CN112755043A - Application of camptothecin derivative with novel structure - Google Patents
Application of camptothecin derivative with novel structure Download PDFInfo
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- CN112755043A CN112755043A CN202011643208.7A CN202011643208A CN112755043A CN 112755043 A CN112755043 A CN 112755043A CN 202011643208 A CN202011643208 A CN 202011643208A CN 112755043 A CN112755043 A CN 112755043A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
Abstract
The invention belongs to the field of organic synthesis, and discloses application of a camptothecin derivative with a novel structure in preparation of an anti-tumor medicament. The invention reduces the toxicity of the novel camptothecin derivative on the premise of ensuring the stability and the antitumor activity of the camptothecin derivative through structural modification, and the effective amount of the camptothecin derivative or the pharmaceutically acceptable hydrochloride thereof is used for preparing antitumor drugs for treating diseases or symptoms such as colorectal cancer and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, relates to a camptothecin derivative, a preparation method thereof and research on treatment of colorectal cancer, and particularly relates to application of the camptothecin derivative with a novel structure in preparation of an anti-tumor drug. The compound which takes SN38 as a basic skeleton and has good inhibition effect on colorectal cancer is modified through structural modification.
Background
Colorectal cancer is one of the most common malignant tumors, and the incidence and the mortality of colorectal cancer are 3 rd of the tumors worldwide, which threatens the life and health of human beings for a long time. In nearly twenty years, due to the rapid development of economy and westernization of life style, the incidence rate of colorectal cancer in China tends to rise year by year, and the incidence age tends to be younger. As one of common digestive tract malignant tumors, the death rate of colorectal cancer is always high, the 3-year survival rate of simple operation is not ideal, and the 5-year survival rate can be obviously improved by chemotherapy and combined chemotherapy, so that the traditional Chinese medicine composition is a clinical main treatment means.
According to the clinical practice guidelines of colon cancer and rectal cancer released by the national comprehensive cancer network in 2018, the FOLFIRI scheme consisting of 5-fluorouracil, calcium folinate and irinotecan (CPT-11) is a standardized treatment scheme for treating advanced colorectal cancer at present, and the wide clinical application of CPT-11 enables the treatment efficiency to be more than half.
The camptothecin derivative has good antitumor activity in vivo and in vitro on various malignant tumors, is commonly used for treating malignant tumors such as gastric cancer, colon cancer, bladder cancer and the like in clinic, is easy to cause gastrointestinal reactions such as nausea, vomiting, inappetence and the like in clinic, and can also cause toxic and side reactions such as bone marrow suppression, leucopenia, thrombocytopenia and the like, and in addition, the compound has poor water solubility and unstable lactone ring.
In order to enhance the antitumor activity, water solubility and stability of camptothecin and reduce toxic and side effects, scientists have performed a great deal of structure optimization work, but the camptothecin drugs currently on the market are only: topotecan, CPT-11, belotecan, 10-hydroxycamptothecin. In the clinical phase, the method comprises the following steps: rubitecan, 9-aminocamptothecin, irinotecan, and lototecan, and the like.
Although there are a number of reports in the literature that research into various novel camptothecins has also advanced, it remains extremely challenging to reduce their toxic side effects while maintaining anti-tumor activity.
Disclosure of Invention
The invention aims to provide a camptothecin derivative with a novel structure, and provides an activity screening result of the compound at a cell level and a target level and application of the camptothecin derivative in preparing an anti-tumor drug.
The invention synthesizes the camptothecin derivative with a novel structure through structure modification,
the camptothecin derivative has a structure shown as follows:
the synthetic route of the camptothecin derivative is as follows:
through a series of optimization and transformation, the novel camptothecin derivative is an excellent TOPO I inhibitor, can effectively inhibit the proliferation of various colorectal cancer cells, and is a potential drug for treating colorectal cancer.
In order to realize the purpose of the invention, the technical scheme is as follows:
the application of camptothecin derivatives with novel structures in preparing antitumor drugs is disclosed, wherein the camptothecin derivatives are shown as a structural formula A:
preferably, the invention provides application of the novel camptothecin derivative shown as the general formula or the pharmaceutically acceptable hydrochloride thereof in preparing the antitumor drugs.
