CN113307838A - Hybrid molecular compound and application thereof in treating tumors - Google Patents
Hybrid molecular compound and application thereof in treating tumors Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a gemcitabine-dexamethasone hybrid molecular compound and application thereof in treating tumors. The hybrid molecular compound has the structure shown in formula I, formula II and formula III.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a gemcitabine-dexamethasone hybrid molecular compound and application thereof in treating tumors.
Background
Gemcitabine (GEM) belongs to nucleoside drugs, is widely used in chemotherapy of various tumor patients, shows good anti-tumor curative effects on various solid tumors such as pancreatic cancer, ovarian cancer, breast cancer, colon cancer and the like, and is currently used as a first-line treatment drug for non-small cell lung cancer, liver cancer and pancreatic cancer. Clinically, gemcitabine is administered by intravenous injection, and the common adverse reactions mainly include bone marrow suppression, gastrointestinal reactions, liver and kidney injuries, rash and the like, and these side effects may affect the compliance of patients and have negative effects on clinical results.
Dexamethasone (Dexamethasone, DEX) is used as a glucocorticoid medicine and is widely used for treating diseases such as autoimmune diseases, inflammatory reactions, allergy, asthma and the like clinically. Researches in recent years show that dexamethasone can inhibit the growth and metastasis of tumors, improve the curative effect of chemotherapeutic drugs and reduce the toxic and side effects of the chemotherapeutic drugs. It is reported that the combination of dexamethasone and gemcitabine shows a remarkable synergistic effect in vitro and in vivo, and the dexamethasone can remarkably enhance the antitumor curative effect of the gemcitabine and reduce the toxic and side effects of the gemcitabine.
The research designs and synthesizes a gemcitabine-dexamethasone hybrid molecule through a hybrid molecule strategy, aims to improve the clinical treatment curative effect of gemcitabine, obtain the hybrid molecule capable of being orally administrated, overcome the defect that gemcitabine can be administrated only by intravenous injection, and improve the compliance of clinical patients.
Disclosure of Invention
The object of the present invention is to provide a novel method which is expected to have some excellent effect or effects for treating tumors, and to provide a drug having more excellent antitumor activity for clinical use.
To this end, the invention provides, in a first aspect, compounds of the following formulae I, II, III:
in particular, the compounds of the present invention are selected from the following compounds 1-9:
compound 1: 2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxoethyl 4- ((1- ((2R,4R,5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1, 2-dihydropyrimidin-4-yl) amino) -4-oxobutanoate;
compound 2: ((2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxyethyl) succinate;
compound 3: (2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxyethyl) succinate;
compound 4: 2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxoethyl 5- ((1- ((2R,4R,5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1, 2-dihydropyrimidin-4-yl) amino) -5-oxopentanoate;
compound 5: ((2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) glutarate;
compound 6: (2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxyethyl) glutarate;
compound 7: 2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl 6- ((1- ((2R,4R,5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1, 2-dihydropyrimidin-4-yl) amino) -6-oxohexanoate;
compound 8: ((2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) adipate;
compound 9: (2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxyethyl) adipate.
In a second aspect, the present invention provides a process for the preparation of compounds of formulae I-III, which process is carried out as follows:
specifically, the preparation method comprises the following steps:
1) dissolving Dexamethasone (DXMS) in pyridine, adding acid anhydride (such as succinic anhydride and glutaric anhydride), and stirring at 0-40 deg.C for 3-12 hr to obtain DXMS-linker;
or dissolving DXMS in aprotic solvent (such as dichloromethane, acetonitrile, N, N-dimethylformamide, acetonitrile, dioxane), adding 1.0-1.5 times equivalent of condensing agent (such as DCC, EDCI), and reacting with diacid compound (such as adipic acid, pimelic acid) at 0-40 deg.C for 3-10 hr in the presence of 0.1-0.5 times equivalent of Dimethylaminopyridine (DMAP) to obtain DXMS-linker;
2) DXMS-Linker is dissolved in an aprotic solvent (e.g., acetonitrile, N, N-dimethylformamide, acetonitrile, dioxane), and reacted with 1-3 equivalents of gemcitabine in the presence of 1-5 equivalents of an organic base (e.g., triethylamine, N, N-diisopropylethylamine) and a condensing agent (e.g., HATU, HBTU) at room temperature for 1-10 hours to give compounds of formulae I-III.
