reaction, the reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography using a dichloromethane: methanol =100 to 20:1 (volume ratio) as eluent to carry out gradient elution, and separating to obtain a compound 6;
(4) Dissolving a compound 6 in an organic solvent, adding palladium carbon, stirring and reacting for 4-24 h at-5-50 ℃ under a hydrogen atmosphere, and then carrying out post-treatment on a reaction solution to obtain a compound shown in a formula (I);
the mass ratio of the compound 6 to palladium on carbon (calculated as palladium) is 5:1 to 3, preferably 5:1 to 2;
the concentration of the solution obtained by dissolving the compound 6 in the organic solvent is 0.02-0.06 mmol/mL;
the organic solvent is one or a mixed solvent of more than two of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide in any proportion, and preferably methanol;
the post-treatment method comprises the following steps: after the reaction is finished, filtering the reaction solution, distilling the filtrate under reduced pressure to remove the solvent, and recrystallizing with ethanol/diethyl ether to obtain the compound shown in the formula (I);
the preparation method of the compound shown in the formula (II) comprises the following steps:
(1) The preparation method is the same as the step (1) of the preparation method of the compound shown in the formula (I);
(2) In step (2) of the process for preparing the compound of formula (I), NH 2 CH 2 Replacing COOH with Boc-L-Lys-OH, and reacting to obtain a compound 10;
(3) Dissolving the compound 9 in an organic solvent, sequentially adding 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N-methylmorpholine and the compound 10, reacting for 2-12 h at 10-50 ℃ (preferably 10-30 ℃), and then carrying out post-treatment on the reaction liquid to obtain a compound 11;
the mass ratio of the compound 9, the 2- (7-azabenzotriazole) -N ', N', N ', N' -tetramethylurea hexafluorophosphate to the N-methylmorpholine to the compound 10 is 10:11:11:10;
the organic solvent is one or a mixed solvent of more than two of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide in any proportion, preferably N, N-dimethylacetamide;
the post-treatment method comprises the following steps: after completion of the reaction, the reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography using a dichloromethane: methanol =100 to 60:1 (volume ratio) of the mixed solution is used as eluent for gradient elution, and the compound 11 is obtained by separation;
(4) Replacing the compound 6 with a compound 11 in the step (4) of the preparation method of the compound shown in the formula (I) to obtain a compound shown in a formula (II) through reaction;
the preparation method of the compound shown in the formula (III) comprises the following steps:
(1) The preparation method is the same as the step (1) of the preparation method of the compound shown in the formula (I);
(2) In step (2) of the process for preparing the compound of formula (I), NH 2 CH 2 Replacement of COOH by NH 2 (CH 2 ) 3 COOH, to obtain a compound 12;
(3) In the step (3) of the preparation method of the compound shown in the formula (II), the compound 10 is replaced by a compound 12, and a compound 13 is obtained through reaction;
(4) In the step (4) of the preparation method of the compound shown in the formula (I), the compound 6 is replaced by a compound 13, and the compound shown in the formula (III) is obtained through reaction;
among the compounds represented by the formula (II) or the formula (III), the side chain-extending compound 9 can be prepared as follows:
(1) Dissolving a compound 4, a compound 7 and a condensing agent HATU in an organic solvent, reacting for 1-5 h at-10-25 ℃ (preferably-5-10 ℃), adding triethylamine into the reaction solution, continuously stirring and reacting for 4-12 h (preferably 4-8 h), and then carrying out post-treatment on the reaction solution to obtain a compound 8;
the ratio of the amounts of the compound 4, the compound 7 and the substance of the condensing agent HATU is 1:1 to 6:1 to 5, preferably 1:1 to 3:1 to 3;
the organic solvent is one or a mixed solvent of more than two of acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N-dimethylformamide and N, N-dimethylacetamide in any proportion, preferably N, N-dimethylformamide;
the volume usage of the organic solvent is 5-15 mL/mmol based on the substance of the compound 4;
the post-treatment method comprises the following steps: after the reaction is finished, concentrating the reaction solution under reduced pressure, dissolving the residue in water, extracting with ethyl acetate, collecting the extract, evaporating to remove the solvent and drying to obtain a compound 8;
(2) Dissolving compound 8 in organic solvent, adding palladium hydroxide and benzyl chloride, and reacting with H at room temperature (20-30 deg.C) 2 Carrying out catalytic hydrogenation, filtering palladium hydroxide after the reaction is finished (TLC monitoring), and concentrating the filtrate in vacuum to obtain a compound 9;
the mass ratio of the compound 8, palladium hydroxide and benzyl chloride is 2:1:4.4;
the organic solvent is a mixed solvent of methanol and ethyl acetate;
in the above compounds 7, 8, 9, 11 and 13, R is as defined in the formula (II) or (III).