Preferably, the tumor cell is a rectal cancer, further specifically LS180, HCT116, HT-29 and CT-26.
The term "pharmaceutically acceptable salt" as used herein, means that a salt of a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, usually aqueous or oily or dispersible, and effective for its intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are useful herein and which are compatible with the chemical nature of the compounds of formula (la).
Advantageous effects
Compared with CPT-11, the novel camptothecin derivative has stronger antitumor activity on tumor cells and lower toxicity on normal cells, and is more suitable for being taken as an antitumor drug.
The invention reduces the toxicity of the novel camptothecin derivative by structural modification on the premise of ensuring the stability and the antitumor activity of the novel camptothecin derivative, and the effective dose of the novel camptothecin derivative or the pharmaceutically acceptable hydrochloride thereof is used for preparing an antitumor medicament for treating diseases or symptoms such as colorectal cancer and the like.
Drawings
FIG. 1 shows the toxicity effect of novel camptothecin derivative A and CPT-11 on mice.
FIG. 2 shows the effect of novel camptothecin derivatives A and CPT-11 on enterotoxicity in mice.
FIG. 3 shows the distribution of novel camptothecin derivative A, CPT-11 and its metabolite SN38 in tumor and colorectal tissues (C for colorectal tissue and T for tumor tissue).
Detailed Description
The synthetic route for the novel camptothecin derivative a is shown below:
EXAMPLE 1 novel camptothecin derivative A
EXAMPLE 1 novel camptothecin derivative A
1) Preparation of Compound A-1: to a solution of SM1(200mg,0.51mmol,1.0eq) in toluene (5ml) was added SM2(335.7mg,1.02mmol,2.0eq) and triphosgene (302mg,1.02mmol,2.0 eq). The reaction mixture was stirred at 120 ℃ for 3 hours with a yield of 60% and the solvent was removed to give 14.9g of crude yellow product which was purified by gel column chromatography (MeOH: DCM ═ 2:100 to 3:100) to give 3.2g of yellow solid.
2) Of Compound APreparation: compound A-1(3.2g,4.3mmol,1.0eq) was taken in MeOH (50mL) and 1N NaOH solution (12.9mL,12.9mmol,3.0eq) was added. The resulting solution was stirred at 0 ℃ for 2 h. Adjusting the pH of the mixture to 7 with hydrochloric acid and adding Na2SO4And (5) drying. And (4) concentrating and purifying the product by gel column chromatography (MeOH: DCM ═ 3: 100-5: 100) to obtain 1.1g of a yellow solid product.
3)LC-MS m/z:664.4.2(M-H)+；RT＝1.165min(2.5min).
4)1H NMR(400MHz,DMSO-d6)δ11.63(s,0H),11.16(s,1H),10.32(s,1H),8.03(dd,J＝11.6,7.3Hz,2H),7.40(dd,J＝6.3,2.7Hz,2H),7.01(s,1H),5.61(d,J＝2.6Hz,1H),5.51(s,2H),5.37(d,J＝22.7Hz,1H),5.30(s,2H),5.09–4.87(m,1H),3.99(s,1H),3.88(s,1H),3.63(s,1H),3.08(q,J＝7.5Hz,2H),2.16(p,J＝7.0Hz,2H),1.29(t,J＝7.5Hz,6H),0.95(d,J＝25.7Hz,3H).
5)HPLC:purity@254nm:96.9％；214nm:97.5％
EXAMPLE 2 pharmacological test
Novel camptothecin derivative A is used for inhibiting colorectal cancer LS180 HCT116 HT-29 and CT-26, and the MTT method is adopted to research the inhibiting effect of the compound on the colorectal cancer LS180 HCT116 HT-29 and CT-26. The method comprises the following steps:
LS180, HCT116, HT-29 and CT-26 cells were plated in 96-well plates at a density of 3X 103Perwell (100. mu.L) at 37 ℃ 5% CO2Cells were allowed to adhere overnight in the incubator. After 24h the cells were treated by adding different concentrations of the compounds to be tested, and for LS180, CT-26 cells the compounds were prepared using stock solutions diluted to 10. mu.M in RPMI-1640 complete medium, controlled with 0.1% DMSO in RPMI-1640 complete medium. For HCT116, HT-29 cells, compounds were prepared using 10 μ M stock dilutions of McCoys 5A complete medium, as controlled by McCoys 5A complete medium solution containing 0.1% DMSO. 3 parallel wells were set for each concentration of each compound, and a volume of 100. mu.L of medium with compound was added to each well. After the addition, 5% CO was added at 37 deg.C2Culturing for 72h under the condition. 10% MTT solution at a concentration of 5mg/mL was added to each well. Standing and incubating for 4h at 37 ℃, discarding the culture medium containing MTT, adding 150 mu L DMSO into each well to dissolve the precipitate,the purple crystals were completely dissolved, the absorbance A was measured at 570nm, and the inhibition of cell proliferation by the drug was calculated from the OD of each well.
