CN115850190B - 5-Fluorouracil derivative and anti-tumor application thereof - Google Patents
5-Fluorouracil derivative and anti-tumor application thereof Download PDFInfo
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- CN115850190B CN115850190B CN202310034758.6A CN202310034758A CN115850190B CN 115850190 B CN115850190 B CN 115850190B CN 202310034758 A CN202310034758 A CN 202310034758A CN 115850190 B CN115850190 B CN 115850190B
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- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 12
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 206010041823 squamous cell carcinoma Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 6
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 201000002740 oral squamous cell carcinoma Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 abstract description 10
- 229960002949 fluorouracil Drugs 0.000 abstract description 7
- 230000035755 proliferation Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 101001081170 Homo sapiens Humanin-like 12 Proteins 0.000 description 2
- 102100027737 Humanin-like 12 Human genes 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000002737 cell proliferation kit Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- -1 compound 1 Chemical compound 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a 5-fluorouracil derivative and an anti-tumor application thereof, belonging to the field of chemical drugs. The structure of the 5-fluorouracil derivative is shown as a formula I. The compound provided by the invention can effectively inhibit the proliferation of squamous cell carcinoma, and the inhibition effect of the compound 3a is obviously better than that of 5-fluorouracil. The invention provides a new choice for preparing the medicine for preventing and/or treating squamous cell carcinoma.
Description
Technical Field
The invention belongs to the field of chemical drugs, and particularly relates to a 5-fluorouracil derivative and an antitumor application thereof.
Background
Oral maxillofacial malignancy is a common malignancy of the head and neck, of which more than about 90% are oral squamous cell carcinoma (oral squamouscell carcinoma, OSCC), the eighth most global malignancy. OSCC is usually found and diagnosed later, and has the characteristics of early metastasis, high postoperative recurrence rate, poor prognosis and the like, so that the death rate of OSCC is high. 90% of early OSCC patients can be cured with a single surgical treatment, but in diagnosed patients, early cases are less than 10%; in addition, more than 70% of OSCC patients undergo radical surgical treatment with various complications such as cosmetic malformations and dysfunctions after surgery. The development of drugs that can effectively treat OSCC is of great importance.
The literature (Heilongjiang medical science, 2 months 2009, volume 32, phase 1) reports that 5-fluorouracil induces apoptosis in oral squamous cell carcinoma cells. However, the antitumor activity of 5-fluorouracil cannot meet clinical demands and needs to be further improved.
Disclosure of Invention
The invention aims to provide a 5-fluorouracil derivative and an anti-tumor application thereof.
The present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof:
wherein R 1 is hydrogen or R 2 is hydrogen orAnd R 1 and R 2 are not simultaneously hydrogen.
Further, the compound is one of the following compounds:
The invention also provides a method for preparing the compound, which comprises the following steps:
And (3) reacting the compound 4 with the compound 1, and separating and purifying to obtain the compound shown in the formula I.
The invention also provides an anti-tumor pharmaceutical composition, which is a preparation prepared by taking the compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the preparation is an oral preparation or an injection preparation.
The invention also provides application of the compound in preparing antitumor drugs.
Further, the tumor is squamous cell carcinoma.
Further, the squamous cell carcinoma is a head and neck squamous cell carcinoma.
Further, the head and neck squamous cell carcinoma is oral squamous cell carcinoma.
Further, the oral squamous cell carcinoma is lingual squamous cell carcinoma.
Experimental results show that the compound provided by the invention can effectively inhibit the proliferation of squamous cell carcinoma, and the inhibition effect of the compound 3a is obviously better than that of 5-fluorouracil. The invention provides a new choice for preparing the medicine for preventing and/or treating squamous cell carcinoma.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1: proliferation inhibitory capacity of each compound against squamous cell carcinoma cells HN30, HN12, cal-27, HSC-3.
Fig. 2: IC 50 values of compound 3a for HN30 and Cal27 cells.
Fig. 3: IC 50 values for compound 1 on HN30 and Cal27 cells.
