A class of lipid tetravalent platinum derivative synthetic compounds and their preparation method and application
By preparing lipid tetravalent platinum-derived synthetics with redox-sensitive responses, the problems of cumbersome preparation and poor stability of nanodrugs are solved, targeted drug release and improved drug stability are achieved, and it is suitable for cancer cell inhibitory drugs.
Patent Information
- Application Number
- CN202310616580.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-05-29
- Publication Date
- 2025-08-29
- Estimated Expiration
- 2043-05-29
AI Technical Summary
The preparation process of existing nanodrugs is cumbersome, with low yield and poor stability, which affects the drug release effect.
A class of lipid tetravalent platinum-derived synthetics are used to achieve targeted drug release through special chemical bonds broken in the redox microenvironment. The preparation method includes the synthesis of PtIV-OH, PtIV-COOH, Lipo-PtIV-COOH, Lipo-PtIV-R8K, Lipo-OxaPtIV-R8K, Lipo-PtIV-ALN and Lipo-PtIV-Zolamide to form a nanoparticle carrier.
The high concentration release of drugs in the target area is achieved, the non-targeted distribution is reduced, the stability and solubility of drugs are improved, the preparation process is simplified and the stability of the product is improved.
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Figure CN116655706B_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biochemical technology, and particularly relates to a lipid tetravalent platinum derivative synthetic compound and a preparation method and application thereof. Background Art
[0002] Nanotechnology is an emerging science and technology that studies materials or structures on a scale of 1-100nm. It involves directly manipulating atoms, molecules, or clusters of atoms and molecules through microfabrication methods, rearranging and recombining them to form new nanoscale materials or structures, and then studying their properties and practical applications. Since its introduction in the last century, nanotechnology has shown tremendous potential in fields such as materials, metallurgy, chemistry, medicine, the environment, and food.
[0003] The continued penetration and impact of nanotechnology in pharmaceutical research has triggered a profound revolution in the field, giving rise to the term nanomedicine. Nanomedicine refers to drugs made by combining nanoscale polymer nanoparticles (NP), nanospheres (NS), and nanocapsules (NC) with drugs in a specific manner. Particle sizes may exceed 100 nm, but are typically less than 500 nm. Nanomedicines can also be nanoparticles directly processed from raw drug substances.
[0004] At present, the preparation of nanomedicines in the existing technology is relatively complicated, with low yield and poor stability, which affects the release of drugs. Summary of the Invention
[0005] To address these issues, the present invention provides a lipid-derived tetravalent platinum-based synthetic compound, its preparation method, and its application. The provided tetravalent platinum prodrug possesses a unique chemical bond that is sensitive to the redox microenvironment and easily breaks in oxidizing or reducing environments. This allows for targeted drug release, increasing drug concentration in the target area, reducing its distribution in non-targeted areas, and minimizing adverse reactions.
[0006] The present invention provides a lipid tetravalent platinum derivative synthetic compound, the structure of which is shown in general formula I:
[0007] Furthermore, the general formula I includes:
[0008]
[0009]
[0010] In another aspect, the present invention provides a method for preparing a lipid tetravalent platinum derivative synthetic compound, comprising the following steps:
[0011] Pt IV Synthesis of -OH: Cisplatin was suspended in water; the mixture was stirred at 40°C overnight to form a clear solution; after cooling to room temperature, a large number of needle-shaped crystals were precipitated; the product was washed with acetone several times and dried in a dryer to separate Pt IV -OH;
[0012] Pt IV Synthesis of -COOH: Pt IV -OH was suspended in anhydrous DMF; succinic anhydride was then added to the above mixture and stirred at room temperature for 48 hours; the filtrate was evaporated under reduced pressure, and the crude product was dispersed in methanol, precipitated in ether, and then dried under vacuum to obtain CisPt as a white solid. IV -COOH;
