CN117777206A - Enzalutamide-derived tetravalent platinum anticancer prodrug, and preparation method and application thereof - Google Patents

Enzalutamide-derived tetravalent platinum anticancer prodrug, and preparation method and application thereof Download PDF

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CN117777206A
CN117777206A CN202311846885.2A CN202311846885A CN117777206A CN 117777206 A CN117777206 A CN 117777206A CN 202311846885 A CN202311846885 A CN 202311846885A CN 117777206 A CN117777206 A CN 117777206A
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enzalutamide
platinum
preparation
tetravalent platinum
derived
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王燕
王奕
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SHANGHAI ZHAOHUI PHARMACEUTICAL CO Ltd
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SHANGHAI ZHAOHUI PHARMACEUTICAL CO Ltd
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Abstract

The invention discloses an enzalutamide derived tetravalent platinum anticancer prodrug, which has a structure shown in a formula (I):the tetravalent platinum anticancer drug of the invention takes cisplatin as a basic parent nucleus, and an enzalutamide derivative ligand is introduced into one or two ends in the axial direction, so that the preparation raw materials of the tetravalent platinum prodrug are simple and easy to obtain, the method is simple and easy to operate, and the tetravalent platinum anticancer drug is suitable for large-scale production. In vitro experiments show that the synthesized Pt (IV) complex has better cancer cell selectivity and inhibition activity, and has potential to be developed into a novel anticancer drug with high efficiency and low toxicity.

Description

Enzalutamide-derived tetravalent platinum anticancer prodrug, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of cisplatin-related pharmaceutical chemistry, and particularly relates to an enzalutamide-derived tetravalent platinum anticancer prodrug, a preparation method thereof and application thereof in preparation of an anti-prostate cancer drug.
Background
Early stages of prostate cancer are androgen dependent, and their early stage treatment mainly employs androgen deprivation therapy (Androgen deprivation therapy, ADT), including surgical castration and drug castration. Although Castration therapy may significantly reduce androgen levels in a patient's body early in the course of treatment, over time the androgen deprivation therapy is no longer effective and low levels of androgens in the body still result in continued tumor progression to Castration-resistant prostate cancer (CRPC). With the recent intensive research into CRPC pathogenesis, the focus of drug development has shifted from initial chemotherapy to rational design development of targeted drugs.
Continued activation of the androgen receptor (androgen receptor, AR) signaling pathway plays a very critical role in the development of CRPC. AR is often highly expressed in CRPC cells, which can sensitize prostate cancer cells to low intracellular concentrations of androgens. AR is therefore an important target for the current treatment of CRPC. AR antagonists are capable of competitively binding to AR, inhibiting endogenous androgens from activating the AR and inhibiting normal activation of the AR signaling pathway, and thus have become hot spots for anti-prostate cancer research. The main focus of research is currently on non-steroidal AR antagonists. Enzalutamide (MDV-3100) is a second generation AR antagonist that binds to the androgen receptor with greater relative affinity than the first generation anti-androgen bicalutamide, reducing the efficiency of its nuclear translocation and compromising DNA binding to the androgen response element and recruitment of coactivators.
Pt (IV) antitumor conjugates are prodrugs of Pt (II) derivatives. Pt (IV) prodrug design is a promising and effective strategy to address the side effects that occur during cisplatin use. In contrast to the four-coordinated planar structure of the Pt (II) complex, the Pt (IV) prodrug has a six-coordinated octahedral coordination configuration, with coordination saturated Pt (IV) compounds being more kinetically inert than Pt (II). When Pt (IV) reaches the tumor site, the prodrug is reduced by intracellular macromolecules such as ascorbic acid, cysteine, glutathione, etc., generating active Pt (II) species and releasing the axial ligand. Thereby acting. There have been many studies on Pt (IV) prodrugs, and it is widely believed that only when reduced to Pt (II) can the anti-tumor activity be exerted. The increased axial ligands in Pt (IV) prodrugs can alter the original Pt-based prodrug properties such as lipophilicity, redox, targeting, etc. Therefore, the invention aims to introduce the enzalutamide as a functional ligand into the axial position of Pt (IV) to synthesize the enzalutamide-Pt (IV) prodrug, thereby achieving the synergistic sensitization effect.