Detailed Description
The raw materials used in the invention can be obtained by purchasing commercial products, and can also be prepared according to a conventional method in the field.
Example 1: preparation of Compounds 3a, 3b, 3c
Equal amounts of 5-fluorouracil (i.e., compound 1,2 mmol) and sodium hydride (2 mmol), excess compound 4 (6 mmol) were dissolved in 5mL of N, N-Dimethylformamide (DMF), heated to reflux, monitored by TLC until the reaction was completed, quenched with water, the aqueous phase extracted 3 times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, the organic solvent was removed by rotary evaporation under reduced pressure, and compounds 3a, 3b, 3c were obtained in this order by flash column chromatography separation and purification, with a total yield of 40%.
Compound 3a assay data ：1H NMR(DMSO-d6,600MHz)δ9.92(s,1H),9.89(s,1H),8.13(d,J＝6.6Hz,1H),7.48-7.44(m,4H),7.28-7.22(m,4H),4.10(t,J＝7.4Hz,2H),3.97(t,J＝6.7Hz,2H),2.70(t,J＝6.8Hz,2H),2.55(t,J＝7.4Hz,2H),2.02(q,J＝3.1Hz,6H),1.81(t,J＝2.9Hz,12H),1.74-1.67(m,12H).LRMS calcd for C42H49FN4O4[M+Na]+715.36,found 715.36.
Compound 3b assay data ：1H NMR(DMSO-d6,600MHz)δ11.78(s,1H),9.94(s,1H),8.02(d,J＝7.0Hz,1H),7.49-7.43(m,2H),7.29-7.23(m,2H),3.90(t,J＝6.7Hz,2H),2.70(t,J＝6.7Hz,2H),2.03(p,J＝3.1Hz,3H),1.82(d,J＝3.3Hz,6H),1.75-1.68(m,6H).LRMS calcd for C23H26FN3O3[M+Na]+434.19,found 434.18.
Compound 3c assay data ：1H NMR(DMSO-d6,600MHz)δ11.09(d,J＝4.0Hz,1H),9.90(s,1H),7.84(t,J＝5.0Hz,1H),7.49-7.43(m,2H),7.28-7.23(m,2H),4.06(t,J＝7.5Hz,2H),2.56(t,J＝7.5Hz,2H),2.04(p,J＝3.4Hz,3H),1.83(d,J＝3.1Hz,6H),1.75-1.69(m,6H).LRMS calcd for C23H26FN3O3[M+Na]+434.19,found 434.19.
The following experiments prove the beneficial effects of the invention.
Experimental example 1: proliferation inhibition of squamous cell carcinoma cells by Compounds
1. Experimental method
Squamous cell carcinoma cell line: HN30, HN12, cal-27, HSC-3.
Test compounds: compounds 3a, 3b, 3c; compound 1 (i.e., 5-fluorouracil).
The experimental procedure was as follows: the above 4 tumor cell lines were all cultured in a standardized incubator at 37 degrees 5% co 2; taking cells in a logarithmic growth phase, digesting, counting, performing plating with the number of 3000 cells per hole of a 96-hole plate, and performing wall-attached culture in a cell culture box overnight; the test compounds were prepared in stock solutions with DMSO at a concentration of 10mM, diluted sequentially (0,1.25,2.5,5, 10 uM) before treatment of the cells, and the control group was added at the highest DMSO concentration; the effect of each compound on proliferation capacity of 4 tumor cells was examined by culturing continuously in a cell culture incubator for 48 hours and measuring with CCK8 cell proliferation kit. Meanwhile, the experimental results of the compound 3a and the compound 1 are analyzed, and the IC 50 value is calculated, so that the influence of the two compounds on the proliferation of tumor cells is compared.
2. Experimental results
The results are shown in FIGS. 1-3. It can be seen that compound 3a has significantly higher anti-tumor cell proliferation capacity than compounds 1, 3b and 3c; furthermore, compound 1 showed higher antitumor activity in a higher concentration range, whereas the antitumor activity of 3b and 3c was not significantly improved. Further comparing the IC 50 results for compound 1 and compound 3a, it was found (fig. 2 and 3) that the IC 50 value for compound 3a was significantly lower than the IC 50 value for compound 1, such as for HN30 and Cal27 cells, the IC 50 value for compound 3a was 7.091uM and 6.536uM, respectively, and the IC 50 value for compound 1 was 21.72uM and 22.78uM, respectively.