In a third aspect, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of tumours.
Wherein the tumor comprises: pancreatic cancer, ovarian cancer, breast cancer, colon cancer, non-small cell lung cancer, liver cancer.
The invention also provides pharmaceutical compositions containing a compound of the invention as an active ingredient. The pharmaceutical composition contains 0.1-99.9% of the compound and 0.1-99.9% of the pharmaceutically acceptable carrier. The pharmaceutical composition is in the form of a formulation suitable for pharmaceutical use.
The pharmaceutical composition of the invention can be prepared into any pharmaceutically acceptable dosage form.
The medicinal preparation is tablet, capsule, granule, pill, powder, unguent, suspension, injection, powder for injection, suppository, cream, drop or patch. Wherein the tablet is a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet or a sustained-release tablet; the capsule is hard capsule, soft capsule or slow release capsule; the powder injection is freeze-dried powder injection.
The pharmaceutical composition of the present invention is in the form of a preparation, wherein each preparation contains 0.1-1000 mg of the compound of the present invention, and each preparation unit, such as each tablet of a tablet, each capsule, or each dose, such as 100mg per dose.
The pharmaceutical composition of the present invention may be prepared into solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, using a solid carrier. The solid carrier which may be used is preferably one or more substances selected from diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, bulking agents and the like, or may be an encapsulating substance. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, capsules and the like represent the most advantageous oral solid dosage forms.
It is particularly advantageous to formulate the above pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of a formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit forms may be in the form of a pack, such as a tablet, capsule or powder in a small tube or vial.
Although the amount of active ingredient contained in the dosage unit form may vary, it is generally adjusted within the range of 1 to 800mg, depending on the potency of the active ingredient selected.
The preferred dosage for a given situation can be determined by one skilled in the art in a routine manner. Generally, the amount of the active ingredient to be initially treated is lower than the optimum dose of the active ingredient, and then the dose to be administered is gradually increased until the optimum therapeutic effect is achieved. For convenience, the total daily dose may be divided into several portions and administered in fractions.
Through pharmacodynamic experiments, the inventor finds that the curative effect of oral administration of the hybrid molecule is better than that of gemcitabine control group administered by tail vein in mouse tumor model experiments, and the result shows that the novel hybrid molecule has excellent antitumor activity and can be orally administered; in addition, no death of 6 mice in the hybrid molecule administration group occurs, and 2 mice in 6 mice in the gemcitabine control group die, which shows that the hybrid molecule has better safety and stability and less toxic and side effects.
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FIG. 1. in vivo anti-tumor activity of Compounds 1-3. A) Mouse body weight change curve; B) tumor volume change curve; C) tumor weight
Detailed Description
In the following examples, the present invention will be explained more specifically. It is to be understood, however, that the following examples are intended to illustrate the present invention without limiting the scope of the present invention in any way.
Example 1 Synthesis of Compound 1, Compound 2 and Compound 3
At room temperature, to a solution of dexamethasone (1g, 2.55mmol) in pyridine (15mL) was added succinic anhydride (510mg, 5.10mmol), stirred at the same temperature for 12h, TLC checked for completion of the reaction, and concentrated. Water (20mL) was added to the residue and stirred vigorously until a white powdery solid formed, and stirring was continued for 2 h. The mixture was filtered, the filter cake was washed with water (10 mL. times.3), and the filter cake was dried in a vacuum oven for 24h to give intermediate DXMS-Linker 1(1.06g, 85% yield) as a white solid; 1H NMR (500MHz, DMSO-d6) δ 12.23(s,1H),7.29(d, J ═ 10.08Hz,1H),6.22(d, J ═ 10.08Hz,1H),6.00(s,1H),5.40(d, J ═ 3.68Hz,1H),5.15(s,1H),5.04(d, J ═ 17.35Hz,1H),4.79(d, J ═ 17.52Hz,1H), 4.14(brs,1H),2.90-2.84(m,1H), 2.65-2.60(m,3H),2.42-2.30(m, 2H),2.18-2.09(m, 2H), 1.78-1.70(m,1H), 1.66-1.54(m,2H), 1.78-1.70(m,1H), 1.49 (m,1H), 1.31H), 1.31.49 (m,1H), 1H, and 1H, and 1H, and the like.