Cell viability was determined as OD of experimental group/OD of control group x 100%.
The results of the novel camptothecin derivative A inhibition assay for colorectal cancer cells LS180, HCT116, HT-29 and CT-26 are shown in Table 1.
TABLE 1 inhibitory Effect of novel camptothecin derivative A on LS180, HCT116, HT-29 and CT-26 cells
The inhibition test results show that: the camptothecin derivative A has 54 percent of inhibition rate on LS180 cells and 10 to 33 percent of inhibition rate on HCT116, HT-29 and CT-26 cells when the concentration is 0.1 mu M. The camptothecin derivative A has about 70% of inhibition effect on the colorectal cancer cells LS180 and HT-29 and about 50% of inhibition effect on the colorectal cancer cells HCT116 and CT-26 when the concentration is 2 mu M. MTT experiment results show that the camptothecin derivative A has obvious inhibitory activity on LS180, HCT116, HT-29 and CT-26 cells and concentration dependence, and the camptothecin derivative A can be used for preparing antitumor drugs.
Toxicity test of novel camptothecin derivative A
Mice were randomly divided into 3 groups (n-12/group) to (a) control group; (b)50mg/kg of novel camptothecin derivative a; (c) CPT-1150 mg/kg. Intraperitoneal injection of CPT-11 and the novel camptothecin derivative A was continued for 4 days. The control group was administered with normal saline intraperitoneally and the body weight, food intake, diarrhea index of the mice were measured for 7 consecutive days, and the mice were scored for diarrhea using (0) normal (normal or no feces); (1) mild diarrhea (wet and soft stools); (2) moderate diarrhea (wet stool, unformed, moderate perianal staining); (3) severe diarrhea (loose stool with severe perianal staining). After 7 days, the mice were sacrificed and the colons of the mice were wrapped with 4% paraformaldehyde and embedded in paraffin for histological analysis. It was cut into 4.5mm thick sections to prepare hematoxylin and eosin (H & E). Paraffin stained sections were examined for histomorphology.
Toxicity testing showed (as shown in figure 1): no animals died during the 7 day observation period. On day 2, CPT-1150 mg/kg and compound of formula A50 mg/kg body weight began to drop. Compared with the control group, the weight and the food intake of the mice in the CPT-1150 mg/kg group are reduced. Compound formula A50 mg/kg mice gained weight starting from day 5 compared to CPT-1150 mg/kg. After administration, the intake of CPT-1150 mg/kg and compound formula A50 mg/kg group mice began to decrease, but the intake of compound formula A50 mg/kg group mice was higher than that of the CPT-1150 mg/kg group.
Of these, both CPT-11 and the novel camptothecin derivative A caused diarrhea on day 3 after administration, but the camptothecin derivative A group at 50mg/kg suffered from diarrhea to a much lower degree than the CPT-1150 mg/kg group.
The toxicity test results show that: CPT-11 produces symptoms such as diarrhea, weight loss, and a decrease in food intake when administered, and consistent with the contents described in the literature, CPT-11 has a dose-limiting toxicity in clinical applications. However, the advantage of the novel camptothecin derivative a compared to CPT-11 is the low toxicity profile upon administration.
