Novel camptothecin derivative and preparation method and application thereof
阅读说明：本技术 新型喜树碱衍生物及其制备方法和应用 (Novel camptothecin derivative and preparation method and application thereof ) 是由 谢永美 赵宇 罗波 于 2019-08-15 设计创作，主要内容包括：本发明涉及新型喜树碱衍生物及其应用、肿瘤细胞生长抑制剂和三元复合物以及提高喜树碱衍生物溶解性的方法。所述的喜树碱衍生物由式1所示的物质经糖基化三氮唑在R<Sup>3</Sup>位置修饰而成；所述式1所示的结构式中R<Sup>1</Sup>代表H、C<Sub>1-10</Sub>的烷基、C<Sub>1-10</Sub>的氘代烷基或C<Sub>1</Sub>-C<Sub>10</Sub>的卤代烷基；R<Sup>2</Sup>代表H、CH<Sub>2</Sub>N(CH<Sub>3</Sub>)<Sub>2</Sub>或CH<Sub>2</Sub>N(CD<Sub>3</Sub>)<Sub>2</Sub>；R<Sup>4</Sup>代表<Image he="179" wi="313" file="DDA0002167762840000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>或H,其中X代表N,O或S；L代表多肽、C<Sub>1-20</Sub>直链烷基或其衍生物、C<Sub>1-20</Sub>直链或支链酰基衍生物、C<Sub>2-100</Sub>乙二醇或其衍生物。所述喜树碱衍生物溶解度较高,制备的抗癌药物具有抗癌谱广、安全性高的优点,体内抗癌活性优于盐酸伊立替康。(The invention relates to novel camptothecin derivatives, applications thereof, tumor cell growth inhibitors and ternary complexes, and a method for improving the solubility of camptothecin derivatives. The camptothecin derivative is prepared by subjecting a substance shown as a formula 1 to glycosylation triazole at R 3 Position modification; r in the structural formula shown in the formula 1 1 Representative H, C 1‑10 Alkyl of (C) 1‑10 Deuterated alkyl or C 1 ‑C 10 A haloalkyl group of (a); r 2 Representative H, CH 2 N(CH 3 ) 2 Or CH 2 N(CD 3 ) 2 ；R 4 Represents Or H, wherein X represents N, O or S; l represents a polypeptide, C 1‑20 Straight-chain alkyl or derivative thereof, C 1‑20 Straight or branched acyl derivative, C 2‑100 Ethylene glycol or a derivative thereof. The camptothecin derivative has high solubility, and the prepared anticancer drug has the advantages of wide anticancer spectrum and high safety, and the in vivo anticancer activity of the camptothecin derivative is superior to that of irinotecan hydrochloride.)
1. The camptothecin derivative is characterized in that the camptothecin derivative is prepared by glycosylating triazole in R with a substance shown as a formula 13Position modification; r in the structural formula shown in the formula 11Representative H, C1-10Alkyl of (C)1-10Deuterated alkyl or C1-C10A haloalkyl group of (a); r2Representative H, CH2N(CH3)2Or CH2N(CD3)2；R4RepresentsOr H, wherein X represents N, O or S; l represents a polypeptide, C1-20Straight-chain alkyl or derivative thereof, C1-20Straight or branched acyl derivative, C2-100A glycol or a derivative thereof, or a pharmaceutically acceptable salt thereof,
2. the camptothecin derivative according to claim 1 wherein R in formula 13Represents
3. The camptothecin derivative of claim 1 or 2, wherein: the R in the formula 11Represents H or-CH2CH3(ii) a The R is2Represents H, -CH2N(CH3)2or-CH2N(CD3)2(ii) a The R is3Represents
4. The camptothecin derivative of claim 3, wherein: the R is1represents-CH2CH3(ii) a The R is2Represents H; the R is3Represents
5. The camptothecin derivative of claim 1, wherein the camptothecin derivative is a derivative of 7-ethyl-10-hydroxycamptothecin, the structural formula of which is shown in formula 2,
6. the camptothecin derivative of claim 1 wherein the glycosylated triazole is of formula 3 or 4, wherein Y is
7. the camptothecin derivative of claim 6 wherein said R is5Any one of monosaccharide residues selected from formulas 5-28:
8. the camptothecin derivative of claim 6 or 7 wherein a or b is an integer from 1 to 20.