The compound shown in the formula (I), the formula (II) or the formula (III) can be used for preparing a photodynamic therapy medicament, and particularly can be used for preparing a medicament for treating squamous cell carcinoma, skin cancer or basal cell carcinoma.
Compared with the prior art, the invention has the beneficial effects that: the invention synthesizes a series of novel compounds with PDT activity.
Drawings
FIG. 1 example 6 shows a luminous intensity of 10KJ/m 2 And the survival rate of HeLa cells at a concentration of 100. Mu.M of the compound after 4 hours of culture.
FIG. 2 example 6 at an illumination intensity of 10KJ/m 2 And the survival rate of HeLa cells at a concentration of 100. Mu.M of the compound after 24 hours of culture.
FIG. 3 viability of HeLa cells in example 6 in the absence of light at a concentration of 100. Mu.M compound cultured for 4h.
FIG. 4 viability of HeLa cells in example 6 at a concentration of 100. Mu.M compound cultured for 24h without light.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these.
Example 1
A250 mL round bottom flask was charged with the starting materials ethyl maltol (7.56g, 60mmol), anhydrous K 2 CO 3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150 mL), the reaction was heated to reflux, TLC monitored for progress, and after completion of the reaction, the mixture was cooled to room temperature. The reaction solvent was concentrated in vacuo, water (100 mL) was added, the mixture was extracted with dichloromethane (50 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give hydroxy-protected pyrone (13.1 g) as a yellow oil in 85-90% yield。
NaOH (0.64g, 169mol) was dissolved in H 2 EtOH (2 2 CH 2 COOH (0.525g, 7 mmol) and the reaction mixture was refluxed at 75 ℃ for 8h. After the reaction is finished, distilling under reduced pressure to remove ethanol, extracting with dichloromethane (45 mL multiplied by 2), washing off unreacted raw materials, taking a water layer, adjusting the pH value to 2-3, extracting with dichloromethane (30 mL multiplied by 5), combining organic layers, drying with anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove the solvent to obtain a light yellow solid, and recrystallizing with ethanol/diethyl ether to obtain a white solid (1.2 g), wherein the yield is 60-70%.
The intermediate (273mg, 1mmol), ALA methyl ester hydrochloride (217mg, 1.2mmol), HCTU (826mg, 2mmol) and DMF (8 mL) were added sequentially to a 25mL round bottom flask, stirred in an ice-water bath for 30min, and N-methylmorpholine (303mg, 3mmol) was added to the reaction solution in three portions (20 min intervals) during which the progress of the reaction was monitored by TLC. After the reaction was completed, the precipitate was filtered off, and the solvent was concentrated in vacuo to give an oily residue, which was dissolved in DCM and washed successively with dilute hydrochloric acid (0.1M), saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure and purified by silica gel column to give a yellow oily intermediate (200 mg) with a yield of 40-50%.
The yellow oily intermediate (1 mmol) obtained above and 5% Pd/C (150 mg) were added to methanol (10 mL) at 30psi H 2 Reacting for 5-6 h under the condition, filtering to remove the catalyst, and concentrating the filtrate. Recrystallizing with methanol/diethyl ether to obtain ALA-HPO conjugate ab (100 mg) shown in formula (I), with yield of 80-90%.
ESI-HRMS:m/z calcd for C 15 H 20 N 2 O 6 Na[M+Na] + :347.1217；found:347.1214.
1 H NMR(400MHz,DMSO-d 6 )δ8.54(t,J＝5.5Hz,1H),7.45(d,J＝7.3Hz,1H),6.09(d,J＝7.3Hz,1H),4.73(s,2H),4.06(d,J＝5.4Hz,2H),3.57(s,3H),2.71(t,J＝6.5Hz,2H),2.55(q,J＝8.9,8.2Hz,2H),1.06(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ205.11,173.09,170.07,167.65,145.26,139.88,134.53,110.96,54.86,51.8,48.86,34.51,27.63,19.30,12.70.