Gemcitabine (1.13g, 4.30mmol), Et3N (0.89mL, 6.45mmol) and HATU (2.45g,6.45mmol) were added to a solution of DXMS-Linker 1(1.06g, 2.15mmol) in DMF (10mL) at room temperature, stirred at the same temperature for 5h, quenched with water (50mL) and extracted with ethyl acetate (30 mL. times.3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by prep-HPLC (acetonitrile: water ═ 70: 30) to give compound 1(792mg, 50% yield), 2(475mg, 32% yield) and 3(316mg, 21% yield) as white solids;
compound 1, lrms (esi) M/z 738[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 11.09(s,1H),8.23(d, J ═ 7.54Hz,1H),7.27(d, J ═ 10.04Hz,1H),7.23(d, J ═ 7.53Hz,1H),6.21(d, J ═ 10.13Hz,1H),6.17(t, J ═ 7.12Hz,1H), 5.99(s, 1H),5.37(d, J ═ 3.70Hz,1H),5.15(s,1H),5.04(d, J ═ 17.52Hz,1H),4.78(d, J ═ 17.52Hz,1H),4.19-4.10(m, 2H),3.88(d, J ═ 8.25Hz,1H),3.80(d, J ═ 17.65), 1H (d, J ═ 17.52Hz,1H),4.19-4.10(m, 2H),3.88(d, J ═ 8.25, 1H),3.80(d, J ═ 17.65, 1H), 1H, 1.84(d, 1.60, 1H), 1.60(m, 2H), 1H), 1.60(m,1H), 1H), 1H, 1.70H, 1H), 1H) 1.65-1.53(m,2H),1.47(s,3H),1.34-1.29(m, 1H),1.12-1.05(m,1H),0.87(s,3H),0.78(d, J ═ 7.12Hz, 3H); 13C NMR (150MHz, CDCl3), δ 205.16,185.76,173.10,172.09,167.54,163.21,145.20,130.11,125.10,123.39(t, J ═ 261.5Hz), 101.74(d, J ═ 174.88Hz), 96.39, 90.92,81.52,70.90(d, J ═ 36.66Hz), 68.87(t, J ═ 21.80Hz),68.54,59.26, 49.06,48.49,43.74, 36.12,35.83, 34.00(d, J ═ 19.40Hz),32.36, 31.71,30.73, 28.20, 27.74, 23.44(d, J ═ 5.65Hz)16.72, 15.55.
Compound 2, lrms (esi) M/z 738[ M + H ] +; h NMR (DMSO-d6,500MHz) δ 7.52(d, 7.15Hz,1H), 7.40(d, J ═ 5.80Hz,1H), 7.29(d, J ═ 10.10Hz,1H),6.41(s,1H),6.22(d, J ═ 10.08Hz,1H),6.17(brs,1H),6.00(s,1H),5.80(d, J ═ 7.15Hz,1H), 5.38(brs,1H),5.15(s, 1H),5.08(d, J ═ 17.63Hz,1H), 4.79(d, J ═ 17.62Hz,1H), 4.39(d, J ═ 11.69Hz,1H),4.32-4.29(m, 1H),4.19(brs,1H), 4.19H, 1H, 6.62 Hz,1H), 2.39 (brm, 2H, 1H, 2.66H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, etc.),74, 2H, etc., 1.54(d, J ═ 12.68Hz,1H), 1.49(s,3H), 1.36-1.33(m,1H),1.10-1.06(m,1H), 0.87(s,3H),0.78(d, J ═ 7.04Hz, 3H); 13C NMR (150MHz, CDCl3) δ 205.09,185.75,172.06,171.85,167.52,166.13,155.00, 153.22,129.45,124.86,123.15(t, J ═ 261.5Hz), 101.74(d, J ═ 174.88Hz),95.36,90.92,77.78,71.00(d, J ═ 36.00Hz),70.58(t, J ═ 23.19Hz),68.56, 63.41,49.06, 43.75, 36.13,35.84, 33.99(d, J ═ 19.39Hz),32.37,30.74,28.90,28.73,27.74,23.43(d, J ═ 5.56Hz),16.73, 15.56.
