CN111110860A - Reduction response type Her2 targeted polypeptide drug conjugate and preparation method and application thereof - Google Patents
Reduction response type Her2 targeted polypeptide drug conjugate and preparation method and application thereof Download PDFInfo
- Publication number
- CN111110860A CN111110860A CN201811282320.5A CN201811282320A CN111110860A CN 111110860 A CN111110860 A CN 111110860A CN 201811282320 A CN201811282320 A CN 201811282320A CN 111110860 A CN111110860 A CN 111110860A
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- Prior art keywords
- drug
- polypeptide
- conjugate
- tumor
- carbonate
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- 229920001184 polypeptide Polymers 0.000 title claims abstract description 86
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- 229940079593 drug Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 101150029707 ERBB2 gene Proteins 0.000 title claims abstract description 24
- 230000009467 reduction Effects 0.000 title claims abstract description 24
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- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 24
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- PORTXTUJPQINJC-UHFFFAOYSA-N 2-(pyridin-2-yldisulfanyl)ethanol Chemical compound OCCSSC1=CC=CC=N1 PORTXTUJPQINJC-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- GMEDUXHKSSWXSL-UHFFFAOYSA-N 3-sulfanylpropylazanium;chloride Chemical compound Cl.NCCCS GMEDUXHKSSWXSL-UHFFFAOYSA-N 0.000 description 1
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- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a reduction response type Her2 targeted polypeptide drug conjugate, a preparation method and application thereof, and the conjugate has a molecular structural formula shown in a formula I:
wherein Aaa1Lys or Arg in L or D form; aaa2Any natural amino acid in L or D form; aaa3Any natural amino acid in L or D form; aaa4Lys or Arg in L or D form; x is CH2NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2. The reduction response type Her2 targeted polypeptide drug conjugate provided by the invention can realizeThe targeted polypeptide can deliver the antitumor drug to specific tumor cells, and the drug can exert the characteristic of specific degradation of disulfide bonds at tumor sites after entering the tumor cells, so that the antitumor drug is rapidly released, the curative effect of the drug is improved, and the toxic and side effects on normal cells are reduced.
Description
Technical Field
The invention relates to a reduction response type Her2 targeted polypeptide drug conjugate and a preparation method and application thereof, in particular to a reduction response type Her2 targeted polypeptide drug conjugate applicable to tumor treatment and a preparation method and application thereof.
Background
Malignant tumor is a common disease and frequently encountered diseases which seriously threaten human health and are caused by the combined action of multiple inducements, account for the second place of the death rate of all diseases, seriously harm the health of people in China, bring serious economic burden to families of patients and national medical systems, and also provide serious challenge for the research and development of novel antitumor drugs, but the obtained effect is not satisfactory, the main reasons comprise that the tumor is easy to generate drug resistance, the chemotherapeutic drugs have poor targeting property to the tumor, and the toxic and side effects are great.
The small molecular targeted peptide can selectively target the drug to a tumor part through receptor interaction, so that the therapeutic drug is concentrated in a focal region, the drug concentration of the focal region is several times or even hundreds times higher than that of a conventional preparation, the efficiency of systemic chemotherapy is improved, and the toxic and side effects of the drug are greatly reduced, for example, LTVSPWWY polypeptide can be specifically combined with a Her2 receptor on the surface of a tumor cell. However, the traditional targeting peptide can only carry a drug to tumor cells, and the drug can not enter the cells because the physicochemical property characteristics of the targeting peptide are difficult to cross cell membranes, and researches show that the polypeptide with a C-terminal sequence of R/KXXR/K (R: arginine, K: lysine, X: any amino acid) has the function of tissue penetration, namely C-terminal rule (Cend R).