Disclosure of Invention
In order to overcome the defects of poor targeting property, easy drug resistance and the like of Pt (II), the invention adopts a multi-target molecule 'pharmacophore split' mode design to take cisplatin as a basis, and synthesizes a series of novel tetravalent platinum anticancer prodrugs based on enzalutamide derivatization by taking the corresponding enzalutamide as an axial ligand. The novel Pt (IV) prodrugs of the invention exhibit synergistic effects and overcome drug resistance compared to Pt (II).
The tetravalent platinum anticancer drug synthesized by the invention takes cisplatin as a basic parent nucleus, and an enzalutamide derivative ligand is introduced into one or two ends in the axial direction, so that the preparation raw materials of the tetravalent platinum prodrug are simple and easy to obtain, the method is simple and easy to operate, and the tetravalent platinum prodrug is suitable for large-scale production. In vitro experiments show that the synthesized Pt (IV) complex has better cancer cell selectivity and inhibition activity, and has potential to be developed into a novel anticancer drug with high efficiency and low toxicity.
The invention provides an enzalutamide derived tetravalent platinum anticancer prodrug, which has a structure shown in a formula (I):
wherein,
n＝1～10；
a represents OH, cl;
selected from cisplatin, carboplatin or oxaliplatin, selected from one of the following fragments:
further, the enzalutamide-derived tetravalent platinum anticancer prodrug is selected from any one of the following compounds:
the invention provides a method for preparing the enzalutamide derived tetravalent platinum anticancer prodrug, which comprises the following steps:
(1) Preparation of enzalutamide derivatives
Taking 1 equivalent of enzalutamide as a raw material, firstly carrying out acid hydrolysis on an amide bond of the enzalutamide in 5 equivalents of concentrated hydrochloric acid 1, 4-dioxane to obtain corresponding carboxylic acid, then connecting the carboxylic acid with 1 equivalent of carbon chain compounds with different lengths under an alkaline condition to obtain a corresponding intermediate protected by tert-butoxycarbonyl, and finally carrying out deprotection under an acidic condition to obtain a corresponding enzalutamide derivative;
wherein the carbon chain compounds with different lengths have the structure shown in a formula (II):
the specific synthetic route is as follows:
(2) Preparation of tetravalent platinum derivatives
When A is Cl, 1.0-1.5 equivalent of NCS is added dropwise to 1 equivalent of aqueous solution of platinum (II), and after the mixture is stirred at room temperature overnight, the corresponding monochloro monohydroxy platinum (IV) is obtained through filtration, concentration, washing and drying;
when A is OH, adding 10-15ml of water into 1 equivalent of platinum (II), stirring at 60 ℃, slowly dripping 20ml of 30% hydrogen peroxide into the suspension, reacting for 4 hours, cooling to obtain bright yellow crystals, and filtering, washing and drying to obtain corresponding platinum (IV) oxide;
the synthetic route is as follows:
(3) Synthesis of target product
Dissolving platinum (IV) prepared in the step (2) by ultrasonic wave, adding 1.0-1.5 equivalents of TBTU and TEA, adding 1.0-1.5 equivalents of enzalutamide derivative prepared in the step (1), stirring for 3 days at 30 ℃, evaporating the solvent in dark environment after TLC monitoring, purifying by silica gel chromatography, and using a dichloromethane-methanol system 50:1 to prepare the anti-cancer prodrug of the tetravalent platinum (IV) derived from the enzalutamide;
the synthetic route is as follows:
further, in the step (2), when A is Cl, 1.0 to 1.2 equivalents of NCS are added dropwise to 1 equivalent of the aqueous solution of platinum (II).
Further, in the step (3), after dissolving the platinum (IV) obtained in the step (2) and performing ultrasonic treatment, 1.0-1.2 equivalents of TBTU and TEA are added, and then 1.0-1.2 equivalents of the enzalutamide derivative obtained in the step (1) are added.
The invention also provides a pharmaceutical composition, which comprises a pharmaceutically effective dose of the tetravalent platinum anticancer prodrug derived from the enzalutamide or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention also provides an anticancer quadrivalent platinum prodrug derived from enzalutamide, pharmaceutically acceptable salts thereof and application of the corresponding pharmaceutical composition in preparation of anti-prostate cancer.
Compared with the prior art, the invention has the beneficial effects.
According to the invention, the aliphatic linking derivative derived from the enzalutamide is introduced into the axial direction of a platinum (IV) intermediate to obtain a series of novel platinum (IV) prodrugs taking the enzalutamide derivative as a ligand. The research shows that the platinum (IV) complex has obvious antitumor activity, especially on prostate cancer cells. In addition, the platinum (IV) prodrug taking the enzalutamide derivative as a ligand can better overcome the cisplatin resistance of prostate cancer cells, and has better effect of resisting prostate cancer. The cisplatin (IV) prodrug has the potential application of targeting treatment of the prostate cancer.