Example 2
A250 mL round bottom flask was charged with ethyl maltol (7.56g, 60mmol), anhydrous K 2 CO 3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150 mL), the reaction was heated to reflux, TLC monitored for progress, and after completion of the reaction, the mixture was cooled to room temperature. The reaction solvent was concentrated in vacuo, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate (13.1 g) as a yellow oil in 90% yield.
NaOH (0.64g, 169mol) was dissolved in H 2 To a mixed solution (100 mL) of EtOH (2). After the reaction, the ethanol is removed by reduced pressure distillation, dichloromethane (45 mL multiplied by 2) is used for washing, unreacted raw materials are washed away, the water layer is taken out, the pH value is adjusted to 2-3, dichloromethane is used for extraction (30 mL multiplied by 5), the organic layers are combined and dried by anhydrous sodium sulfate, filtration is carried out, the solvent is removed by reduced pressure distillation of the filtrate, light yellow solid is obtained, ethanol/ether is used for recrystallization, and the benzyl protected pyridone (1.2 g) containing free carboxyl is obtained, and the yield is 60%.
In a 25mL round bottom flask, ALA methyl ester hydrochloride (0.181g, 1mmol), phenylalanine protected at one amino end (0.360g, 1.2mmol), HATU (0.760 g, 2mmol) and DMF (8 mL) were added in this order, stirred in an ice-water bath for 30min, triethylamine (0.303g, 3mmol) was added to the reaction solution in three portions (20 min intervals each), stirred overnight, the reaction was completed, the precipitate was filtered off, the solvent was removed by distillation under reduced pressure to give an oily residue, the residue was dissolved in DCM, and washed with dilute hydrochloric acid, a saturated sodium bicarbonate solution and water in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give 0.355g of the ALA-phenylalanine coupling compound with a yield of 60%.
A coupling compound of ALA with phenylalanine (0.482g, 1mmol) was dissolved in methanol/ethyl acetate (10mL, 1. Catalytic amounts of palladium hydroxide and benzyl chloride (0.277g, 2.2mmol) were added. At room temperature with 30psi H 2 Catalytic hydrogenation was carried out for 30min, pd/C was filtered off, and the filtrate was concentrated in vacuo to give a yellow oil (0.451g, 91%).
The intermediate (0.468g, 1mmol), the product of coupling between ALA methyl ester and amino acid (0.354g, 1.2mmol), HATU (0.760g, 2mmol) and DMF (8 mL) were sequentially added to a 25mL round-bottomed flask, and the mixture was stirred at room temperature for 30min, followed by slowly adding N-methylmorpholine (0.303g, 3mmol) to the reaction mixture. The progress of the reaction was monitored by TLC and after 5h the reaction was complete, the precipitate was filtered off and the solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in DCM and washed successively with saturated sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography using dichloromethane/methanol = 200.
The benzyl-protected pyridone containing free carboxyl groups (0.366g, 0.5 mmol) obtained above was dissolved in methanol (10 mL) and catalytic amount of Pd/C at 30psi H was added 2 Hydrogenation was carried out for 2h. Pd/C was filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil a 1 b 1 0.281g, yield 85%.
ESI-HRMS:m/z calcd for C 33 H 47 N 4 O 9 [M+H] + :643.3338；found:643.3354.
1 H NMR(400MHz,DMSO-d 6 )δ8.32(t,J＝5.5Hz,1H),7.90(d,J＝8.4Hz,1H),7.51(d,J＝7.3Hz,1H),7.27–7.13(m,5H),6.82(d,J＝8.2Hz,1H),6.10(d,J＝7.3Hz,1H),4.59(td,J＝8.8,4.8Hz,1H),3.98–3.79(m,6H),3.56(s,3H),3.02(dd,J＝13.9,4.9Hz,1H),2.81(dd,J＝13.9,9.2Hz,1H),2.66(dt,J＝10.8,6.8Hz,4H),2.47(t,J＝6.6Hz,2H),1.56(q,J＝7.4Hz,4H),1.36(s,9H),1.24(s,2H),1.11(d,J＝7.4Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ203.94,172.85,172.13,171.35,169.26,155.81,145.68,136.92,136.73,134.54,129.29,128.44,126.76,111.55,79.99,77.31,54.34,53.92,53.26,51.84,49.06,38.08,34.38,32.21,30.89,28.30,27.51,22.22,19.25,12.71.