The intracellular glutathione concentration (0.5-10 mM/L) is more than 200 times of the extracellular glutathione concentration (2-20 MuM/L), the disulfide bond is reduced to generate sulfhydryl in the presence of a certain amount of reducing agents such as Glutathione (GSH) or Dithiothreitol (DTT), but the disulfide bond is very stable under the environment of normal body temperature, pH, oxidation and the like of a human body, namely the extracellular glutathione concentration is not enough to reduce the disulfide bond, and the tumor histiocyte is anoxic compared with the normal histiocyte and has more reducing environment. Therefore, the hydrophilic polymer and the hydrophobic drug can be linked through disulfide bonds, and the drug is reduced by GSH after entering target cells, namely, the disulfide bonds are broken to generate sulfydryl, so that the drug is quickly and effectively released and diffused to structures such as cell nucleus and the like, and cancer cells are killed. Currently, the most commonly used disulfide linker arms are mainly 2,2 ' -dithiodiacetic acid, 3 ' -dithiodipropionic acid, etc., for example, 3 ' -dithiodipropionic acid is used as the prodrug of the linker arm, and under reducing conditions such as GSH and DTT, the disulfide bonds are rapidly broken, but the released drug usually carries a "tail" rather than the original drug molecule.
Disclosure of Invention
The invention provides a reduction response type Her2 targeted polypeptide drug conjugate and a preparation method and application thereof, aiming at the defects of poor selectivity, poor water solubility, insufficient membrane penetrating capability of targeted polypeptide, insufficient reduction response release raw drug and the like of the existing antitumor drugs.
The technical scheme for solving the technical problems is as follows:
a reduction-responsive Her2 targeted polypeptide drug conjugate has a molecular structure shown as formula I:
wherein Aaa1Lys or Arg in L or D form; aaa2Any natural amino acid in L or D form; aaa3Any natural amino acid in L or D form; aaa4Lys or Arg in L or D form; x is CH2NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2.
Further, the reduction-responsive Her2 targeted polypeptide drug conjugate is preferably Aaa1Is L-type Arg, Aaa2Is L-type Gly, Aaa3Is L-type Asp, Aaa4Is L-type Arg and has a structural formula shown as a formula II:
wherein X is CH2NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2.
Furthermore, the anti-tumor drug is any one of taxane drugs, camptothecin drugs and vinblastine drugs.
Further, the taxane drug is one of paclitaxel, docetaxel, cabazitaxel and larotaxel, the camptothecin drug is one of camptothecin, irinotecan, topotecan, 10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecin, and the vinblastine drug is one of vinblastine, vincristine and vinorelbine.
The mechanism of releasing original drug molecules of the polypeptide drug conjugate provided by the invention is as follows:
the invention adopts the idea of tumor microenvironment targeted drug delivery, and by introducing a self-destruction type disulfide bond connecting arm sensitive to a reduction environment, under the reduction condition provided by glutathione in tumor cells, the disulfide bond of a polypeptide drug conjugate is broken, and a free sulfhydryl is generated after the disulfide bond is broken, and because of the influence of structural stability factors, the sulfhydryl can nucleophilically attack an adjacent ester bond to generate a stable five-membered ring or six-membered ring structure, and simultaneously release a raw drug molecule of an anticancer drug, taking cabazitaxel as an example, the mechanism of the reduction response release of the raw drug molecule is shown in figure 4.
The polypeptide drug conjugate provided by the invention has the beneficial effects that:
1) the polypeptide drug conjugate provided by the invention is characterized in that a C-terminal is introduced into a C-terminal, wherein the C-terminal accords with C-terminal rule (Cend R) -R/KXXR/K (R: arginine; k is lysine; x is any amino acid), so that the targeted polypeptide not only can deliver the antitumor drug to specific tumor cells to realize targeted drug delivery, but also increases the membrane penetrating capability of the drug on the tumor cells, improves the targeting property of the drug, increases the curative effect of the drug and reduces the toxic and side effect on normal cells.
2) The polypeptide drug conjugate provided by the invention also exerts the characteristic of specific degradation of disulfide bonds at tumor sites. Compared with the conventional connecting arms such as 2,2 '-dithiodiacetic acid, 3' -dithiodipropionic acid and the like, the anticancer drug in the form of original drug molecules can be obtained without further hydrolysis.
The invention also claims the application of the polypeptide drug conjugate in the field of antitumor drugs.
Further, the tumors refer to gastric cancer and breast cancer.