Compound 3, lrms (esi) M/z 738[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 7.69(d, J ═ 7.35Hz,1H), 7.44(brs, 1H),7.40(brs, 1H),7.30(d, J ═ 10.15Hz,1H),6.25(brs, 1H),6.23(d, J ═ 10.15Hz,1H), 6.00(s,1H), 5.81(d, J ═ 7.53Hz,1H), 5.39(d, J ═ 4.49Hz,1H), 5.36(brs,1H),5.22(t, J ═ 5.34Hz,1H), 5.15(s,1H),5.08(d, J ═ 17.75Hz,1H), 4.79(d, J ═ 17.75Hz,1H), 4.16-4.15 (s,1H), 3.65 (m-2H), 2H, 3.65 (m-2H), 2.60 (1H, 2 m-2H), 3.65 (1H, 2 m-2H), 2 m-2H, 2 m-60 (1H), 2H, 2 m-60H, 2 m-60H), 2H),1.79-1.75(m, 1H),1.66-1.60(m,1H),1.54(d, J ═ 12.89Hz,1H), 1.49(s,3H), 1.39-1.31(m, 1H),1.09-1.04(m,1H),0.88(s,3H),0.79(d, J ═ 7.24Hz, 3H); 13C NMR (150MHz, CDCl3) δ 205.11,185.76,171.63,171.11,167.52, 166.19,155.01,153.24, 129.45, 124.56,122.13(t, J ═ 261.5Hz), 101.84(d, J ═ 185.45Hz),95.27, 90.93,79.06,71.08(d, J ═ 36.00Hz),68.62,59.62,49.06,48.42(t, J ═ 9.65Hz),43.76,36.11,35.86,33.99(d, J ═ 19.29Hz),32.37, 30.74, 28.77, 28.70,27.75,23.44(d, J ═ 5.29Hz), 16.72, 15.56.
Example 2 Synthesis of Compound 4, Compound 5, Compound 6
The synthesis method of the compound 4, the compound 5 and the compound 6 is similar to that of the example 1, succinic anhydride is replaced by glutaric anhydride, and dexamethasone is used as a raw material to prepare the compound 4, the compound 5 and the compound 6 through two-step reaction.
Compound 4, lrms (esi) M/z 752[ M + H ] +; h NMR (DMSO-d6,500MHz) δ 11.06(s, 1H), 8.26(d, J ═ 7.54Hz,1H), 7.23(d, J ═ 10.04Hz,1H), 7.20(d, J ═ 7.53Hz,1H), 6.22(d, J ═ 10.13Hz,1H), 6.15(t, J ═ 7.12Hz,1H), 5.90(s,1H), 5.38(d, J ═ 3.70Hz,1H), 5.16(s,1H),5.03(d, J ═ 17.52Hz,1H),4.79(d, J ═ 17.52Hz,1H),4.19-4.10(m, 2H),3.89(d, J ═ 8.25Hz,1H),3.80(d, J ═ 17.52Hz,1H), 1H, 84(d, J ═ 17.52Hz,1H), 1H),4.19-4.10(m, 2H),3.89(d, J ═ 8.25, 1H, 80, 3.80, 1H, 60 (d, 1.84, 1H), 2H, 1.70H, 1H, 6, 1H, 60 (d, 1H), 2H, 1H, 60, 1H, 60H, 1H, 6H, 1H), 2H, 1H, 6, 1H, 6H, 1H, 6H, 1H, 6, 1H, 6, 1H, 2H, 1H, etc., 1H) 1.65-1.53(m,2H),1.47(s,3H),1.34-1.29(m, 1H),1.12-1.05(m,1H),0.87(s,3H),0.78(d, J ═ 7.12Hz,3H).