Example 3
A250 mL round bottom flask was charged with ethyl maltol (7.56g, 60mmol), anhydrous K 2 CO 3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150 mL), the reaction was heated to reflux, TLC monitored for progress, and after completion of the reaction, the mixture was cooled to room temperature. The reaction solvent was concentrated in vacuo, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate (13.1 g) as a yellow oil in 90% yield.
NaOH (0.64g, 169mol) was dissolved in H 2 To a mixed solution (100 mL) of EtOH (2). After the reaction is finished, distilling under reduced pressure to remove ethanol, washing with dichloromethane (45 mL multiplied by 2), washing away unreacted raw materials, taking a water layer, adjusting the pH value to 2-3, extracting with dichloromethane (30 mL multiplied by 5), combining organic layers, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent from the filtrate to obtain a light yellow solid, and recrystallizing with ethanol/diethyl ether to obtain the benzyl protected pyridone (1.2 g) containing free carboxyl, wherein the yield is 60%.
In a 25mL round bottom flask, ALA methyl ester hydrochloride (0.181g, 1mmol), leucine protected at one amino end (0.265g, 1.2mmol), HATU (0.760g, 2mmol) and DMF (8 mL) were sequentially added, stirred in an ice-water bath for 30min, triethylamine (0.303g, 3mmol) was further added to the reaction solution in three times (20 min intervals each), stirring was continued overnight, the reaction was completed, the precipitate was filtered off, the solvent was removed by distillation under reduced pressure to obtain an oily residue, the residue was dissolved in DCM, and washed with dilute hydrochloric acid, a saturated sodium bicarbonate solution and water in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 0.301g of the ALA-leucine conjugate compound with a yield of 60%.
A coupling compound of ALA methyl ester and leucine (0.376g, 1mmol) was dissolved in methanol/ethyl acetate (10mL, 1. Catalytic amounts of palladium hydroxide and benzyl chloride (0.277g, 2.2mmol) were added. At room temperature with 30psi H 2 Catalytic hydrogenation was carried out for 30min, pd/C was filtered off, and the filtrate was concentrated in vacuo to give a yellow oil (0.351g, 89%).
To a 25mL round-bottomed flask, the above-mentioned yellow oily substance (0.468g, 1mmol), benzyl-protected pyridone containing a free carboxyl group (0.354g, 1.2mmol), HATU (0.760g, 2mmol) and DMF (8 mL) were added in this order, and the mixture was stirred at room temperature for 30min, and N-methylmorpholine (0.303g, 3mmol) was slowly added to the reaction mixture. The progress of the reaction was monitored by TLC and after 5h the reaction was complete, the precipitate was filtered off and the solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in DCM and washed successively with saturated sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography using dichloromethane/methanol = 200.
The oily product (0.366g, 0.5mmol) was dissolved in methanol (10 mL) and catalytic amount of Pd/C in 30psi H was added 2 Hydrogenation was carried out for 2h. Pd/C was filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil a 2 b 2 0.281g, yield 85%.
ESI-HRMS:m/z calcd for C 30 H 49 N 4 O 9 [M+H] + :609.3476；found:609.3494.
1 H NMR(400MHz,Chloroform-d)δ8.18(s,1H),7.83(d,J＝4.2,1H),7.53(s,1H),6.87(s,1H),6.10(d,J＝2.9Hz,1H),4.47–4.29(m,1H),4.37–4.34(m,1H),3.95–3.90(m,3H),3.87(s,2H),3.56(t,J＝2.9Hz,3H),2.68(q,J＝6.1Hz,4H),2.50(t,J＝6.4Hz,2H),1.63(q,J＝6.8Hz,4H),1.54–1.42(m,3H),1.41–1.21(m,11H),1.12(dt,J＝10.0,6.0Hz,3H),0.85(dt,J＝19.4,5.2Hz,6H). 13 C NMR(100MHz,Chloroform-d)δ205.16,172.55,172.27,171.76,169.01,155.30,145.09,137.55,133.43,110.61,78.07,53.94,52.18,51.32,50.66,48.23,41.08,33.84,30.63,28.11,27.08,23.98,23.01,21.52,22.21,21.52,18.55,12.66.
Example 4
A250 mL round bottom flask was charged with ethyl maltol (7.56g, 60mmol), anhydrous K 2 CO 3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150 mL), the reaction was heated to reflux, TLC monitored for progress, and after completion of the reaction, the mixture was cooled to room temperature. The reaction solvent was concentrated in vacuo, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate (13.1 g) as a yellow oil in 90% yield.