[0013] Lipo-Pt IV Synthesis of -COOH: Pt IV -COOH was suspended in 10 mL of anhydrous DMF; hexadecyl isocyanate was then added; the reaction mixture was stirred at 75 °C overnight until a clear yellow solution was obtained; the solvent was removed under reduced pressure, and Lipo-Pt was recrystallized from MeOH. IV -COOH, resulting in a yellow solid;
[0014] Lipo-Pt IV Synthesis of -R8K:Lipo-Pt IV -R8K is derived from Lipo-Pt IV -COOH and peptide condensation reaction, first, Lipo-Pt IV -COOH and EDCl were suspended in anhydrous DMF; after stirring for half an hour, the peptide was added to the above mixture; then, during the five-day reaction process, the solvent in the above reaction solution was evaporated to dryness; then methanol and Pd / C were added to the mixture and reacted under a hydrogen atmosphere for 12 hours; finally, Lipo-Pt was separated by preparative liquid chromatography IV -Product of R8K;
[0015] Lipo-OxaPt IV -R8K synthesis: Lipo-OxaPt IV-COOH, EDCl, and NHS were suspended in anhydrous DMF; after stirring the mixture for half an hour, the polypeptide was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, MeOH and Pb / C were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered through celite, and then the solvent was removed using a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column;
[0016] Lipo-Pt IV -ALN synthesis: Lipo-Pt IV -COOH, EDCl, and NHS were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, alendronic acid was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, MeOH and Pb / C were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered through celite, and then the solvent was removed using a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column;
[0017] Lipo-Pt IV -Zolamide synthesis: Lipo-Pt IV -COOH, EDCl and NHS were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, oxazolamine was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, MeOH and Pb / C were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered through celite, and the solvent was then removed using a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column.
[0018] Furthermore, it is characterized in that:
[0019] Pt IV The chemical formula of -OH is: Cl2H8N2O2P;
[0020] Pt IV The chemical formula of -COOH is: C4H 12 CI2N2O5Pt;
[0021] Lipo-Pt IV The chemical formula of -COOH is: C 21 H 44 CI2N3O6Pt;
[0022] Lipo-Pt IV The chemical formula of -R8K is: C 75 H 156 Cl2N 37 O 15 Pt 3+ ;
[0023] Lipo-OxaPt IV The chemical formula of -R8K is: C 83 H 165 N 37 O 19 Pt 4+ ;
[0024] Lipo-Pt IV The chemical formula of -ALN is: C 25 H 56 Cl2N4NaO 12 P2Pt + ;
[0025] Lipo-Pt IV The chemical formula of -Zolamide is: C 23 H 47 Cl2N7O7 S2Pt + .
[0026] In addition, the present invention proposes the use of a class of lipid tetravalent platinum derivative synthetic compounds in the preparation of cancer cell inhibitory drugs.
[0027] The beneficial effects of the present invention are:
[0028] The tetravalent platinum prodrug provided by the present invention has a special chemical bond that is sensitive to the redox microenvironment and is easily broken in an oxidizing or reducing environment. This can achieve targeted drug release, increase drug concentration in the target area, reduce its distribution in the non-targeted part, and reduce adverse reactions. The tetravalent platinum prodrug can self-assemble into nanoparticles in solution to encapsulate the drug. The drug is loaded into a nanoscale carrier, which can significantly improve the solubility of the drug and enhance the stability of the drug. The preparation method of the tetravalent platinum prodrug has a simple process flow and high product stability. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.
[0030] Figure 1 The nuclear targeting nanomicelles (NTPt IV ) particle size distribution diagram;
[0031] Figure 2 A diagram showing the cancer cell inhibition effect of the nucleus-targeted nanomicelles in an embodiment of the present invention is shown. DETAILED DESCRIPTION
[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.
[0033] The present invention provides a lipid tetravalent platinum derivative synthetic compound, the structure of which is shown in Formula I:
[0034]
[0035]
[0036] As shown in the above structural formula, wherein:
[0037] Pt IV Synthesis of -OH: Cisplatin (500 mg, 1.65 mmol) was suspended in water (30% w / v, 20 mL); the mixture was stirred at 40°C overnight to form a clear solution; after cooling to room temperature, a large amount of needle-shaped crystals precipitated; the product was washed with acetone several times and dried in a desiccator to separate Pt IV -OH, yield 89%; Pt IV The chemical formula of -OH is: Cl2H8N2O2P.