Drawings
FIG. 1 is a synthetic route diagram of a target product;
FIG. 2 is a graph showing the inhibition of LNCap, LNCap-ENV, TRAMP-C1-DDP cells by 6a,6b,6C,7a,7b,8a in the examples.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The term "pharmaceutically acceptable" as used herein means having no unacceptable toxicity in a compound such as a salt. Pharmaceutically acceptable salts include inorganic anions such as chloride, sulfate, sulfite, nitrate, nitrite, phosphate, hydrogen phosphate, and the like. The organic anions include acetate, propionate, cinnamate, benzoate, citrate, lactate, gluconate, and the like.
The enzalutamide-derived tetravalent platinum anticancer prodrug of the present invention may be administered to a patient in the form of a pharmaceutically acceptable salt or pharmaceutical composition. A complex is formulated with a suitable carrier or excipient to form a pharmaceutical composition to ensure that a therapeutically effective dose is achieved. By "therapeutically effective amount" is meant that amount of the enzalutamide-derived tetravalent platinum anticancer prodrug necessary to achieve a therapeutic effect.
The enzalutamide derived tetravalent platinum anticancer prodrug and the composition containing the compound can be prepared into various dosage forms, including solid dosage forms, semisolid dosage forms, liquid preparations and aerosols (Remington's Pharmaceutical Sciences, mack Publishing Company (1995), philiadelphia, PA,19th ed). Specific dosage forms of these several types of dosage forms include tablets, pills, dragees, granules, gels, ointments, solutions, suppositories, injections, inhalants and sprays. These dosage forms can be used for both local or systemic administration and for immediate or sustained release administration.
When the enzalutamide derived tetravalent platinum anticancer prodrugs and compositions containing these compounds are administered by injection, the compounds may be formulated into solutions, suspensions and emulsions with water-or lipid-soluble solvents. The fat-soluble solvent specifically includes vegetable oils and the like, synthetic fatty acid glycerides, higher fatty acid esters, and glycol esters (proylenglycol). Such compounds are more soluble in ethanol solutions and in trace amounts of DMSO.
When the enzalutamide-derived tetravalent platinum anticancer prodrugs and compositions containing these compounds are administered orally, they may be formulated into complexes with pharmaceutically acceptable excipients using conventional techniques. These excipients can be used to prepare a variety of dosage forms for patients, such as tablets, pills, suspensions, gels, and the like. The preparation of oral preparation is carried out by mixing compound with solid excipient, grinding mixture, adding adjuvant, and granulating. Adjuvants which can be used for preparing oral dosage forms include: sugars such as lactose, sucrose, mannitol, or sorbitol; celluloses such as corn starch, wheat starch, potato starch, gelatin, west Huang Shujiao, methyl cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, etc.
The enzalutamide derived tetravalent platinum anticancer prodrugs of the present invention and compositions containing these compounds may also be formulated as sprays by a pressurizer and a nebulizer or a dry powder inhalation device. Can be used as a suitable propellant in the ejector, such as dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide, dimethyl ether and the like. The dose of aerosol administration may be regulated by the valve of the injector.
The various dosage forms to which the present invention relates relate to therapeutically effective doses of enzalutamide derived tetravalent platinum anticancer prodrugs and compositions containing these compounds. The effective therapeutic dose of such compounds depends on the patient being treated. The weight of the patient, the condition of the patient, the mode of administration, and the subjective judgment of the prescribing physician are all factors considered in determining the appropriate dosage. The therapeutically effective amount of the enzalutamide derived tetravalent platinum anticancer prodrugs and compositions containing these compounds should be determined by a prescribing physician with the ability and high experience.
Although the effective therapeutic dose of enzalutamide derived tetravalent platinum anticancer prodrugs and compositions containing these compounds will vary depending on the patient's condition, generally suitable dosing ranges from 10mg to 500mg.