NaOH (0.64g, 169mol) was dissolved in H 2 To a mixed solution (100 mL) of EtOH (2. After the reaction is finished, distilling under reduced pressure to remove ethanol, washing with dichloromethane (45 mL multiplied by 2), washing away unreacted raw materials, taking a water layer, adjusting the pH value to 2-3, extracting with dichloromethane (30 mL multiplied by 5), combining organic layers, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent from the filtrate to obtain a light yellow solid, and recrystallizing with ethanol/diethyl ether to obtain the benzyl protected pyridone (1.2 g) containing free carboxyl, wherein the yield is 60%.
In a 25mL round bottom flask, ALA methyl ester hydrochloride (0.181g, 1mmol), phenylalanine protected at one amino end (0.360g, 1.2mmol), HATU (0.760 g, 2mmol) and DMF (8 mL) were added in this order, stirred in an ice-water bath for 30min, triethylamine (0.303g, 3mmol) was added to the reaction solution in three portions (20 min intervals each), stirred overnight, the reaction was completed, the precipitate was filtered off, the solvent was removed by distillation under reduced pressure to give an oily residue, the residue was dissolved in DCM, and washed with dilute hydrochloric acid, a saturated sodium bicarbonate solution and water in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give 0.355g of the ALA-phenylalanine coupling compound with a yield of 60%.
A coupling compound of ALA methyl ester and phenylalanine (0.482g, 1mmol) was dissolved in methanol/ethyl acetate (1 mmol)10mL, 1. Catalytic amounts of palladium hydroxide and benzyl chloride (0.277g, 2.2mmol) were added. At room temperature with 30psi H 2 Catalytic hydrogenation was carried out for 30min, pd/C was filtered off, and the filtrate was concentrated in vacuo to give a yellow oil (0.451g, 91%).
The yellow oily substance (0.468g, 1mmol) obtained above, benzyl-protected pyridone containing a free carboxyl group (0.354g, 1.2mmol), HATU (0.760g, 2mmol) and DMF (8 mL) were sequentially added to a 25mL round-bottomed flask, and the mixture was stirred at room temperature for 30min, and N-methylmorpholine (0.303g, 3mmol) was slowly added to the reaction mixture. The progress of the reaction was monitored by TLC and after 5h the reaction was complete, the precipitate was filtered off and the solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in DCM and washed successively with saturated sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate, the organic layer was concentrated, and column chromatography was performed using dichloromethane/methanol = 200.
The oily product (0.366g, 0.5mmol) was dissolved in methanol (10 mL) and catalytic amount of Pd/C in 30psi H was added 2 Hydrogenation was carried out for 2h. Pd/C was filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil a 3 b 3 0.281g, yield 85%.
ESI-HRMS:m/z calcd for C 27 H 26 N 3 O 7 [M+H] + :514.2553；found:514.2598.
1 H NMR(400MHz,DMSO-d 6 )δ8.39(t,J＝5.6Hz,1H),8.25(d,J＝8.5Hz,1H),7.43(d,J＝7.3Hz,1H),7.33–7.13(m,5H),6.12(d,J＝7.2Hz,1H),4.64(ddd,J＝10.4,8.5,4.4Hz,1H),3.99(d,J＝5.7Hz,4H),3.81–3.65(m,2H),3.59(s,3H),3.08(dd,J＝13.8,4.4Hz,1H),2.77(dd,J＝13.8,10.5Hz,1H),2.72–2.61(m,4H),2.50(s,2H),2.13(hept,J＝7.4Hz,2H),1.76(hept,J＝6.7Hz,2H),1.08(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ205.82,173.09,172.20,171.62,169.55,145.57,138.51,137.95,134.19,129.61,128.48,126.70,111.30,54.23,52.06,51.85,48.85,38.11,34.32,31.89,27.60,27.39,18.89,13.14.
Example 5
A250 mL round bottom flask was charged with ethyl maltol (7.56g, 60mmol), anhydrous K 2 CO 3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150 mL), the reaction was heated to reflux, TLC monitored for progress, and after completion of the reaction, the mixture was cooled to room temperature. The reaction solvent was concentrated in vacuo, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate (13.1 g) as a yellow oil in 90% yield.