The experimental result shows that the compound provided by the invention can effectively inhibit the proliferation of squamous cell carcinoma, and the inhibition effect of the compound 3a is obviously better than that of 5-fluorouracil.
Claims (10)
1. A compound of formula I a pharmaceutically acceptable salt thereof:
wherein R 1 is hydrogen or R 2 is hydrogen orAnd R 1 and R 2 are not simultaneously hydrogen.
2. The compound, pharmaceutically acceptable salt thereof, according to claim 1, wherein: the compound is one of the following compounds:
3. a process for preparing a compound according to any one of claims 1-2, characterized in that: the method comprises the following steps:
And (3) reacting the compound 4 with the compound 1, and separating and purifying to obtain the compound shown in the formula I.
4. An anti-tumor pharmaceutical composition, characterized in that: a formulation comprising a compound according to any one of claims 1-2 as active ingredient, together with pharmaceutically acceptable excipients.
5. The pharmaceutical composition according to claim 4, wherein: the preparation is oral preparation or injection preparation.
6. Use of a compound according to any one of claims 1-2 for the preparation of an anti-tumour medicament.
7. Use according to claim 6, characterized in that: the tumor is squamous cell carcinoma.
8. Use according to claim 7, characterized in that: the squamous cell carcinoma is of the head and neck.
9. Use according to claim 8, characterized in that: the head and neck squamous cell carcinoma is oral squamous cell carcinoma.
10. Use according to claim 9, characterized in that: the oral squamous cell carcinoma is lingual squamous cell carcinoma.
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| CN202310034758.6A CN115850190B (en) | 2023-01-10 | 2023-01-10 | 5-Fluorouracil derivative and anti-tumor application thereof |
| PCT/CN2024/071476 WO2024149270A1 (en) | 2023-01-10 | 2024-01-10 | 5-fluorouracil derivative and anti-tumor use thereof |
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| CN117986195A (en) * | 2023-01-10 | 2024-05-07 | 四川大学 | Novel heterocyclic compound and preparation method and application thereof |
| CN115850190B (en) * | 2023-01-10 | 2024-09-10 | 四川大学 | 5-Fluorouracil derivative and anti-tumor application thereof |
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| CN117986195A (en) * | 2023-01-10 | 2024-05-07 | 四川大学 | Novel heterocyclic compound and preparation method and application thereof |
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| EP0010941B1 (en) * | 1978-10-30 | 1982-05-12 | Fujisawa Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives, preparation thereof and their pharmaceutical compositions |
| JPS5668674A (en) * | 1979-11-08 | 1981-06-09 | Shionogi & Co Ltd | 5-fluorouracil derivative |
| CN107698521B (en) * | 2016-03-23 | 2020-08-07 | 上海华理生物医药股份有限公司 | Preparation and application of 5-fluorouracil substituted carboxylic acid derivative |
| MX2021011209A (en) * | 2019-03-15 | 2022-01-19 | Massachusetts Gen Hospital | Novel small molecule inhibitors of tead transcription factors. |
| CN110467574A (en) * | 2019-07-17 | 2019-11-19 | 蒋周倩 | Compound adamantane acid -5 FU 5 fluorouracil methyl esters synthesis and application |
| CN114773274A (en) * | 2022-04-29 | 2022-07-22 | 四川大学华西医院 | Novel 4, 6-pyrimidine derivatives and application thereof in antitumor drugs |
| CN114907274A (en) * | 2022-05-11 | 2022-08-16 | 宁夏医科大学 | 5-fluorouracil-1-alkyl acid derivative, preparation method and application thereof |
| CN115850190B (en) * | 2023-01-10 | 2024-09-10 | 四川大学 | 5-Fluorouracil derivative and anti-tumor application thereof |
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