Compound 5, lrms (esi) M/z 752[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 7.55(d,7.15Hz,1H),7.43(d, J ═ 5.80Hz,1H),7.30(d, J ═ 10.10Hz,1H), 6.43(s,1H),6.25(d, J ═ 10.08Hz,1H), 6.18(brs,1H),6.01(s,1H), 5.84(d, J ═ 7.15Hz,1H), 5.39(brs,1H), 5.16(s,1H), 5.09(d, J ═ 17.60Hz,1H),4.75(d, J ═ 17.62Hz,1H),4.34(d, J ═ 11.69Hz,1H),4.32-4.27(m,1H),4.15(brs,1H), 4.12H, 1H, 2H, 1H, 2-1H, 2H, 2.74H, 2H, 1H, 2H, 3H, 2H, etc., 1.54(d, J ═ 12.68Hz,1H),1.45(s,3H),1.36-1.33(m,1H),1.10-1.06(m,1H),0.88(s,3H),0.77(d, J ═ 7.04Hz,3H).
Compound 6, lrms (esi) M/z 752[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 7.68(d, J ═ 7.35Hz,1H),7.41(brs,1H),7.38(brs,1H),7.31(d, J ═ 10.15Hz,1H), 6.26(brs, 1H),6.24(d, J ═ 10.15Hz,1H),6.01(s,1H),5.81(d, J ═ 7.53Hz,1H),5.40(d, J ═ 4.49Hz,1H),5.35(brs,1H),5.21(t, J ═ 5.34Hz,1H),5.16(s,1H),5.03(d, J ═ 17.75Hz,1H), 4.77(d, J ═ 17.75Hz,1H),4.16 (s,1H), 4.75 (H), 2.65 (m-2H), 3.65 (m-2H), 2.75 (3.65, 2H), 2.65 (m-2H, 3.53, 2.60H), 2.67, 2.60 (m-2H, 2 m-3.53, 2H), 2H, 2 m-4.67, 2 m-3.7 (2 m), 1.79-1.70(m,1H),1.66-1.62(m,1H),1.54(d, J ═ 12.89Hz,1H),1.45(s,3H),1.39-1.33(m,1H),1.09-1.04(m,1H),0.88(s,3H),0.79(d, J ═ 7.24Hz,3H).
Example 3 Synthesis of Compound 7, Compound 8, Compound 9
To a solution of dexamethasone (1g, 2.55mmol) in dichloromethane (15mL) was added DCC (618mg, 3.00mmol), DMAP (25mg, 0.2mmol), and adipic acid (372mg, 2.55mmol) at room temperature, stirred at the same temperature for 12h, and the reaction was checked by TLC for completion. Concentrating, and performing silica gel column chromatography to obtain intermediate DXMS-Linker 3(1.07g, 76% yield) as white solid;
gemcitabine (526mg, 2.00mmol), Et3N (0.83mL, 6.00mmol) and HATU (1.14g,3.00mmol) were added to a solution of DXMS-Linker 3(1.00g, 1.92mmol) in DMF (10mL) at room temperature, stirred at the same temperature for 5h, quenched with water (50mL), and extracted with ethyl acetate (30 mL. times.3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by prep-HPLC (acetonitrile: water ═ 70: 30) to give compound 1(660mg, yield 45%), 2(308mg, yield 21%) and 3(146mg, yield 10%) as white solids;
compound 7, lrms (esi) M/z 766[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 11.10(s,1H),8.25(d, J ═ 7.54Hz,1H), 7.20(d, J ═ 10.04Hz,1H),7.15(d, J ═ 7.53Hz,1H), 6.24(d, J ═ 10.13Hz,1H),6.17(t, J ═ 7.12Hz,1H), 5.93(s, 1H),5.40(d, J ═ 3.70Hz,1H),5.15(s,1H), 5.05(d, J ═ 17.52Hz,1H), 4.80(d, J ═ 17.52Hz,1H), 4.17-4.13(m, 2H), 3.86(d, J ═ 8.25Hz,1H),3.80(d, J ═ 17.52Hz,1H), 3.88(d, J ═ 17.52Hz,1H), 1H, 60(m, 2H), 3.86(d, J ═ 8.25H, 1H),3.80(d, 1H), 1H, 60, 1H, 5.70H, 1H, 5.70H, 1H, 5.70H, 1H, 5, 2H, 5, 15 (m,2H), 1H) 1.65-1.53(m,6H),1.47(s, 3H),1.34-1.29(m,1H),1.12-1.05(m,1H),0.87(s,3H),0.78(d, J ═ 7.12Hz,3H).