Example 1: preparation of enzalutamide derivatives
The preparation route is as follows:
the specific synthesis method comprises the following reaction steps:
[1] preparation of Compound 2
In a 100ml eggplant type bottle, 1 equivalent of 2.15mmol of enzalutamide 1g is dissolved in 20ml of 1,4 dioxane, 5 equivalent of 10.75mmol of concentrated hydrochloric acid 0.9ml is added, and the mixture is heated to 110 ℃ and stirred for 16h; after TLC detection the reaction was completed, the mixture was poured into equal volume of water, extracted with ethyl acetate (3×10 ml), the organic phases were combined, washed with aqueous saturated chlorinated solution and dried over anhydrous sodium sulfate; the solvent was removed under reduced pressure to give a white solid which was purified by silica gel chromatography using dichloromethane-methanol 50:1 to give 650mg of a white solid in 66.9% yield.
The 1H NMR data for compound 2 are as follows:
1 H NMR(500MHz,DMSO-d6)δ1.53(s,6H),7.35(dd,J＝1.9,8.2Hz,1H),7.45(dd,J＝1.9,11.0Hz,1H),8.01-8.10(m,2H),8.27(d,J＝1.8Hz,1H),8.33(d,J＝8.2Hz,1H),13.47(s,1H)。
[2] preparation of Compound 3a
In a 100ml eggplant-type bottle, 5 equivalents of DIPEA and 1.2 equivalents of HATU were added to a DMF solution of 1 equivalent of 1mmol of compound 2 and 1.1 equivalent of amine fatty chains, reacted at room temperature for 30min, after tlc monitoring the reaction was completed, the mixture was poured into an equal volume of water, extracted with ethyl acetate (3×2 ml), the organic phases were combined, washed with a saturated aqueous chlorinated solution, and the organic phase was dried over anhydrous sodium sulfate; the solvent was removed under reduced pressure to give a white solid which was purified by silica gel chromatography using petroleum ether-ethyl acetate 2:1 to give the corresponding compound 3a.
The 1H NMR data for compound 3a are as follows: 1H NMR (500 MHz, chloro-d) δ8.12 (d, J=1.9, 0.9Hz, 1H), 7.95 (t, J=5.1 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.84-7.76 (m, 2H), 7.26 (dd, J=12.1, 2.2Hz, 1H), 6.93 (dd, J=6.8, 2.2Hz, 1H), 3.51 (q, J=5.4 Hz, 2H), 2.65 (t, J=5.6 Hz, 2H), 1.58 (s, 6H) 1.42 (s, 9H).
Preparation of compound 3 b:
compound 3b was prepared according to the method for preparing compound 3a.
Compound 3b 1 The H NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ8.12(dq,J＝1.9,1.0Hz,1H),7.84(d,J＝7.5Hz,1H),7.84-7.76(m,2H),7.26(dd,J＝12.1,2.2Hz,1H),7.13(d,J＝5.1Hz,1H),6.93(dd,J＝6.8,2.2Hz,1H),3.36(td,J＝5.8,5.1Hz,2H),2.38(t,J＝7.5Hz,2H),1.93(tt,J＝7.5,5.7Hz,2H),1.58(s,6H),1.42(s,9H)。
preparation of compound 3 c:
compound 3c was prepared according to the method for preparing compound 3a.
Compound 3c 1 The H NMR data are as follows: 1 H NMR(500MHz,Chloroform-d)δ8.12(dq,J＝1.9,1.0Hz,1H),7.84(d,J＝7.5Hz,1H),7.84-7.76(m,2H),7.26(dd,J＝12.1,2.2Hz,1H),7.20(t,J＝5.0Hz,1H),6.93(dd,J＝6.8,2.2Hz,1H),3.28(q,J＝5.2Hz,2H),2.34(t,J＝7.2Hz,2H),1.70(ttd,J＝7.2,5.3,1.3Hz,2H),1.66-1.58(m,2H),1.58(s,6H)，1.41(s,9H).
[3] preparation of Compound 4a
Compound 3a was dissolved in TFA: DCM volume ratio 1:1 solution, stirred at room temperature for 30min, and the solvent was evaporated under reduced pressure to give the corresponding deprotected product 4a, which was subjected to the next reaction without purification.
Preparation of Compound 4b
Compound 3b was dissolved in TFA: DCM volume ratio 1:1 solution, stirred at room temperature for 30min, and the solvent was evaporated under reduced pressure to give the corresponding deprotected product 4b, which was subjected to the next reaction without purification.
Preparation of Compound 4c
Compound 3c was dissolved in TFA: DCM volume ratio 1:1 solution, stirred at room temperature for 30min, and the solvent was evaporated under reduced pressure to give the corresponding deprotected product 4c, which was subjected to the next reaction without purification.