NaOH (0.64g, 169mol) was dissolved in H 2 To a mixed solution (100 mL) of EtOH (2. After the reaction is finished, distilling under reduced pressure to remove ethanol, washing with dichloromethane (45 mL multiplied by 2), washing away unreacted raw materials, taking a water layer, adjusting the pH value to 2-3, extracting with dichloromethane (30 mL multiplied by 5), combining organic layers, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent from the filtrate to obtain a light yellow solid, and recrystallizing with ethanol/diethyl ether to obtain the benzyl protected pyridone (1.0 g) containing free carboxyl, wherein the yield is 62%.
In a 25mL round bottom flask, ALA methyl ester hydrochloride (0.181g, 1mmol), leucine protected at one amino end (0.265g, 1.2mmol), HATU (0.760g, 2mmol) and DMF (8 mL) were sequentially added, stirred in an ice-water bath for 30min, triethylamine (0.303g, 3mmol) was further added to the reaction solution in three times (20 min intervals each), stirring was continued overnight, the reaction was completed, the precipitate was filtered off, the solvent was removed by distillation under reduced pressure to obtain an oily residue, the residue was dissolved in DCM, and washed with dilute hydrochloric acid, a saturated sodium bicarbonate solution and water in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 0.301g of the ALA methyl ester-leucine conjugate compound with a yield of 60%.
A coupling compound of ALA and leucine (0.376g, 1mmol) was dissolved in methanol/ethyl acetate (10mL, 1. Catalytic amounts of palladium hydroxide and benzyl chloride (0.277g, 2.2mmol) were added. At room temperatureLower 30psi of H 2 Catalytic hydrogenation was carried out for 30min, pd/C was filtered off, and the filtrate was concentrated in vacuo to give a yellow oil (0.351g, 89%).
The yellow oily intermediate (0.468g, 1mmol) obtained above, benzyl-protected pyridone containing a free carboxyl group (0.354g, 1.2mmol), HATU (0.760g, 2mmol) and DMF (8 mL) were sequentially added to a 25mL round-bottomed flask, and the mixture was stirred at room temperature for 30min, and N-methylmorpholine (0.303g, 3mmol) was slowly added to the reaction mixture. The progress of the reaction was monitored by TLC and after 5h the reaction was complete, the precipitate was filtered off and the solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in DCM and washed successively with saturated sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography using dichloromethane/methanol = 200.
The above oily compound (0.366g, 0.5mmol) was dissolved in methanol (10 mL) and a catalytic amount of Pd/C in 30psi H was added 2 Hydrogenation was carried out for 2h. Pd/C was filtered, and the filtrate was concentrated under reduced pressure to give a colorless oil a 4 b 4 0.281g, yield 85%.
ESI-HRMS:m/z calcd for C 24 H 38 N 3 O 7 [M+H] + :480.2710；found:480.2796.
1 H NMR(400MHz,DMSO-d 6 )δ8.22(t,J＝5.7Hz,1H),8.08(d,J＝8.1Hz,1H),7.52(d,J＝7.3Hz,1H),6.11(d,J＝7.2Hz,1H),4.34(q,J＝7.7Hz,1H),3.90(dt,J＝13.0,6.3Hz,4H),3.53(s,5H),2.76–2.60(m,4H),2.47(d,J＝6.6Hz,2H),2.20(t,J＝7.1Hz,2H),1.86(h,J＝7.1Hz,2H),1.61(dp,J＝13.3,6.8Hz,1H),1.46(t,J＝7.3Hz,2H),1.10(t,J＝7.4Hz,3H),0.87(dd,J＝16.6,6.5Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ205.81,173.08,173.04,171.69,169.57,145.56,138.01,134.13,111.28,52.17,51.84,51.32,48.76,41.25,34.32,31.86,27.58,27.45,24.71,23.48,21.95,13.16.
Example 6
The following are the pharmacological test data for some of the compounds of the invention:
1. phototoxicity test
The experimental method comprises the following steps: the cells were incubated at approximately 2.5X 10 5 Density of/well plated in 24-well plates, after 48h of incubation, cells were washed with phosphate buffer. 1mL of compound solutions containing different concentrations (50-10. Mu.M) were added to the designated wells and incubated for 4h. The blank (without compound) and different concentrations of compound were each subjected to 4 parallel experiments, irradiated with blue light for 5min, immediately replaced with fresh medium after irradiation, and the cells were incubated for a further 18h. Cytotoxicity was determined using MTT. The MTT detection method comprises the following steps: all media was removed from the well plate, 1mL MTT-containing media was added to each well, capped and placed in an incubator for 4h. All media in the plate was removed again, 1mL of dimethyl sulfoxide was added to each well, shaken for 5min, absorbance at 520nm was measured, the average cell viability at each concentration of each prodrug was calculated and expressed as a percentage of the control,
the values for cell viability and concentration are tabulated and presented in bar graph form.