Compound 8, lrms (esi) M/z 766[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 7.55(d,7.15Hz,1H),7.45(d, J ═ 5.80Hz,1H), 7.32(d, J ═ 10.10Hz,1H),6.41(s,1H),6.26(d, J ═ 10.08Hz,1H),6.19(brs,1H),6.03(s, 1H), 5.83(d, J ═ 7.15Hz,1H), 5.38(brs,1H),5.15(s, 1H),5.08(d, J ═ 17.60Hz,1H),4.74(d, J ═ 17.62Hz,1H), 4.30(d, J ═ 11.69Hz,1H),4.32-4.25(m,1H),4.13(brs,1H), 4.7 (brs,1H), 4.95H, 1H, 2H, 3.7 (brm), 3.7H, 1H, 3.7 (brm, 1H, 3.7H), 2H, 3.7H, 1H, 3.7 (brm, 1H), 3.7H, 1H, 3, 3.7H, 2H, 1H, 3, 3.7H, 3, 2H, 3H, 2H, 3, 2H, 3H, 2H, 3H, 2H, 3H, 2H, 3H, 1H, 3H, 2H, 3H, 2H, 3H, 2H, 3H, 2H, 3H, 2H, 1H, 2H, 3H, 2H, 1H, 2H, 3H, 2H, 1H, 2H, 1H, 2H, 3H, 2H, 3H, 2H, 3H, 1H, 2H, 1H, 2H, 1H, 3H, 2H, 1H, 2, 1.54(d, J ═ 12.68Hz,1H),1.45(s,3H),1.36-1.33(m,1H),1.10-1.06(m,1H),0.88(s,3H),0.77(d, J ═ 7.04Hz,3H).
Compound 9, lrms (esi) M/z 766[ M + H ] +; h NMR (DMSO-d6,500mhz) δ 7.68(d, J ═ 7.35Hz,1H),7.41(brs,1H),7.38(brs,1H),7.31(d, J ═ 10.15Hz,1H),6.24(brs,1H),6.22(d, J ═ 10.15Hz,1H),6.01(s,1H),5.81(d, J ═ 7.53Hz,1H),5.40(d, J ═ 4.49Hz,1H),5.35(brs,1H),5.21(t, J ═ 5.34Hz,1H),5.16(s,1H),5.03(d, J ═ 17.75Hz,1H),4.75(d, J ═ 17.75Hz,1H),4.16 (s,1H), 4.75(d, J ═ 17.75, 1H),4.16 (H, 10.65, 2.60, 2H),3.75 (m-2H), 2.75 (3.65, 2H, 2 m-2H), 2 (3.53, 2 m-2H, 2m, 2H, 3.53, 2m, 2m, 3.09), 1.72-1.70(m,1H),1.68-1.62(m,5H),1.54(d, J ═ 12.89Hz,1H),1.45(s,3H),1.39-1.33(m,1H),1.09-1.04(m,1H),0.88(s,3H),0.79(d, J ═ 7.24Hz,3H).
Biological example 1 evaluation of antitumor Activity in vitro
The growth state of adherent cells is observed under an inverted microscope, and passage is required when the cell confluence degree in the culture bottle is found to reach 80% -90%. And (3) absorbing the culture solution in the bottle, adding 1-2mL of sterile PBS to wash the cells gently, removing the PBS, adding 1mL of 0.25% trypsin, shaking the culture bottle gently to enable the culture bottle to cover the cells uniformly, removing the trypsin after a moment, and placing the culture bottle in an incubator for 2-3 min. After the cells became enlarged and rounded under the lens and the gaps increased, the flask was gently tapped and a small amount of culture medium was added to stop the digestion. The cell suspension was gently pipetted to disperse it evenly and the appropriate ratio was inoculated into cell culture flasks with about 5mL of fresh medium per flask. The cells in the bottle are dispersed evenly according to the method of drawing 8, the bottle is placed in a cell incubator for culture, and the cell density and the growth state thereof are observed after 2 to 3 days.