The preparation method of the reduction-responsive Her2 targeted polypeptide drug conjugate disclosed by the invention comprises the following steps:
the first method comprises the following steps:
1) pyridyl dithiol or pyridyl dithioamine containing 2-3 carbon atoms is used as a raw material to carry out coupling reaction with p-nitrophenyl chloroformate to prepare carbonate or amino carbonate;
2) carrying out ester exchange reaction on the carbonate or the amino carbonate obtained in the step 1) and a hydrophobic anti-tumor drug containing hydroxyl groups to generate a conjugate;
3) carrying out sulfhydryl-disulfide bond exchange reaction on the conjugate obtained in the step 2) and the targeted polypeptide to prepare a polypeptide drug conjugate containing a disulfide bond;
wherein X is NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2;
the second method comprises the following steps:
1)4- (2-pyridyl disulfide group) butyric acid or 5- (2-pyridyl disulfide group) valeric acid is taken as a raw material to generate esterification reaction with hydrophobic antitumor drugs containing hydroxyl groups to generate esterification products of the hydrophobic antitumor drugs;
2) carrying out sulfhydryl-disulfide bond exchange reaction on the esterification product obtained in the step 1) and the target polypeptide to prepare a polypeptide drug conjugate containing a disulfide bond;
the reaction route is as follows:
ROH is a hydrophobic anti-tumor drug; n is 1 or 2.
Further, the specific operation steps of the first method are as follows:
step 1): under the alkaline condition, pyridyl dithiol or pyridyl dithioamine is dissolved in a solvent to obtain a solution, p-nitro phenyl chloroformate is dropwise added into the solution under the stirring at room temperature, and the molar ratio of the pyridyl dithiol or pyridyl dithioamine to the p-nitro phenyl chloroformate is controlled to be 1: (1-3), reacting at room temperature for 1-10 hours, and carrying out post-treatment on the reaction liquid to obtain carbonate or amino carbonate;
step 2): dissolving the carbonate or amino carbonate obtained in the step 1) and the hydrophobic anti-tumor medicine containing hydroxyl groups in a solvent according to a molar ratio of 1 (1-3) under an alkaline condition, carrying out reflux reaction for 1-10 hours, cooling to room temperature, and carrying out post-treatment on a reaction solution to obtain a conjugate of the carbonate or amino carbonate and the hydrophobic anti-tumor medicine containing hydroxyl groups;
step 3): and (3) dropwise adding the targeting polypeptide into the conjugate solution obtained in the step 2) under stirring in an inert atmosphere, wherein the molar ratio of the targeting polypeptide to the conjugate is 1 (1-3), reacting at room temperature for 12-48 hours, and performing post-treatment to obtain the disulfide bond-containing targeting polypeptide drug conjugate.
Further, the specific operation steps of the second method are as follows:
step 1): 4- (2-pyridyl disulfide group) butyric acid or 5- (2-pyridyl disulfide group) valeric acid is used as a raw material, and the raw material is mixed with a hydrophobic drug containing a hydroxyl group according to the molar ratio of (1-3): 1, dissolving in a solvent, reacting at room temperature for 12-36 hours, and washing, separating and vacuum drying reaction liquid to obtain an esterification product of the hydrophobic anti-tumor drug;
step 2): dropwise adding the targeting polypeptide into the esterified product solution obtained in the step 1) under stirring in an inert atmosphere, wherein the molar ratio of the targeting polypeptide to the esterified product is 1 (1-3), reacting at room temperature for 12-48 hours, and performing post-treatment to obtain the targeting polypeptide drug conjugate containing the disulfide bond.
Drawings
FIG. 1 is a MALDI-TOF-MS plot of the Her2 targeted polypeptide cabazitaxel conjugate obtained in example 1;
FIG. 2 is a graph comparing the proliferation inhibitory activity of the Her 2-targeted polypeptide cabazitaxel conjugate obtained in example 1 and cabazitaxel on gastric cancer cell N87;
fig. 3 is a comparison of the proliferation inhibitory activity of the Her 2-targeted polypeptide cabazitaxel conjugate obtained in example 1 and cabazitaxel on breast cancer cells BT 474.
Fig. 4 is a schematic diagram of the mechanism of the reduction response of the polypeptide drug conjugate to release the original drug molecule.