9. The camptothecin derivative of claim 7 wherein said R is5Selected from monosaccharide residues of any one of formulas 5, 6, 18 and 19:
10. the camptothecin derivative according to any one of claims 1 to 9, wherein said derivative is one of the following compounds:
11. the camptothecin derivative of claim 10 wherein X is selected from N or O.
12. The camptothecin derivative of claim 10 wherein Y is
13. The camptothecin derivative of claim 12 wherein d is an integer from 0 to 1.
14. The camptothecin derivative of claim 8 wherein a is 1 and b is an integer from 1 to 4.
15. A process for the synthesis of a camptothecin derivative according to any one of claims 1 to 14, comprising the steps of:
1) synthesizing azide by chemical reaction;
2) synthesizing terminal alkyne through chemical reaction;
3) the azide and terminal alkyne were dissolved in THF-H2Sequentially adding anhydrous copper sulfate and sodium ascorbate into the O to perform click reaction, then stirring at room temperature overnight, concentrating, and performing column chromatography separation to obtain the camptothecin derivative;
the azide compound is
16. The method for improving the solubility of the camptothecin derivative is characterized in that the method is to carry out glycosylation triazole modification on the 7-ethyl-10-hydroxycamptothecin derivative, the structural formula of the 7-ethyl-10-hydroxycamptothecin derivative is shown as a formula 2, and the glycosylation triazole is arranged at R3Modifying the position of (a); r in the structural formula shown in the formula 23Represents
17. The method of claim 16, wherein the glycosylated triazole has a formula of formula 3 or 4, wherein Y is
18. The method of claim 17, wherein R is5The structural formula of the compound is shown in any one of formulas 5-28.
19. The method of claim 18, wherein R is5Selected from any one of monosaccharide residue formulae 5, 6, 18, and 19.
20. The method of claim 17, wherein a is 1 and b is an integer from 1 to 4.
21. The method of claim 17, wherein Y is
22. The method of claim 21, wherein d is an integer from 0 to 1.
23. An inhibitor of tumor cell growth, which is prepared from the camptothecin derivative according to any one of claims 1 to 14.
24. The tumor cell growth inhibitor according to claim 23, which is capable of inhibiting tumor cell growth and promoting tumor cell apoptosis by cleaving DNA strands through a ternary complex with topoisomerase I, DNA.
25. The tumor cell growth inhibitor according to claim 23 or 24, wherein the tumor is colorectal tumor, lung tumor and breast tumor, liver cancer, stomach cancer, esophageal cancer, leukemia, prostate cancer, osteosarcoma, cervical cancer, thyroid cancer, ovarian cancer or pancreatic cancer.
26. Ternary complex, formed from the tumor cell growth inhibitor of any one of claims 22-24 and topoisomerase I, DNA.
27. Use of a camptothecin derivative according to any one of claims 1 to 14 for the preparation of an anticancer drug.
28. The use of claim 27, wherein the cancer is colorectal, lung and breast cancer, liver cancer, stomach cancer, esophageal cancer, leukemia, prostate cancer, osteosarcoma, cervical cancer, thyroid cancer, ovarian cancer or pancreatic cancer.
29. The use of claim 27, wherein the anti-cancer drug is capable of achieving anti-cancer effects by breaking DNA strands, inhibiting tumor cell growth and promoting apoptosis of tumor cells by forming a ternary complex with topoisomerase I, DNA, wherein the tumor cells are SW-480 and/or HT-29 and/or HCT-116 and/or a549 and/or H1975 and/or HepG2 and/or BGC-823 and/or ECA-109 and/or K562 and/or PC3 and/or 143B and/MDA-MB-231 and/or Hela and/or TPC-1 and/or SKOV-3 and/or PANC-1.
30. A formulation prepared from the camptothecin derivative of any one of claims 1-14.
31. The formulation of claim 30, wherein the formulation comprises a pharmaceutically acceptable carrier and/or adjuvant.