(1) Preparation of MTT (5mg/ml) solution: 250mg of MTT powder was weighed, dissolved in 50ml of 1 × PBS and mixed well, the solution was filtered on a clean bench using a 0.22 μm microporous filter and dispensed into brown EP tubes and stored at-20 ℃.
(2) MTT method for detecting proliferation inhibition effect of hybrid molecules on tumor cells
1) Plate paving: ASPC-1 cells, H460 cells, HepG2 cells, HCT116 cells and GEM-Resistant AspC-1 in logarithmic growth phase are digested by trypsin, collected and counted, inoculated into a 96-well plate according to 3000-. To prevent the effects of edge effects, only 200. mu.L of sterile PBS was added around the perimeter of the 96-well plate.
2) Adding medicine: according to the experimental requirements, drugs with various concentrations are added, and a blank control group is arranged at the same time. Three multiple holes are arranged at each concentration, and the conditions are the same except the types and the concentrations of the medicines.
3) And (3) terminating the reaction: after a period of drug action, 10. mu.L of MTT solution was added to each well in a clean bench, the culture was continued in an incubator for 4h, and then the liquid in the wells was aspirated by a suction pump, 150. mu.L of DMSO was added to each well, and the mixture was shaken for 15 min. The microplate reader detects the absorbance value at the wavelength of 570 nm.
4) Calculation of cell viability
TABLE 1 in vitro antitumor Activity of Compounds 1-3
In vitro activity test results show that the compound 1 and the compound 2 show better inhibitory activity (IC) on U266, HCT116 and H46050<10 μ M); compound 3 shows better in vitro anti-tumor activity (IC) on all cell lines except HepG250<10 μ M); notably, compound 3 was shown to confer protection against U266 and HCT460 in vitroHas more excellent tumor inhibition effect and IC50Less than 1. mu.M.
Biological example 2 evaluation of antitumor Activity in vivo
Cells in logarithmic growth phase are counted according to the cell number of 1 multiplied by 106Inoculating to axillary part of BALB/c mouse, and treating tumor under aseptic condition after tumor grows to a certain volume. Cutting the tumor mass into pieces of 1.5mm3The small blocks with uniform sizes are inoculated under the axilla of BALB/c mice, and the day of inoculation is day 0. The tumor length is 200mm3On the left and right sides, the mice were grouped according to tumor volume, and each group had 6 BALB/c mice, which were divided into 5 groups: blank control group, compound 110 mg/kg group, compound 210 mg/kg group, compound 310 mg/kg group, GEM-HCl 8.7mg/kg group. The administration mode of the compound 1 is intragastric administration, 5 times per week, and 15 times in 3 weeks; the administration mode of the compound 2 and the compound 310 mg/kg group is intraperitoneal administration, 5 times per week, and 3 weeks and 15 times; the GEM-HCl 8.7mg/kg group was administered via the tail vein 1 time/3 days for 7 times. Mouse body weight and tumor volume were measured weekly and tumor growth curves were plotted. After the experiment, the mice were euthanized, tumor masses were stripped and weighed, and the tumor inhibition rates of the groups were calculated.
The experimental results are shown in the following figure 1, and the compounds 1-3 show better safety, and the body weight of the mouse does not change obviously (figure 1A); the tumor-inhibiting effect of the compounds 1 to 3 was significant, the tumor volume was significantly inhibited (fig. 1B), the tumor weight average of the administration group was lower than that of the control group, and the tumor weight average of the compound 1 to 3 administration group was lower than that of the gemcitabine administration group (fig. 1C).
In addition, as shown in table 2, 2 mice died in 6 mice in the gemcitabine intravenous injection group, and no mice died in the compound 1-3 administration group, indicating that the hybrid molecule 1-3 has better safety; the tumor inhibition rate (68.61-74.22%) of the compounds 1-3 is significantly better than that of the gemcitabine control group (42.94%).