Detailed Description
The principles and features of this invention are described below in conjunction with examples, which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
Example 1:
a reduction-responsive Her2 targeted polypeptide cabazitaxel conjugate has a structural formula shown as b.
Preparation of polypeptide chain the synthesis of the target polypeptide of the present invention was carried out using a solid phase polypeptide synthesis method using Fmoc strategy and a polypeptide synthesizer manufactured by CSBio Inc.
LTVSPWYCRGDR selection of reagents for synthesis:
(1) carrier resin: Fmoc-Arg (Pbf) Wang, degree of substitution: 0.67
(2) Selected protected amino acids: Fmoc-Leu-OH, Fmoc-Thr (tBu) -OH, Fmoc-Val-OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Trp (Boc) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-D-Cys (Trt) -OH, Fmoc-Arg (pbf) -OH, Fmoc-Gly-OH, Fmoc-Asp (OtBu) -OH, 3-fold excess of protecting amino acid used in the reaction.
(3) The deprotection reagent used in the invention is: piperidine/N, N-dimethylformamide in a ratio of 20: 80.
(4) The coupling reagents used in the present invention are: DIEA/HBTU.
(5) The cleavage reagents used in the present invention were: TFA/triisopropylsilane/water/1, 2-ethanedithiol in the following ratios: 94:2:2:2. Precipitating with 10 times volume of ether, purifying the obtained crude polypeptide with C18 preparative column, detecting wavelength: 214nm, mobile phase a: acetonitrile (containing 0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). And (3) determining the molecular weight of the obtained pure product by MS-MALDI-TOF, determining the purity of the sample by HPLC, and freeze-drying to obtain the target polypeptide.
The specific preparation method of the Her2 targeted polypeptide cabazitaxel conjugate comprises the following steps:
1) preparation of 4-nitrophenyl-2- (2-pyridyldithio) ethyl carbonate:
2- (2-Pyridyldithio) ethanol (0.5g, 2.67mmol) and triethylamine (0.56g, 5.6 mmol) were dissolved in 15mL of dichloromethane, and phenyl p-nitrochloroformate (0.65g, 3.2.0mmol) was slowly dropped into the solution with stirring at 0 ℃ and reacted at room temperature for 6 hours after dropping. Concentrating, separating with silica gel column, concentrating, and vacuum drying to obtain white solid product 0.5g with yield of 53%.
2) Preparation of 2- (2-pyridyldithio) ethyl carbonate conjugate with cabazitaxel:
4-Nitrophenyl-2- (2-pyridyldithio) ethyl carbonate (0.5g, 1.4mmol) and Cabazitaxel (1.0g, 1.2mmol) were dissolved in 50mL of dichloromethane, 0.7mL of triethylamine was added, and the reaction was warmed to reflux for 5 hours. After the reaction, the temperature is reduced to room temperature, the organic phase is washed by dilute hydrochloric acid water, liquid separation, drying, concentration, purification by a silica gel column, concentration and vacuum drying are carried out, 0.75g of white solid is obtained, and the yield is 60%.
Of the product detected1H NMR indicated that a conjugate of 2- (2-pyridyldithio) ethyl carbonate and cabazitaxel (Py-SS (O) -Caba) having the structure shown in formula a was obtained.
3) LTVSPWYCRGDR preparation of Cabazitaxel:
LTVSPWYCRGDR polypeptide (50mg, 0.034mmol) was dissolved in 2mL DMSO, and a solution of Py-SS (O) -Caba (53mg, 0.05mmol) in DMSO (2mL) was added thereto under nitrogen with stirring, and the reaction was carried out at room temperature for 24 hours. And (3) directly carrying out preparation liquid phase purification on the reaction liquid: detection wavelength: 254nm, mobile phase A: acetonitrile (containing 0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). The molecular weight of the obtained pure product is determined by MS-MALDI-TOF, which shows that the polypeptide cabazitaxel conjugate (polypeptide-disulfide bond (O) -cabazitaxel) with the structure shown as the formula b is obtained, and the target conjugate is obtained by freeze drying, wherein the yield is 34%.