[0038] Pt IV Synthesis of -COOH: Pt IV -OH (400 mg, 1.2 mmol) was suspended in 200 mL of anhydrous DMF; succinic anhydride (133 mg, 1.2 mmol) was then added to the mixture and stirred at room temperature for 48 hours; the filtrate was evaporated under reduced pressure, and the crude product was dispersed in methanol which was precipitated in ether and then dried under vacuum to obtain Pt IV -COOH (yield, 59%); Pt IV The chemical formula of -COOH is: C4H 12 CI2N2O5Pt.
[0039] As shown in Formula II and Formula III:
[0040]
[0041] The above formula, where:
[0042] Lipo-Pt IV Synthesis of -COOH: Pt IV-COOH (200 mg, 0.46 mmol) was suspended in 10 mL of anhydrous DMF; hexadecyl isocyanate (122 mg, 0.46 mmol) was then added; the reaction mixture was stirred at 75° C. overnight until a clear yellow solution was obtained; the solvent was removed under reduced pressure and Lipo-Pt(IV)-COOH was recrystallized from MeOH to obtain a yellow solid (yield, 63%); Lipo-Pt IV The chemical formula of -COOH is: C 21 H 44 CI2N3O6Pt.
[0043] Lipo-Pt IV Synthesis of -R8K:Lipo-Pt IV -R8K is derived from Lipo-Pt IV -COOH and peptide condensation reaction, first, Lipo-Pt IV -COOH (100 mg, 0.143 mmol) and EDCl (33 mg, 0.214 mmol) were suspended in 10 mL of anhydrous DMF; after stirring for half an hour, peptide ((D-Arg)8(L-Lys)(Cbz), R8K-NH2) (200 mg. 143 mmol) was added to the above mixture; subsequently, during the five-day reaction process, the solvent in the above reaction solution was evaporated to dryness; then methanol and Pd / C were added to the mixture, and the mixture was reacted under a hydrogen atmosphere for 12 hours; finally, Lipo-Pt was separated by preparative liquid chromatography. IV -R8K product (yield: 57%); Lipo-Pt IV The chemical formula of -R8K is: C 75 H 156 Cl2N 37 O 15 Pt 3+ .
[0044] Lipo-OxaPt IV -R8K synthesis: Lipo-OxaPt IV-COOH (114 mg, 0.143 mmol), EDCl (100 mg, 0.215 mmol) and NHS (100 mg, 0.215 mmol) were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, R8K-NH2 (180 mg, 0.143 mmol) was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, 20 mL of MeOH and Pb / C (200 mg) were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered with diatomaceous earth, and the solvent was subsequently removed with a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column, Lipo-Pt IV -R8K is a yellow solid; Lipo-Pt IV The chemical formula of -R8K is: C 83 H 165 N 37 O 19 Pt 4+ .
[0045] Lipo-Pt IV -ALN synthesis: Lipo-Pt IV -COOH (114 mg, 0.143 mmol), EDCl (100 mg, 0.215 mmol) and NHS (100 mg, 0.215 mmol) were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, alendronic acid (50 mg, 0.143 mmol) was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, 20 mL of MeOH and Pb / C (200 mg) were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered with celite, and the solvent was subsequently removed with a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column; Lipo-Pt IV -ALN is a yellow solid. Lipo-Cis-Pt IV The chemical formula of -ALN is: C 25 H 56 Cl2N4NaO 12 P2Pt + .
[0046] As shown in Formula IV:
[0047]
[0048] As shown in the above formula, where:
[0049] Lipo-Pt IV -Zolamide synthesis: Lipo-Pt IV-COOH (114 mg, 0.143 mmol), EDCl (100 mg, 0.215 mmol) and NHS (100 mg, 0.215 mmol) were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, oxazolamine (45 mg, 0.143 mmol) was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, 20 mL of MeOH and Pb / C (200 mg) were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered with diatomaceous earth, and the solvent was subsequently removed by a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column, Lipo-Pt IV -Zolamide is a yellow solid. IV The chemical formula of -Zolamide is: C 23 H 47 Cl2N7O7S2Pt + .