Example 2: preparation of cisplatin (IV) derivative oxidized cisplatin
The preparation route pattern is as follows:
0.4g of cisplatin (1.33 mmol) is taken in a 100mL round bottom flask wrapped by aluminum foil, 12mL of water is added and stirred at 60 ℃, 20mL of 30% hydrogen peroxide is slowly added dropwise to the suspension for reaction for 4 hours, the mixture is cooled at room temperature overnight, and the mixture is placed in a refrigerator at 4 ℃ for cooling for 2 days to obtain bright yellow crystals. Filtration, washing with a small amount of water, and vacuum drying gave the pure product, which was used without further purification.
Example 3: preparation of cisplatin (IV) derivative mono-chloro monohydroxy cisplatin
The preparation route pattern is as follows:
to an aqueous solution (450 mL) of cisplatin (8.0 mmol,1 eq) was added NCS (1.2 g,8.8mmoL,1.1 eq) dropwise. After the mixture was stirred at room temperature overnight, the black deposit was removed by filtration. The filtrate was concentrated under reduced pressure, and a yellow solid precipitated. The solid was collected, washed with ethanol and diethyl ether, respectively, and then dried in vacuo to give the desired product, which was used without further purification.
Example 4: preparation of carboplatin (IV) derivative carboplatin oxide
The preparation route pattern is as follows:
0.4g of carboplatin (1.07 mmol) is taken in a 100mL round bottom flask wrapped by aluminum foil, 12mL of water is added and stirred at 60 ℃, 20mL of 30% hydrogen peroxide is slowly added dropwise to the suspension for reaction for 4h, the mixture is cooled at room temperature overnight, and the mixture is placed in a refrigerator at 4 ℃ for cooling for 2 days to obtain bright yellow crystals. Filtration, washing with a small amount of water, and vacuum drying gave the pure product, which was used without further purification.
Example 5: preparation of carboplatin (IV) derivative mono-chloro monohydroxy carboplatin
The preparation route pattern is as follows:
to an aqueous solution (450 mL) of cisplatin (8.0 mmol,1 eq) was added NCS (1.2 g,8.8mmoL,1.1 eq) dropwise. After the mixture was stirred at room temperature overnight, the black deposit was removed by filtration. The filtrate was concentrated under reduced pressure, and a yellow solid precipitated. The solid was collected, washed with ethanol and diethyl ether, respectively, and then dried in vacuo to give the desired product, which was used without further purification.
Example 6: preparation of oxaliplatin (IV) derivative oxidized oxaliplatin
The preparation route pattern is as follows:
0.4g oxaliplatin (1.01 mmol) is taken in a 100mL round bottom flask wrapped by aluminum foil, 12mL of water is added and stirred at 60 ℃, 20mL of 30% hydrogen peroxide is slowly added dropwise to the suspension for reaction for 4h, the mixture is cooled at room temperature overnight, and the mixture is placed in a refrigerator at 4 ℃ for cooling for 2 days to obtain bright yellow crystals. Filtration, washing with a small amount of water, and vacuum drying gives the pure product, which is used without further purification
Example 7: preparation of oxaliplatin (IV) derivative monochloromonohydroxy oxaliplatin
The preparation route pattern is as follows:
to an aqueous solution (450 mL) of oxaliplatin (8.0 mmol,1 eq) was added NCS (1.2 g,8.8mmoL,1.1 eq) dropwise. After the mixture was stirred at room temperature overnight, the black deposit was removed by filtration. The filtrate was concentrated under reduced pressure, and a yellow solid precipitated. The solid was collected, washed with ethanol and diethyl ether, respectively, and then dried in vacuo to give the desired product, which was used without further purification.
Example 8: preparation of the target product 6a
The preparation route pattern is as follows:
in a 50ml eggplant-type bottle covered with aluminum foil, cisplatin oxide (50 mg,0.14mmol,1 eq) was added to DMF and sonicated for 10min, followed by TBTU (54.6 mg,0.17mmol,1.2 eq), TEA (17.2 mg,0.17mmol,1.2 eq), compound 4a (88.9 mg,0.17mmol,1.2 eq), stirred at 30℃for 3 days, after completion of TLC monitoring the reaction the solvent was evaporated in the dark, purified by silica gel chromatography eluting with a gradient of dichloromethane-methanol system 50:1 to give 39.5mg of a pale yellow solid in 36.8% yield.