Technical Field
The invention relates to novel camptothecin derivatives, applications thereof, tumor cell growth inhibitors and ternary complexes, and a method for improving the solubility of camptothecin derivatives. The camptothecin derivative can be used for preparing antitumor drugs.
Background
Camptothecin (CPT) is an alkaloid containing quinoline ring extracted from the peel and fruit of camptotheca acuminata of davidiaceae in china in 1966 by american chemist Wall. Early studies found that CPT has antitumor activity, but the poor solubility of CPT in water greatly reduces its clinical application value, and later, scientists hydrolyzed the ester ring in their molecules by salt-forming method to increase water solubility, but the antitumor activity is reduced. In addition, CPT itself has strong side effects such as hemorrhagic cystitis, severe myelosuppression, and the like. Due to the above drawbacks, scientists had to stop clinical studies of CPT in the 70's of the 20 th century. In 1985, Hsiang et al discovered that CPT is a specific inhibitor of topoisomerase I (ToPoI) to revive the study of CPT. Researchers at home and abroad develop a series of camptothecin derivatives on the basis of researching the pharmacological mechanism and structure-activity relationship of the camptothecin derivatives. Irinotecan hydrochloride (CPT-11) is a water-soluble camptothecin derivative and is clinically used for treating colorectal cancer, lung cancer, breast cancer and the like, but the antitumor activity of the irinotecan hydrochloride is still low and the side effect is great. The development of various camptothecin derivatives and the improvement of the medicinal performance of the camptothecin derivatives are challenges for the development of tumor drugs.
Camptothecin derivatives such as topotecan, belotecan and 10-hydroxycamptothecin are developed and applied to human bodies successively, but the compatibility of the derivatives with human bodies is always a great challenge in the pharmaceutical industry. For example, SN-38, as a metabolite of irinotecan, has an in vitro antitumor activity 100-1000 times that of irinotecan, but has very poor solubility and is almost insoluble in common drug solvents and water, so that the drug forming property is poor (Santi et al, J Med chem.2014,57(6):2303-2314), and has great limitations in clinical application.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a camptothecin derivative having high water solubility.
In order to achieve the purpose, the invention adopts the following scheme:
the camptothecin derivative is prepared by subjecting a substance shown as a formula 1 to glycosylation triazole at R3Position modification; r in the structural formula shown in the formula 11Representative H, C1-10Alkyl of (C)1-10Deuterated alkyl or C1-C10A haloalkyl group of (a); r2Representative H, CH2N(CH3)2Or CH2N(CD3)2；R4RepresentsOr H, wherein X represents N, O or S; l represents a polypeptide, C1-20Straight-chain alkyl or derivative thereof, C1-20Straight or branched acyl derivative, C2-100A glycol or a derivative thereof, or a pharmaceutically acceptable salt thereof,
further, in the formula I, R is3Represents
Further, said R in said formula I1Represents H or-CH2CH3(ii) a The R is2Represents H, -CH2N(CH3)2or-CH2N(CD3)2(ii) a The R is3Represents
Further, a is 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, 100.
Further, b is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, 100.
Further, c is 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, 100.
Further, d is 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, 100.
Further, R is1represents-CH2CH3(ii) a The R is2Represents H; the R is3Represents
Further, the camptothecin derivative is 7-ethyl-10-hydroxycamptothecin derivative, the structural formula is shown as formula II,
further, the glycosylated triazole has a structural formula shown in formula III or IV, wherein Y is
further, R is5Any one of monosaccharide residues selected from formulas 5-28:
further, a or b is an integer of 1 to 20.
Further, R is5Selected from monosaccharide residues of any one of
further, the derivative is one of the following compounds:
further, X is selected from N or O.
Further, Y is
Further, d is an integer of 0 to 1.
Further, a is 1, and b is an integer of 1 to 4.
The invention also aims to provide a synthetic method of the camptothecin derivative, and the method can be applied to industrial production.