[0050] In addition, the present invention provides a method for preparing a lipid tetravalent platinum derivative synthetic compound as follows:
[0051] Pt IV Synthesis of -OH: Cisplatin (500 mg, 1.65 mmol) was suspended in water (30% w / v, 20 mL); the mixture was stirred at 40°C overnight to form a clear solution; after cooling to room temperature, a large amount of needle-shaped crystals precipitated; the product was washed with acetone several times and dried in a desiccator to separate Pt IV -OH, yield 89%; Pt IV The chemical formula of -OH is: Cl2H8N2O2P.
[0052] Pt IV Synthesis of -COOH: Pt IV -OH (400 mg, 1.2 mmol) was suspended in 200 mL of anhydrous DMF; succinic anhydride (133 mg, 1.2 mmol) was then added to the mixture and stirred at room temperature for 48 hours; the filtrate was evaporated under reduced pressure, and the crude product was dispersed in methanol which was precipitated in ether and then dried under vacuum to obtain Pt IV -COOH (yield, 59%); Pt IV The chemical formula of -COOH is: C4H 12 CI2N2O5Pt.
[0053] Lipo-Pt IV Synthesis of -COOH: Pt IV-COOH (200 mg, 0.46 mmol) was suspended in 10 mL of anhydrous DMF; hexadecyl isocyanate (122 mg, 0.46 mmol) was then added; the reaction mixture was stirred at 75°C overnight until a clear yellow solution was obtained; the solvent was removed under reduced pressure and C16-Pt(IV)-COOH was recrystallized from MeOH to obtain a yellow solid (yield, 63%); Lipo-Pt IV The chemical formula of -COOH is: C 21 H 44 CI2N3O6Pt.
[0054] Lipo-Pt IV Synthesis of -R8K:Lipo-Pt IV -R8K is derived from Lipo-Pt IV -COOH and peptide condensation reaction, first, Lipo-Pt IV -COOH (100 mg, 0.143 mmol) and EDCl (33 mg, 0.214 mmol) were suspended in 10 mL of anhydrous DMF; after stirring for half an hour, peptide ((D-Arg)8(L-Lys)(Cbz), R8K-NH2) (200 mg. 143 mmol) was added to the above mixture; subsequently, during the five-day reaction process, the solvent in the above reaction solution was evaporated to dryness; then methanol and Pd / C were added to the mixture, and the mixture was reacted under a hydrogen atmosphere for 12 hours; finally, Lipo-Pt was separated by preparative liquid chromatography. IV -R8K product (yield: 57%); Lipo-Pt IV The chemical formula of -R8K is: C 75 H 156 Cl2N 37 O 15 Pt 3+ .
[0055] Lipo-OxaPt IV -R8K synthesis: Lipo-OxaPt IV-COOH (114 mg, 0.143 mmol), EDCl (100 mg, 0.215 mmol) and NHS (100 mg, 0.215 mmol) were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, R8K-NH2 (180 mg, 0.143 mmol) was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, 20 mL of MeOH and Pb / C (200 mg) were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered with diatomaceous earth, and then the solvent was removed with a rotary evaporator; subsequently, the crude product was purified by using an HPLC instrument with a C18 preparative column, Lipo-OxaPt IV -R8K is a yellow solid; Lipo-OxaPt IV The chemical formula of -R8K is: C 83 H 165 N 37 O 19 Pt 4+ .
[0056] Lipo-Pt IV -ALN synthesis: Lipo-Pt IV -COOH (114 mg, 0.143 mmol), EDCl (100 mg, 0.215 mmol) and NHS (100 mg, 0.215 mmol) were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, alendronic acid (50 mg, 0.143 mmol) was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, 20 mL of MeOH and Pb / C (200 mg) were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered with celite, and then the solvent was removed by a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column; Lipo-PtIV-ALN was a yellow solid. Lipo-Pt IV The chemical formula of -ALN is: C 25 H 56 Cl2N4NaO 12 P2Pt + .