Target product 6a 1 The H NMR data are as follows:
1 H NMR(500MHz,DMSO-d6)：δ1.56(s,6H),2.44-2.00(m,4H),5.90(s,6H),7.38(dd,J＝1.9,8.2Hz,1H),7.42(dd,J＝1.9,11.0Hz,1H),8.10-8.01(m,2H),8.27(d,J＝1.8Hz,1H),8.33(d,J＝8.2Hz,1H),8.94(s,1H).
example 9: preparation of target product 6b
The preparation route pattern is as follows:
in a 50ml eggplant-type bottle covered with aluminum foil, cisplatin oxide (50 mg,0.14mmol,1 eq) was added to DMF and sonicated for 10min, followed by TBTU (54.6 mg,0.17mmol,1.2 eq), TEA (17.2 mg,0.17mmol,1.2 eq), compound 4b (91.2 mg,0.17mmol,1.2 eq), stirred at 30℃for 3 days, after completion of TLC monitoring the reaction the solvent was evaporated in the dark, purified by silica gel chromatography eluting with a gradient of dichloromethane-methanol system 50:1 to give 55.4mg of pale yellow solid in 46.4% yield.
Target product 6b 1 The H NMR data are as follows:
1 H NMR(500MHz,DMSO-d6):δ1.60(s,6H),2.12-2.00(m,3H)，2.33-2.15(m,3H)，5.90(s,6H)，7.38(dd,J＝1.9,8.2Hz,1H)，7.42(dd,J＝1.9,11.0Hz,1H)，8.01-8.10(m,2H)，8.16(d,J＝1.8Hz,1H)，8.29(d,J＝7.6Hz,1H)，8.93(s,1H)。
example 10: preparation of target product 6c
The preparation route pattern is as follows:
in a 50ml eggplant-type bottle covered with aluminum foil, monochloro monohydroxy cisplatin (50 mg,0.14mmol,1 eq) was added to DMF and sonicated for 10min, followed by TBTU (54.6 mg,0.17mmol,1.2 eq), TEA (17.2 mg,0.17mmol,1.2 eq), compound 4a (91.2 mg,0.17mmol,1.2 eq) stirred at 30℃for 3 days, after completion of the TLC monitoring the reaction the solvent was evaporated in the dark, purified by silica gel chromatography eluting with a gradient of dichloromethane-methanol system 50:1 to give 44.2mg of a pale yellow solid in 40% yield.
Target product 6c 1 The H NMR data are as follows:
1 H NMR(500MHz,DMSO-d6)δ1.54(s,6H)，2.91(t,J＝5.3Hz,2H)，3.55-3.49(m,2H)，6.00(s,6H)，6.93(d,J＝6.8,1.9Hz,1H)，7.26(d,J＝12.1Hz,1H)，7.80 -7.74(m,2H)，7.92(d,J＝7.5Hz,1H)，8.16(d,J＝1.9,0.9Hz,1H)，8.44(t,J＝5.1Hz,1H)
example 11: preparation of the target product 7a
The preparation route pattern is as follows:
oxaliplatin oxide (50 mg,0.13mmol,1 eq) was added to DMF in an aluminum foil covered 50ml eggplant bottle, sonicated for 10min, followed by TBTU (48.6 mg,0.15mmol,1.2 eq), TEA (15.2 mg,0.15mmol,1.2 eq), compound 4a (78.3 mg,0.15mmol,1.2 eq), stirred at 30℃for 3 days, after completion of the TLC monitoring the reaction the solvent was evaporated in the dark and purified by silica gel chromatography using dichloromethane-methanol system 50:1 to give 33.2mg of a pale yellow solid in 26.9% yield.
Target product 7a 1 The H NMR data are as follows:
1 H NMR(500MHz,DMSO-d6)：δ1.12(t,J＝16.8Hz,3H)，1.28-1.20(m,1H)，1.49(d,J＝7.6Hz,2H)，1.53(s,6H)，2.05(d,J＝11.1,2H)，2.51-2.50(m,2H)，3.26-3.188(m,4H)，7.38(dd,J＝1.9,8.2Hz,1H)，7.42(dd,J＝1.9,11.0Hz,1H)，8.01-8.10(m,2H)，8.27(d,J＝1.8Hz,1H)，8.33(d,J＝8.2Hz,1H)，8.94(s,1H)。
example 12: preparation of target Compound 7b
The preparation route pattern is as follows:
oxaliplatin oxide (50 mg,0.13mmol,1 eq) was added to DMF in an aluminum foil covered 50ml eggplant bottle, sonicated for 10min, followed by TBTU (48.6 mg,0.15mmol,1.2 eq), TEA (15.2 mg,0.15mmol,1.2 eq), compound 4b (83.69 mg,0.15mmol,1.2 eq), stirred at 30℃for 3 days, after completion of the TLC monitoring the reaction the solvent was evaporated in the dark and purified by silica gel chromatography using dichloromethane-methanol system 50:1 to give 23.75mg of a pale yellow solid in 19.2% yield.