In order to achieve the purpose, the invention adopts the following scheme:
the method comprises the following steps:
1) synthesizing azide by chemical reaction;
2) synthesizing terminal alkyne through chemical reaction;
3) the azide and terminal alkyne were dissolved in THF-H2Sequentially adding anhydrous copper sulfate and sodium ascorbate into the O to perform click reaction, then stirring at room temperature overnight, concentrating, and performing column chromatography separation to obtain the camptothecin derivative;
the azide compound is
Preferably, Z is nothing or O, and e is 0 to 1.
The invention also aims to provide a method for improving the solubility of the camptothecin derivative, which is suitable for industrial application.
In order to achieve the purpose, the invention adopts the following scheme:
the method comprises the step of modifying 7-ethyl-10-hydroxycamptothecin derivative by glycosylated triazole, wherein the structural formula of the 7-ethyl-10-hydroxycamptothecin derivative is shown as a formula 2, and the glycosylated triazole is in the R3Modifying the position of (a); said formula 2In the structural formula R3Represents
Further, the glycosylated triazole has a structural formula shown in
Further, R is5The structural formula of the compound is shown in any one of formulas 5-28.
Further, R is5Selected from any one of
Further, a is 1, and b is an integer of 1 to 4.
Further, Y is
Further, d is an integer of 0 to 1.
The fourth purpose of the invention is to provide a tumor cell growth inhibitor which has an anticancer effect.
In order to achieve the purpose, the invention adopts the following scheme:
the tumor cell growth inhibitor is prepared from the camptothecin derivative.
The camptothecin derivative can contain any pharmaceutically acceptable carrier and auxiliary agent.
Further, the tumor cell growth inhibitor can break DNA chains by forming a ternary complex with topoisomerase I, DNA, inhibit tumor cell growth and promote tumor cell apoptosis.
Further, the tumor is colorectal tumor, lung tumor and mastadenoma, liver cancer, stomach cancer, esophageal cancer, leukemia, prostate cancer, osteosarcoma, cervical cancer, thyroid cancer, ovarian cancer or pancreatic cancer.
The fifth objective of the present invention is to provide a ternary complex, which can inhibit tumor cell growth.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the ternary complex is formed by the tumor cell growth inhibitor and topoisomerase I, DNA. The ternary complex breaks DNA chains, inhibits tumor cell growth and promotes tumor cell apoptosis.
The sixth purpose of the invention is to provide the application of the camptothecin derivative, and the application provides a new idea for treating cancer.
In order to achieve the purpose, the invention adopts the following scheme:
the camptothecin derivative is applied to the preparation of anti-cancer drugs.
Further, the cancer is colorectal cancer, lung cancer, breast cancer, liver cancer, stomach cancer, esophageal cancer, leukemia, prostate cancer, osteosarcoma, cervical cancer, thyroid cancer, ovarian cancer or pancreatic cancer.
Further, the anti-cancer drug can achieve the anti-cancer effect by breaking DNA chains, inhibiting the growth of tumor cells and promoting the apoptosis of tumor cells by forming a ternary complex with topoisomerase I, DNA, wherein the tumor cells are SW-480 and/or HT-29 and/or HCT-116 and/or A549 and/or H1975 and/or HepG2 and/or BGC-823 and/or ECA-109 and/or K562 and/or PC3 and/or 143B and/or MDA-MB-231 and/or Hela and/or TPC-1 and/or SKOV-3 and/or PANC-1.
The seventh object of the present invention is to provide a preparation which is effective in inhibiting the growth of tumor cells.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the preparation prepared from the camptothecin derivative.
Further, the preparation contains pharmaceutically acceptable carriers and/or auxiliary agents.
The pharmaceutically acceptable dosage form comprises the traditional Chinese medicine composition of the invention and optionally one or more pharmaceutically acceptable carriers, diluents or excipients and is added in a proper step in the preparation process. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The pharmaceutical formulations are adapted for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral, topical or injection administration is preferred. Pharmaceutical formulations adapted for oral administration are provided in discrete units, such as solutions or suspensions in aqueous or non-aqueous liquids; a capsule or tablet; powder or granules; edible foam formulations or foam formulations, and the like.