The synthetic route is as follows:
example 2:
a reduction-responsive Her2 targeted polypeptide SN-38 conjugate has a structural formula shown as d. Preparation of polypeptide chain the synthesis of the target polypeptide of the present invention was carried out using a solid phase polypeptide synthesis method using Fmoc strategy and a polypeptide synthesizer manufactured by CSBio Inc.
LTVSPWYCRGNK selection of reagents for synthesis:
(1) carrier resin: Fmoc-lys-Wang, degree of substitution: 0.67
(2) Selected protected amino acids: Fmoc-Leu-OH, Fmoc-Thr (tBu) -OH, Fmoc-Val-OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Trp (Boc) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-D-Cys (Trt) -OH, Fmoc-Arg (pbf) -OH, Fmoc-Gly-OH, Fmoc-Asn (Trt) -OH, Fmoc-Lys (Boc) -OH, 3-fold excess of the protecting amino acid used in the reaction.
(3) The deprotection reagent used in the invention is: piperidine/N, N-dimethylformamide in a ratio of 20: 80.
(4) The coupling reagents used in the present invention are: DIEA/HBTU.
(5) The cleavage reagents used in the present invention were: TFA/triisopropylsilane/water/1, 2-ethanedithiol in the following ratios: 94:2:2:2. Precipitating with 10 times volume of ether, purifying the obtained crude polypeptide with C18 preparative column, detecting wavelength: 214nm, mobile phase a: acetonitrile (containing 0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). And (3) determining the molecular weight of the obtained pure product by MS-MALDI-TOF, determining the purity of the sample by HPLC, and freeze-drying to obtain the target polypeptide.
The specific preparation method of the Her2 targeted polypeptide SN-38 conjugate is as follows:
1) preparation of TBDPS-7-ethyl-10-hydroxycamptothecin:
7-Ethyl-10-hydroxycamptothecin (2.0g, 5.1mmol) was added to 100mL of dichloromethane, triethylamine (3.2mL, 23mmol) and TBDPSCl (5.3mL, 20.4mmol) were added, and the mixture was refluxed overnight. Cooling to room temperature, washing the organic phase with dilute hydrochloric acid, saturated sodium bicarbonate and saturated salt in sequence, separating, drying, and concentrating under reduced pressure. The concentrated solution was dropped into a large amount of n-hexane for precipitation, filtered, and vacuum-dried to obtain 3.0g of a yellow solid with a yield of 93%.
2) Preparation of TBDPS-PySS-7-ethyl-10-hydroxycamptothecin:
TBDPS-7-ethyl-10-hydroxycamptothecin (3.0g, 4.8mmol), 4- (2-pyridyldithio) butanoic acid (1.2g, 5.2mmol), 4-dimethylaminopyridine (DMAP, 0.75g, 6.1mmol), N, N-diisopropylethylamine (DIEA, 1.0mL, 6.1mmol) were dissolved in 300mL of DCM, and 1-ethyl-3- (dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI, 1.2g, 6.1mmol) was added under ice-bath and reacted at room temperature for 24 hours. The reaction mixture was washed with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine in this order, separated, dried, and then the solvent was evaporated under reduced pressure, and vacuum dried to obtain 3.8g of a yellow solid with a yield of 95%.
3) Preparation of PySS (20) -7-ethyl-10-hydroxycamptothecin:
TBDPS-PySS-7-ethyl-10-hydroxycamptothecin (3.8g, 4.5mmol) and TBAF (4.7 g, 18mmol) were dissolved in 500mL of a mixture of THF and 0.05M HCl (volume ratio 1: 1) and reacted at room temperature. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification by silica gel column, concentration and vacuum drying gave 2.3g of yellow solid with a yield of 84%. Subjecting the product to1H NMR and MS tests show that the 4- (2-pyridyldithio) butyric acid with the structure shown in the formula c and 7-ethyl-10-hydroxycamptothecin (20-position) conjugate (PySS (20) -SN38) are obtained.