TABLE 2 growth inhibition of H460 nude mice transplanted tumors by Compounds 1-3
Claims (10)
2. the compound of claim 1, selected from the group consisting of:
compound 1: 2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxoethyl 4- ((1- ((2R,4R,5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1, 2-dihydropyrimidin-4-yl) amino) -4-oxobutanoate;
compound 2: ((2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxyethyl) succinate;
compound 3: (2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxyethyl) succinate;
compound 4: 2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxoethyl 5- ((1- ((2R,4R,5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1, 2-dihydropyrimidin-4-yl) amino) -5-oxopentanoate;
compound 5: ((2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) glutarate;
compound 6: (2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopentyl [ a ] phenanthren-17-yl) -2-oxyethyl) glutarate;
compound 7: 2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl 6- ((1- ((2R,4R,5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1, 2-dihydropyrimidin-4-yl) amino) -6-oxohexanoate;
compound 8: ((2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methyl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) adipate;
compound 9: (2S,3R,5R) -5- (4-amino-2-oxopyrimidin-1 (2H) -yl) -4, 4-difluoro-2- (hydroxymethyl) tetrahydrofuran-3-yl (2- ((9R,10S,11S,13S,16R,17R) -9-fluoro-11, 17-dihydroxy-10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecahydro-3H-cyclopenta [ a ] phenanthren-17-yl) -2-oxyethyl) adipate.
4. The method of claim 3, comprising the steps of:
1) dissolving Dexamethasone (DXMS) in pyridine, adding anhydride, and stirring at 0-40 deg.C for 3-12 hr to obtain DXMS-linker;
or dissolving DXMS in aprotic solvent, adding 1.0-1.5 times equivalent of condensing agent (such as DCC, EDCI) into the reaction solution, and reacting with diacid compound at 0-40 deg.C for 3-10 hr in the presence of 0.1-0.5 times equivalent of Dimethylaminopyridine (DMAP) to obtain DXMS-linker;
2) dissolving DXMS-Linker in aprotic solvent, and reacting with 1-3 times of gemcitabine in the presence of 1-5 times of equivalent of organic base and condensing agent at room temperature for 1-10 hours to obtain the compound shown in formula I-III.
5. The production method according to claim 4,
the acid anhydride is selected from: succinic anhydride or glutaric anhydride;
the aprotic solvent is selected from: dichloromethane, acetonitrile, N-dimethylformamide, dioxane;
the diacid compound is selected from: adipic acid, pimelic acid;
the organic base is selected from: triethylamine, N-diisopropylethylamine;
the condensing agent is selected from: HATU or HBTU.
6. The method of claim 3, comprising the steps of:
adding succinic anhydride (510mg, 5.10mmol) into a pyridine (15mL) solution of dexamethasone (1g, 2.55mmol) at room temperature, stirring at the same temperature for 12h, detecting complete reaction by TLC, and concentrating; adding water (20mL) into the residue, stirring vigorously, and continuing to stir for 2h after a white powdery solid is generated; filtering the mixture, washing a filter cake with water (10mL multiplied by 3), placing the filter cake in a vacuum drying oven for drying for 24 hours to obtain an intermediate DXMS-Linker 1,
gemcitabine (1.13g, 4.30mmol), Et3N (0.89mL, 6.45mmol) and HATU (2.45g,6.45mmol) were added to a solution of DXMS-Linker 1(1.06g, 2.15mmol) in DMF (10mL) at room temperature, stirred at the same temperature for 5h, quenched with water (50mL), extracted with ethyl acetate (30 mL. times.3); combining the organic layers, drying over anhydrous MgSO4, filtering, and concentrating; the residue was purified by prep-HPLC (acetonitrile: water ═ 70: 30) to give compounds of formula I, formula II, and formula III.
7. The use of a compound according to claim 1 for the preparation of an anti-tumor medicament.
8. The use of claim 7, wherein said tumor comprises pancreatic cancer, ovarian cancer, breast cancer, colon cancer, non-small cell lung cancer, liver cancer.
9. A pharmaceutical composition comprising a compound of claim 1.
10. The pharmaceutical composition of claim 9, comprising a pharmaceutically acceptable carrier, formulated into any pharmaceutical dosage form.
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CN103130854A (en) * | 2013-01-31 | 2013-06-05 | 华东师范大学 | Vitamin E succinic acid esterification gemcitabine prodrug and application |
CN104693257A (en) * | 2015-02-03 | 2015-06-10 | 南通大学 | Benzenesulfonyl furazan modified gemcitabine derivative and preparation method and use thereof |
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