[0057] Lipo-Pt IV -Zolamide synthesis: Lipo-Pt IV-COOH (114 mg, 0.143 mmol), EDCl (100 mg, 0.215 mmol) and NHS (100 mg, 0.215 mmol) were suspended in 10 ml of anhydrous DMF; after stirring the mixture for half an hour, oxazolamine (45 mg, 0.143 mmol) was added; the reaction was continued at room temperature for 2 days, and after evaporating the DMF in the mixture, 20 mL of MeOH and Pb / C (200 mg) were added to the mixture; after reacting for 6 hours under a hydrogen atmosphere, the solution was filtered with diatomaceous earth, and the solvent was subsequently removed by a rotary evaporator; the crude product was then purified by using an HPLC instrument with a C18 preparative column, Lipo-Pt IV -Zolamide is a yellow solid. IV The chemical formula of -Zolamide is: C 23 H 47 Cl2N7O7S2Pt + .
[0058] In addition, the above-mentioned lipid tetravalent platinum derivative synthetic compound is used in the preparation of cancer cell inhibitory drugs.
[0059] like Figure 1 As shown, Figure 1 The nuclear targeting nanomicelles (NTPt IV ) particle size distribution diagram;
[0060] like Figure 2 As shown, Figure 2 A diagram showing the cancer cell inhibition effect of the nucleus-targeted nanomicelles in an embodiment of the present invention is shown.
[0061] The tetravalent platinum prodrug provided in this embodiment has a special chemical bond that is sensitive to the redox microenvironment and is easily broken in an oxidizing or reducing environment. This can achieve targeted drug release, increase drug concentration in the target area, reduce its distribution in the non-targeted part, and reduce adverse reactions. The tetravalent platinum prodrug can self-assemble into nanoparticles in solution to encapsulate the drug. Encapsulating the drug in the nanoscale carrier can significantly improve the solubility of the drug and enhance the stability of the drug. The preparation method of the tetravalent platinum prodrug has a simple process flow and high product stability.
[0062] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A lipid tetravalent platinum derivative synthetic compound, characterized in that: The structure is shown in general formula I: Formula I.
2. A method for preparing a lipid tetravalent platinum derivative compound according to claim 1, characterized in that: The steps include: Pt IV Synthesis of -OH: Cisplatin was suspended in water; the mixture was stirred at 40°C overnight to form a clear solution; after cooling to room temperature, a large number of needle-shaped crystals were precipitated; the product was washed with acetone several times and dried in a dryer to separate Pt IV -OH; Pt IV Synthesis of -COOH: Pt IV -OH was suspended in anhydrous DMF; succinic anhydride was then added to the above mixture and stirred at room temperature for 48 hours; the filtrate was evaporated under reduced pressure, and the crude product was dispersed in methanol, precipitated in ether, and then dried under vacuum to obtain Pt IV -COOH; Lipo-Pt IV Synthesis of -COOH: Pt IV -COOH was suspended in 10 mL of anhydrous DMF; hexadecyl isocyanate was then added; the reaction mixture was stirred at 75 °C overnight until a clear yellow solution was obtained; the solvent was removed under reduced pressure, and Lipo-Pt was recrystallized from MeOH. IV -COOH, resulting in a yellow solid; Lipo-Pt IV Synthesis of -R8K:Lipo-Pt IV -R8K is derived from Lipo-Pt IV -COOH and peptide condensation reaction, first, Lipo-Pt IV -COOH and EDCl were suspended in anhydrous DMF; after stirring for half an hour, the peptide was added to the above mixture; then, during the five-day reaction process, the solvent in the above reaction solution was evaporated to dryness; then methanol and Pd / C were added to the mixture and reacted under a hydrogen atmosphere for 12 hours; finally, Lipo-Pt was separated by preparative liquid chromatography IV - Product of R8K.
3. Use of a lipid tetravalent platinum derivative synthetic compound according to claim 1 in the preparation of cancer cell inhibitory drugs.