Target product 7b 1 The H NMR data are as follows:
1 H NMR(500MHz,DMSO-d6)δ1.47-1.39(m,1H)，1.52-1.43(m,3H)，1.54(s,6H)，1.58(t,J＝13.9Hz,2H)，1.69(d,J＝14.0Hz,2H)，1.87(t,J＝7.9Hz,2H)，2.61(d,J＝15.8Hz,1H)，2.79(d,J＝10.6Hz,2H)，3.34(d,J＝5.8Hz,2H)，6.44(d,J＝10.4Hz,2H)，6.53(s,1H),6.93(d,J＝6.8,Hz,1H)，7.26(d,J＝12.1,Hz,1H)，7.80-7.74(m,4H)，7.92(d,J＝7.5Hz,1H)，8.09(t,J＝5.1Hz,1H)，8.16(s,J＝1.8Hz,1H)。
example 13: preparation of target Compound 8a
The preparation route pattern is as follows:
carboplatin oxide (50 mg,0.12mmol,1 eq) was added to DMF in an aluminum foil covered 50ml eggplant bottle, sonicated for 10min, followed by TBTU (45.4 mg,0.14mmol,1.2 eq), TEA (14.2 mg,0.14mmol,1.2 eq), compound 4a (78.1 mg,0.14mmol,1.2 eq), stirred at 30℃for 3 days, after completion of TLC monitoring the reaction the solvent was evaporated in the dark, purified by silica gel chromatography eluting with a gradient of dichloromethane-methanol system 50:1 to give a pale yellow solid 40.9mg, yield 32.1%.
Target product 8a 1 The H NMR data are as follows:
1 H NMR(500MHz,DMSO-d6)δ1.54(s,6H)，1.75(p,J＝7.5Hz,2H)，2.20(t,J＝7.5Hz,4H)，2.78(t,J＝5.3Hz,2H)，3.55-3.49(m,2H)，6.89(s,6H)，7.26(d,J＝12.1Hz,1H)，7.80-7.74(m,2H)，7.92(d,J＝7.5Hz,1H)，8.07(s,1H)，8.16(d,J＝1.9Hz,1H)，8.44(s,J＝5.1Hz,1H)。
example 14: in vitro antitumor Activity assay
In vitro antitumor Activity assay of platinum (IV) prepared in the above examples
Experimental cells: LNCap, LNCap-ENV, TRAMP-C1-DPP, MCF-7: all derived from giving away
After culturing cells in 96-well plates for 24 hours, starting a dosing experiment, adding prepared dosing solutions into corresponding 96-well plates, setting 6 compound wells for each concentration group, wherein the volume of liquid medicine added into each well is 100 mu L, adding 100 mu L of drug-free serum-free blank culture medium into each well of a blank group and a negative control group, and arranging three 96-well plates in parallel for each dosing group, wherein the three 96-well plates are respectively used for investigating cytotoxicity conditions when drugs act on cells for 72 hours. After administration, 96 wells were placed in an incubator and incubated for 72 hours, 20. Mu.L of CCK 8 reagent was added to each well of the 96 well plates, and after incubation in the incubator at 37℃for 2 hours, the 96 well plates were removed and absorbance of each well was measured at a wavelength of 450 nm. The cell viability calculation formula is: cell availability (%) = (absorbance of dosing group absorbance blank) ×100%/(absorbance of negative control group absorbance blank), cell relative survival is on the ordinate with the drug concentration log value on the abscissa, and IC50 value for each dosing group was calculated using GraphPad Prism.
To explore the biological activity of platinum (IV) prodrugs at the cellular level, several different cell lines were selected for investigation. Wherein the LNCap enzalutamide resistant cell line, TRAMP-C1 cisplatin resistant cell line was used to investigate whether tetravalent platinum prodrugs overcome single resistance. Potential selectivity studies of MCF-7 as a platinum (IV) prodrug. IC50 data for each dosing group is shown in Table 1.