4) LTVSPWYCRGNK-preparation of SN 38:
LTVSPWYCRGNK polypeptide (97mg, 0.068mmol) was dissolved in 4mL DMSO, and a solution of PySS (20) -SN38(60mg, 0.1mmol) in DMSO (2mL) was added thereto under nitrogen protection with stirring, and the reaction was carried out at room temperature for 24 hours. And (3) directly carrying out preparation liquid phase purification on the reaction liquid: detection wavelength: 254nm, mobile phase A: acetonitrile (containing 0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). The molecular weight of the obtained product is determined by MS-MALDI-TOF, which shows that the product with the structure shown in the formula d is obtained, and the target conjugate is obtained by freeze drying with the yield of 30 mg.
The synthetic route is as follows:
example 3:
a reduction-responsive Her2 targeted polypeptide vinorelbine conjugate has a structural formula shown as f.
Preparation of polypeptide chain: the synthesis of the targeting polypeptide of the present invention was carried out using a solid phase polypeptide synthesis method using Fmoc strategy using a polypeptide synthesizer manufactured by CSBio Inc.
LTVSPWYCKELK selection of reagents for synthesis:
(1) carrier resin: Fmoc-Arg (Pbf) Wang, degree of substitution: 0.67
(2) Selected protected amino acids: Fmoc-Leu-OH, Fmoc-Thr (tBu) -OH, Fmoc-Val-OH, Fmoc-Ser (tBu) -OH, Fmoc-Pro-OH, Fmoc-Trp (Boc) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-D-Cys (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Glu (OtBu) -OH, 3-fold excess of the protecting amino acid used in the reaction.
(3) The deprotection reagent used in the invention is: piperidine/N, N-dimethylformamide in a ratio of 20: 80.
(4) The coupling reagents used in the present invention are: DIEA/HBTU.
(5) The cleavage reagents used in the present invention were: TFA/triisopropylsilane/water/1, 2-ethanedithiol in the following ratios: 94:2:2:2. Precipitating with 10 times volume of ether, purifying the obtained crude polypeptide with C18 preparative column, detecting wavelength: 214nm, mobile phase a: acetonitrile (containing 0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). And (3) determining the molecular weight of the obtained pure product by MS-MALDI-TOF, determining the purity of the sample by HPLC, and freeze-drying to obtain the target polypeptide.
The specific preparation method of the Her2 targeted polypeptide vinorelbine conjugate comprises the following steps:
1) preparation of pyridyldithio propylamine hydrochloride:
mercaptopropylamine hydrochloride (1.0g, 7.9mmol) and 2, 2' -dithiodipyridine (PySSPy, 2.3g, 9.4mmol) were added to 60mL of methanol and reacted at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, the target product was precipitated with diethyl ether, filtered, and dried under vacuum to give 1.39g of a pale yellow oily liquid product with a yield of 74.4%.
2) Preparation of 4-nitrophenyl- (2-pyridyldithio) propylaminocarbonate:
pyridyl dithiopropylamine hydrochloride (1.39g, 5.9mmol) and triethylamine (0.72g, 7.1mmol) were dissolved in 50mL of dichloromethane, and p-nitrophenyl chloroformate (1.65g, 8.26mmol) was slowly dropped into the solution under ice bath, and after dropping, the reaction was carried out at room temperature for 5 hours. Concentrating, separating with silica gel column, concentrating, and vacuum drying to obtain light yellow oily liquid 1.70g with yield of 79.8%.
3) Preparation of 3- (2-pyridyldithio) propylamino vinorelbine carbonate:
4-Nitrophenyl- (2-pyridyldithio) propylaminocarbonate (1.0g, 2.7mmol) and vinorelbine (2.1g, 2.7mmol) were dissolved in 150mL of methylene chloride, 1mL of triethylamine was added, and the reaction was then warmed to reflux for 8 hours. After the reaction is finished, cooling to room temperature, washing an organic phase by using dilute hydrochloric acid, separating liquid, drying, concentrating, purifying by using a silica gel column, concentrating, and drying in vacuum to obtain 1.7g of light yellow solid (PySS (N) -vinorelbine) shown in the formula e, wherein the yield is 63%.