For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be mixed with a pharmaceutically acceptable oral, non-toxic inert carrier (e.g., ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound to a suitable fine size and mixing with a pharmaceutically acceptable carrier (e.g., an edible sugar such as starch or mannitol) which is also pulverized. Flavoring, preservative, dispersing and coloring agents may also be present. Capsules are prepared by preparing a powdered mixture as described above and filling into shaped gelatin shells. Glidants and lubricants (e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) may be added to the powder mixture prior to the filling operation. Disintegrating or solubilizing agents (e.g., agar-agar, calcium carbonate or sodium carbonate) that will improve the availability of the drug when the capsule is taken can also be added.
Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β -lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol and the like.
Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, tablets are prepared by making a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into tablets. The powdered mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, optionally with a binder (for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (for example paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (for example bentonite, kaolin or dicalcium phosphate). The powdered mixture can be granulated by wetting with a binder (e.g., syrup, starch slurry, acacia slurry or a solution of cellulosic or polymeric material) and then pressure sieving. An alternative to granulation is to pass the powder mixture through a tablet press, with the result that poorly formed agglomerates are broken up into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the dies of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure may also be combined with a free-flowing inert carrier and compressed into tablets without going through a granulation or pre-compression step. A transparent or opaque protective coating material may be provided which consists of a shellac seal coat, a sugar or polymeric material coat and a waxy polishing coat. Dyes may be added to these coatings to distinguish different unit doses.
Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs can be prepared through the use of non-toxic vehicles. Preservatives, flavoring additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners), and the like may also be added.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for an extended period of time. For example, the active ingredient may be delivered by iontophoretic patches, as generally described in pharmaceutical research,1986,3(6), 318.
Pharmaceutical preparations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches. Pharmaceutical formulations suitable for nasal administration, wherein the carrier is a solid, include coarse powders having a particle size in the range of, for example, 20 to 500 microns, which are administered by nasal inhalation, i.e. by rapid inhalation through the nasal passage from a coarse powder container adjacent the nose. Suitable formulations in which the carrier is a liquid, suitable for administration as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient.
Pharmaceutical formulations suitable for administration by inhalation include fine particle powders or aerosols, which may be prepared in different types of metered dose compressed aerosols, nebulized inhalers, insufflators, or other devices for delivering aerosol sprays. Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient, and aqueous and non-aqueous sterile suspensions. The formulations may be presented in unit-dose or multi-dose containers, for example sealed amkside and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. The injection solution for topical application can be prepared from sterile powder for injection, granule and tablet.
The pharmaceutical preparations may be in unit dosage form, each unit dosage containing a predetermined amount of the active ingredient. The administration can be used as a long term or short term therapy. The amount of active ingredient mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient as described above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in terms of antiviral efficacy without causing any harmful or toxic side effects.
The invention has the beneficial effects that:
1) the invention provides novel camptothecin derivatives, and the solubility is obviously higher than that of SN 38;
2) the tumor cell growth inhibitor and the prepared anticancer drug have wide anticancer spectrum, and the anticancer activity of the tumor cell growth inhibitor and the prepared anticancer drug is superior to that of irinotecan hydrochloride;
3) the tumor cell growth inhibitor and the prepared anticancer drug have high safety, and no obvious side effect is generated when the tumor cell growth inhibitor and the prepared anticancer drug are used at high dose.
Drawings
FIG. 1: nude mouse tumor volume-time plot;
FIG. 2: graph of body weight versus time for nude mice.
FIG. 3: compound 58 tumor volume-time profiles in nude mice in a multi-dose compound in vivo antitumor activity study.
FIG. 4: compound 67 tumor volume-time profiles in nude mice in a multi-dose compound in vivo antitumor activity study.
FIG. 5: time-course of body weight in the study of anti-tumor activity in vivo for multiple doses of the compound.
Detailed Description
The invention is further illustrated by the following specific examples, which, however, are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The materials used in the tests and the experimental methods are described generically and specifically. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be clear to those skilled in the art that, in the following, the materials used and the methods of operation are well known in the art, unless otherwise specified.
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