Table 1 IC50 values for each of the administration groups acted for 72h respectively
As shown in Table 1, the antiproliferative activity of the compounds on LNCap, LNCap-ENV, TRAMP-C1-DPP and MCF-7 is detected, and the IC50 values of the compounds 6a,6b,6C,7a,7b and 8a are obviously lower than those of cisplatin, oxaliplatin, carboplatin and enzalutamide, so that the compounds have better antiproliferative capacity on cancer cells. Meanwhile, the composition also shows excellent inhibitory activity on cisplatin and enzalutamide resistant prostate cancer cell lines.
The compounds of the present invention, methods for their preparation and use are described herein in connection with certain specific embodiments and examples, and are set forth and described in great detail. It should be understood, however, that the detailed description and examples presented herein are intended by way of illustration only and are not intended to limit the scope of the invention. Indeed, it will be apparent to those skilled in the art that the present invention may be practiced in other embodiments that depart from the spirit and scope of the invention as set forth herein.

Claims (7)

1. An enzalutamide-derived tetravalent platinum anticancer prodrug having a structure represented by formula (i):
wherein,
n＝1～10；
a represents OH, cl;
selected from cisplatin, carboplatin or oxaliplatin, selected from one of the following fragments:
2. the enzalutamide-derived tetravalent platinum anticancer prodrug of claim 1, wherein: the enzalutamide derived tetravalent platinum anticancer prodrug is selected from any one of the following compounds:
3. a method of preparing the enzalutamide derived tetravalent platinum anticancer prodrug of claim 1 or 2, comprising the steps of:
(1) Preparation of enzalutamide derivatives
Taking 1 equivalent of enzalutamide as a raw material, firstly carrying out acid hydrolysis on an amide bond of the enzalutamide in 5 equivalents of concentrated hydrochloric acid 1, 4-dioxane to obtain corresponding carboxylic acid, then connecting the carboxylic acid with 1 equivalent of carbon chain compounds with different lengths under an alkaline condition to obtain a corresponding intermediate protected by tert-butoxycarbonyl, and finally carrying out deprotection under an acidic condition to obtain a corresponding enzalutamide derivative;
wherein the carbon chain compounds with different lengths have the structure shown in a formula (II):
(2) Preparation of tetravalent platinum derivatives
When A is Cl, 1.0-1.5 equivalent of NCS is added dropwise to 1 equivalent of aqueous solution of platinum (II), and after the mixture is stirred at room temperature overnight, the corresponding monochloro monohydroxy platinum (IV) is obtained through filtration, concentration, washing and drying;
when A is OH, adding 10-15ml of water into 1 equivalent of platinum (II), stirring at 60 ℃, slowly dripping 20ml of 30% hydrogen peroxide into the suspension, reacting for 4 hours, cooling to obtain bright yellow crystals, and filtering, washing and drying to obtain corresponding platinum (IV) oxide;
(3) Synthesis of target product
Dissolving platinum (IV) prepared in the step (2) by ultrasonic treatment, adding 1.0-1.5 equivalents of TBTU and TEA, adding 1.0-1.5 equivalents of enzalutamide derivative prepared in the step (1), stirring for 3 days at 30 ℃, and using a methylene dichloride-methanol system 50:1 to prepare the anti-cancer prodrug of the tetravalent platinum (IV) derived from the enzalutamide.
4. A method according to claim 3, characterized in that: in the step (2), when A is Cl, 1.0 to 1.2 equivalents of NCS are added dropwise to 1 equivalent of an aqueous solution of platinum (II).
5. A method according to claim 3, characterized in that: in the step (3), after dissolving the platinum (IV) prepared in the step (2) and ultrasonic treating, adding 1.0-1.2 equivalents of TBTU and TEA, and then adding 1.0-1.2 equivalents of the enzalutamide derivative prepared in the step (1).
6. A pharmaceutical composition comprising a pharmaceutically effective dose of the enzalutamide derived tetravalent platinum anticancer prodrug of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. The use of enzalutamide derived tetravalent platinum anticancer prodrug and pharmaceutically acceptable salts thereof according to claim 1 or 2, and corresponding pharmaceutical compositions for the preparation of an anti-prostate cancer.
CN202311846885.2A 2023-12-29 2023-12-29 Enzalutamide-derived tetravalent platinum anticancer prodrug, and preparation method and application thereof Pending CN117777206A (en)

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