4) LTVSPWYCKELK preparation of vinorelbine:
LTVSPWYCKELK polypeptide (50mg, 0.034mmol) was dissolved in 2mL DMSO, and a solution of PySS (N) -vinorelbine (51mg, 0.05mmol) in DMSO (2mL) was added thereto under nitrogen with stirring, and reacted at room temperature for 24 hours. And (3) directly carrying out preparation liquid phase purification on the reaction liquid: detection wavelength: 254nm, mobile phase A: acetonitrile (containing 0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). And (3) determining the molecular weight of the obtained pure product by MS-MALDI-TOF, indicating that the polypeptide vinorelbine conjugate with the structure shown in the formula f is obtained, and freeze-drying the polypeptide vinorelbine conjugate to obtain 32mg of the target conjugate with the yield of 40%.
The synthetic route is as follows:
in order to verify the proliferation inhibition effect of the polypeptide drug conjugate on tumor cells, the polypeptide conjugate cabazitaxel and cabazitaxel obtained in example 1 are used for carrying out an in vitro anti-tumor cell effect comparison experiment, the gastric cancer cell N87 and the breast cancer cell BT474 are used as examples for carrying out the proliferation inhibition effect experiment of the polypeptide conjugate cabazitaxel drug and cabazitaxel obtained in example 1, and the specific operation process is as follows:
1) gastric cancer cell N87
Taking cells in logarithmic growth phase, adjusting appropriate cell density, inoculating into 96-well plate, culturing at 37 deg.C and 5% CO in 100 μ l/well2In the incubator. After overnight culture, the drug was administered for 48 h. A blank group and an administration group are respectively arranged, and each group is provided with 4 multiple holes. The in vitro anti-gastric cancer effect is shown in fig. 2. As can be seen from FIG. 2, the polypeptide-disulfide bond (O) -cabazitaxel has similar cytotoxicity to cabazitaxel, and the polypeptide-disulfide bond (O) -cabazitaxel has half of the lethal dose IC of gastric cancer cell N87500.166 μ M, has strong antitumor activity.
2) Breast cancer cell BT474
Taking cells in logarithmic growth phase, adjusting appropriate cell density, inoculating into 96-well plate, culturing at 37 deg.C and 5% CO in 100 μ l/well2In the incubator. After overnight culture, the drug was administered for 48 h. A blank group and an administration group are respectively arranged, and each group is provided with 4 multiple holes. The in vitro anti-breast cancer effect is shown in figure 3. As can be seen from FIG. 3, the polypeptide-disulfide bond (O) -cabazitaxel has similar cytotoxicity to cabazitaxel, and the polypeptide-disulfide bond (O) -cabazitaxel has half lethal dose IC to breast cancer cells BT474500.089 μ M, has strong antitumor activity.
In conclusion, the polypeptide drug conjugate provided by the invention has good water solubility, and experiments prove that the polypeptide drug conjugate has basically the same anti-tumor activity as the original drug and can exert the inhibition effect on tumor cells within 48 hours.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A reduction-responsive Her2 targeted polypeptide drug conjugate has a molecular structure shown as formula I:
wherein Aaa1Lys or Arg in L or D form; aaa2Any natural amino acid in L or D form; aaa3Any natural amino acid in L or D form; aaa4Lys or Arg in L or D form; x is CH2NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2.
2. The reduction-responsive Her2 targeted polypeptide drug conjugate of claim 1, having a structural formula as shown in formula ii:
wherein X is CH2NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2.
3. The reduction-responsive Her2 targeted polypeptide drug conjugate as claimed in claim 1 or 2, wherein the anti-tumor drug is any one of taxanes, camptothecins and vinblastines.
4. The reduction-responsive Her2 targeted polypeptide drug conjugate of claim 3, wherein the taxane drug is one of paclitaxel, docetaxel, cabazitaxel, and larotaxel, the camptothecin drug is one of camptothecin, irinotecan, topotecan, 10-hydroxycamptothecin, and 7-ethyl-10-hydroxycamptothecin, and the vinblastine drug is one of vinblastine, vincristine, and vinorelbine.
5. The application of the reduction-responsive Her2 targeted polypeptide drug conjugate as claimed in any one of claims 1-4 in the field of antitumor drugs.