Furthermore, the study of the effect of camptothecin derivative a and CPT-11 on enterotoxicity in mice also revealed that, as shown in fig. 2: compared with the CPT-11 group, the colorectal tissue structures of the control group and the novel camptothecin derivative group A are more complete; the CPT-11 group caused extensive colorectal tissue damage, manifested by epithelial damage and severe inflammatory infiltration, as shown by atrophy of intestinal crypts (decreased number of crypts, increased distance between bottoms of crypts), decreased number of goblet cells and disappearance of mucus within goblet cells, and also, lymphocyte invasion into epithelial cells and lumens, lymphocytosis at the base of crypts and at the muscularis mucosae. The novel camptothecin derivative A50 mg/kg group only shows goblet cell reduction, and a small amount of lymphocyte infiltration occurs in the crypt; further proves that the novel camptothecin derivative A group has lower toxicity compared with the CPT-11 group, and the novel camptothecin derivative A is suitable for being used as an anti-tumor medicament.
The above description: when the compound is also used as an antitumor drug, compared with CPT-11, the compound of the formula A has smaller toxic and side effects while keeping the inhibitory activity on tumor cells, so that the compound of the formula A is more suitable for being used as an antitumor drug. The reason for the analysis is that the novel camptothecin derivative A has better bioavailability and stronger target property on tumor cells and lower tissue concentration on normal intestinal cells compared with CPT-11, and therefore has better drugability than CPT-11. Furthermore, pharmacokinetic and tissue distribution data for camptothecin derivative a also confirm the above analysis.
The pharmacokinetic results are shown in table 2, the AUC value of the novel camptothecin derivative a is 67949.48 which is far better than the AUC value 379.58 of CPT-11, which indicates that the novel camptothecin derivative a has higher bioavailability and therefore shows better antitumor activity.
TABLE 2 pharmacokinetic parameters of novel camptothecin derivatives A after administration to mice
Furthermore, the tissue distribution results of camptothecin derivative a and CPT-11 are shown in fig. 3: the concentration of the novel camptothecin derivative A in colorectal tissues is obviously lower than that of CPT-11, and 1/10 and 1/2 of CPT are respectively obtained in 0.25h and 1h of administration, so that the toxicity of the novel camptothecin derivative A to normal intestinal cells is obviously lower than that of CPT-11, and adverse effects such as delayed diarrhea and the like cannot be generated in administration. In addition, the concentration of the metabolite SN38 of the novel camptothecin derivative A in the tumor is far higher than that of the metabolite SN38 of CPT-11, and the concentration of the metabolite SN38 of the novel camptothecin derivative A is 6 times of that of the metabolite SN38 of CPT-11 when the novel camptothecin derivative A is administered for 0.25h and 1h, so that the novel camptothecin derivative A has higher tumor target distribution in tumor tissues, and simultaneously, because the concentration of the novel camptothecin derivative A in normal cells is obviously lower than that of the CPT-11, the novel camptothecin derivative A shows stronger antitumor activity on tumor cells and lower toxicity on normal cells compared with the CPT-11, and further proves that the novel camptothecin derivative A is more suitable for being administered as an antitumor drug compared with the CPT-11.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (4)
1. The application of camptothecin derivatives with novel structures in preparing antitumor drugs is disclosed, wherein the camptothecin derivatives are shown as a structural formula A:
2. the use according to claim 1, characterized in that said camptothecin derivative or a pharmaceutically acceptable hydrochloride thereof is used for the preparation of an antitumor medicament.
3. Use according to claim 1, characterized in that said tumor cells are rectal cancer cells.
4. The use according to claim 3, wherein said tumor cells are LS180, HCT116, HT-29 and CT-26.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103961709A (en) * | 2013-02-05 | 2014-08-06 | 中国科学院上海药物研究所 | Application of combination of histone methyltransgerase inhibitor and chemotherapeutic agent in treatment of tumors |
| WO2017216791A1 (en) * | 2016-06-13 | 2017-12-21 | Ariel Scientific Innovations Ltd. | Anticancer drug conjugates |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103961709A (en) * | 2013-02-05 | 2014-08-06 | 中国科学院上海药物研究所 | Application of combination of histone methyltransgerase inhibitor and chemotherapeutic agent in treatment of tumors |
| WO2017216791A1 (en) * | 2016-06-13 | 2017-12-21 | Ariel Scientific Innovations Ltd. | Anticancer drug conjugates |
Non-Patent Citations (1)
| Title |
|---|
| ALICIA J. SAWDON ET AL.: "Enhanced Anticancer Activity of 5’-DFUR-PCLMPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs", 《NANOMATERIALS》 * |
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