Mean cell viability = absorbance (mean of each prodrug)/absorbance (mean of control) x 100%
To determine the "dark" toxicity of the compounds, the previous procedure was repeated, but without irradiation with light.
From fig. 1, it can be seen from the experimental results that:
(1) After 4h incubation of the compound with cells (fig. 1): 100 μ M of Compound a1b1 at irradiation of 10KJ/M compared to the control group (ALA group) 2 It is more effective.
(2) After 24h of compound and cell culture (fig. 2): irradiation of 10KJ/m 2 When compounds a1b1, a2b2, a3b3 and a4b4 have a lower cell viability, it is suggested that they are more photoactive, especially compound a1b1 has similar cytotoxicity to ALA. Therefore, we further tested the cytotoxicity of ALA, ALA-DFP, compound a1b1 by increasing the concentration to 250. Mu.M.
These results indicate that ALA-HPO can enter cells, and that cytosolic esterases are presumed to break the bond between the PpIX prodrug and HPO molecule, liberate ALA, and metabolically produce the photoactive active substance PpIX, so that the synthesized series of target compounds can effectively function in cells.
2. Dark toxicity test
(1) After 4h incubation with compound (fig. 3): all compounds showed no dark toxicity at the relevant concentrations;
(2) After 24h incubation with compound (fig. 4): compounds ab and a1b1 showed dark toxicity at relevant concentrations of 50 or 100 μ M compared to untreated controls.
Finally, it is to be noted that the above-mentioned list is only a few specific embodiments of the present invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Claims (4)
1. An anti-tumor photosensitizer ALA hybrid 3-hydroxypyridine-4H-ketone derivative has a structural formula shown as follows:
2. the process for the preparation of the derivative of the antitumor photosensitiser ALA hybrid 3-hydroxypyridin-4H-one as claimed in claim 1, comprising the steps of:
(1) Dissolving the compound 1, benzyl bromide and an alkaline substance in an organic solvent, reacting for 2-12 h at 25-90 ℃, and then carrying out post-treatment on the reaction solution to obtain a compound 2;
the mass ratio of the compound 1, the benzyl bromide and the alkaline substance is 1:1 to 6:1 to 5;
the alkaline substance is one or a mixture of more than two of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate and triethylamine in any proportion;
(2) Dissolving a compound 2, boc-L-Lys-OH and an alkaline substance in an organic solvent, reacting for 1-12 h at 40-100 ℃, and then carrying out post-treatment on a reaction solution to obtain a compound 10;
the ratio of the amounts of the compound 2, boc-L-Lys-OH and basic substance is 1:1 to 5:0.5 to 2;
the alkaline substance is one or a mixture of more than two of potassium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate and triethylamine in any proportion;
(3) Dissolving the compound 9 in an organic solvent, sequentially adding 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N-methylmorpholine and the compound 10, reacting for 2-12 h at 10-50 ℃, and then carrying out post-treatment on the reaction liquid to obtain a compound 11;
the mass ratio of the compound 9, 2- (7-azabenzotriazole) -N ', N', N ', N' -tetramethylurea hexafluorophosphate to N-methylmorpholine to the compound 10 is 10:11:11:10;
(4) Dissolving the compound 11 in an organic solvent, adding palladium carbon, stirring and reacting for 4-24H at-5-50 ℃ under a hydrogen atmosphere, and then carrying out post-treatment on reaction liquid to obtain a derivative of a product of an anti-tumor photosensitizer ALA hybrid 3-hydroxypyridine-4H-ketone;
the ratio of the compound 11 to the amount of palladium carbon in terms of palladium is 5:1 to 3;
in the compound 9 and the compound 11, R is benzyl.
3. Use of the derivative of the anti-tumor photosensitizer ALA hybrid 3-hydroxypyridin-4H-one as claimed in claim 1 for the preparation of a medicament for the photodynamic treatment of tumors.
4. Use of the derivative of the anti-tumor photosensitizer ALA hybrid 3-hydroxypyridin-4H-one as claimed in claim 1 for the preparation of a medicament for the treatment of squamous cell carcinoma, skin carcinoma or basal cell carcinoma.
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