6. The use according to claim 5, wherein said tumors are gastric cancer and breast cancer.
7. The method for preparing a reduction-responsive Her2 targeted polypeptide drug conjugate as claimed in any one of claims 1-4, wherein the method comprises the following steps:
the first method comprises the following steps:
1) pyridyl dithiol or pyridyl dithioamine containing 2-3 carbon atoms is used as a raw material to carry out coupling reaction with p-nitrophenyl chloroformate to prepare carbonate or amino carbonate;
2) carrying out ester exchange reaction on the carbonate or the amino carbonate obtained in the step 1) and a hydrophobic anti-tumor drug containing hydroxyl groups to generate a conjugate;
3) carrying out sulfhydryl-disulfide bond exchange reaction on the conjugate obtained in the step 2) and the targeted polypeptide to prepare a polypeptide drug conjugate containing a disulfide bond;
wherein X is NH or O; ROH is a hydrophobic anti-tumor drug; n is 1 or 2;
the second method comprises the following steps:
1)4- (2-pyridyl disulfide group) butyric acid or 5- (2-pyridyl disulfide group) valeric acid is taken as a raw material to generate esterification reaction with hydrophobic antitumor drugs containing hydroxyl groups to generate esterification products of the hydrophobic antitumor drugs;
2) carrying out sulfhydryl-disulfide bond exchange reaction on the esterification product obtained in the step 1) and the target polypeptide to prepare a polypeptide drug conjugate containing a disulfide bond;
the reaction route is as follows:
wherein ROH is a hydrophobic anti-tumor drug; n is 1 or 2.
8. The preparation method according to claim 7, wherein the specific operation steps of the first method are as follows:
step 1): under the alkaline condition, pyridyl dithiol or pyridyl dithioamine is dissolved in a solvent to obtain a solution, p-nitro phenyl chloroformate is dropwise added into the solution under the stirring at room temperature, and the molar ratio of the pyridyl dithiol or pyridyl dithioamine to the p-nitro phenyl chloroformate is controlled to be 1: (1-3), reacting at room temperature for 1-10 hours, and carrying out post-treatment on the reaction liquid to obtain carbonate or amino carbonate;
step 2): dissolving the carbonate or amino carbonate obtained in the step 1) and the hydrophobic anti-tumor medicine containing hydroxyl groups in a solvent according to a molar ratio of 1 (1-3) under an alkaline condition, carrying out reflux reaction for 1-10 hours, cooling to room temperature, and carrying out post-treatment on a reaction solution to obtain a conjugate of the carbonate or amino carbonate and the hydrophobic anti-tumor medicine containing hydroxyl groups;
step 3): and (3) dropwise adding the targeting polypeptide into the conjugate solution obtained in the step 2) under stirring in an inert atmosphere, wherein the molar ratio of the targeting polypeptide to the conjugate is 1 (1-3), reacting at room temperature for 12-48 hours, and performing post-treatment to obtain the disulfide bond-containing targeting polypeptide drug conjugate.
9. The preparation method according to claim 7, wherein the specific operation steps of the second method are as follows:
step 1): 4- (2-pyridyl disulfide group) butyric acid or 5- (2-pyridyl disulfide group) valeric acid is used as a raw material, and the raw material is mixed with a hydrophobic drug containing a hydroxyl group according to the molar ratio of (1-3): 1, dissolving in a solvent, reacting at room temperature for 12-36 hours, and washing, separating and vacuum drying reaction liquid to obtain an esterification product of the hydrophobic anti-tumor drug;
step 2): dropwise adding the targeting polypeptide into the esterified product solution obtained in the step 1) under stirring in an inert atmosphere, wherein the molar ratio of the targeting polypeptide to the esterified product is 1 (1-3), reacting at room temperature for 12-48 hours, and performing post-treatment to obtain the targeting polypeptide drug conjugate containing the disulfide bond.
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| CN115869312A (en) * | 2022-12-27 | 2023-03-31 | 哈尔滨吉象隆生物技术有限公司 | PDC (polycrystalline diamond compact) antitumor drug as well as preparation method and application thereof |
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