CN118027110A - 3, 5-Bis (4-substituent benzylidene) piperidin-4-one-platinum complex and preparation method and application thereof - Google Patents

3, 5-Bis (4-substituent benzylidene) piperidin-4-one-platinum complex and preparation method and application thereof Download PDF

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CN118027110A
CN118027110A CN202410148481.4A CN202410148481A CN118027110A CN 118027110 A CN118027110 A CN 118027110A CN 202410148481 A CN202410148481 A CN 202410148481A CN 118027110 A CN118027110 A CN 118027110A
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piperidin
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张业
韦健华
黄日镇
陈晓曼
毛志臣
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Guilin Medical University
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Guilin Medical University
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Abstract

The invention discloses four examples of 3, 5-bis (4-substituent benzylidene) piperidin-4-one-platinum complexes, and a preparation method and application thereof. The complex is obtained by carrying out coordination reaction between curcumin analogues and oxaliplatin intermediates in an organic solvent. Tests of the applicant show that the complexes have more remarkable inhibition activity relative to ligands or oxaliplatin, and simultaneously have lower toxic and side effects relative to oxaliplatin, thereby being expected to be used for preparing antitumor drugs.

Description

3, 5-Bis (4-substituent benzylidene) piperidin-4-one-platinum complex and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a3, 5-bis (4-substituent benzylidene) piperidine-4-ketone-platinum complex, and a preparation method and application thereof.
Background
Platinum anti-tumor drugs are the most popular chemotherapeutics in the twentieth century, but the drug resistance and toxic and side effects limit the further application of (D.Wong,S.J.Lippard,Nat.Rev.Drug Discov.4(2005)307-320),(T.W.Hambley,Coord.Chem.Rev.166(1997)181-223). platinum prodrug complex strategies, and are expected to break through the application barriers (X.Wang, Z.J.Guo, chem.Soc.Rev.42 (2013) 202-224). Therefore, the design and screening of novel high-efficiency low-toxicity platinum-based antitumor complexes is highly interesting to pharmaceutical chemists.
Curcumin analogues are symmetrical beta diketone structure compounds, have better characteristics than natural curcumin, and have the anti-tumor, immunoregulation, chemical sensitization and cytoprotection effects, so that the curcumin analogues have wide prospects in the tumor prevention and treatment process. The invention patent with publication number CN110878095A discloses the preparation and application of a bifunctional molecule based on curcumin and its derivative structure, and indicates the role of the bifunctional molecule in neuroprotection. However, there are no reports of 3, 5-bis (4-substituted benzylidene) piperidin-4-one-platinum complexes and their cytotoxicity.
Disclosure of Invention
The invention aims to provide a series of 3, 5-bis (4-substituent benzylidene) piperidine-4-ketone-platinum complexes, and a preparation method and application thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
the 3, 5-bis (4-substituent benzylidene) piperidin-4-one-platinum complex is a complex with a structure shown in the following formula (I) or pharmaceutically acceptable salt thereof:
Wherein R is F, NO 2、CH3 or OCH 3.
In the general structure of the complex, when R represents F, the corresponding target complex is called a complex I1; when R represents NO 2, the corresponding target complex is referred to as complex I2; when R represents CH 3, the corresponding target complex is referred to as complex I3; when R represents OCH 3, the corresponding target complex is referred to as complex I4.
The preparation method of the 3, 5-bis (4-substituent benzylidene) piperidine-4-ketone-platinum complex is characterized by comprising the following steps: the ligand shown in the following formula (L) and the compound shown in the following formula (1) are taken out to carry out coordination reaction in an organic solvent, so that a corresponding crude product of the target complex is prepared;
Wherein R is F, NO 2、CH3 or OCH 3.
In the application, when R in the structure shown in the formula (L) represents F, the corresponding ligand is called ligand L1, and the ligand L1 and the compound shown in the formula (1) carry out coordination reaction to obtain a complex I1; when R in the structure shown in the formula (L) represents NO 2, the corresponding ligand is called ligand L2, and the ligand L2 and the compound shown in the formula (1) carry out coordination reaction to obtain a complex I2; when R in the structure shown in the formula (L) represents CH 3, the corresponding ligand is called ligand L3, and the ligand L3 and the compound shown in the formula (1) carry out coordination reaction to obtain a complex I3; when R in the structure shown in the formula (L) represents OCH 3, the corresponding ligand is called ligand L4, and the ligand L4 and the compound shown in the formula (1) carry out coordination reaction to obtain a complex I4.
In the above-mentioned process for producing the complex, it is preferable to add a condensing agent before the reaction. The yield of the whole reaction can be effectively improved by adding a condensing agent before the reaction. The condensing agent is a conventional choice or a conventional combination in the prior art, specifically may be one or more selected from HATU (2- (7-azabenzotriazol) -N, N '-tetramethyluronium hexafluorophosphate), et 3 N (triethylamine), DIPEA (N, N-diisopropylethylamine), HOBT (1-hydroxybenzotriazole), EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride) and TBTU (O-benzotriazol-N, N' -tetramethyluronium tetrafluoroborate), preferably a combination of HATU, HOBT or TBTU and one selected from Et 3 N, DIPEA and EDCI, further preferably a combination of tbtu+et 3 N. The amount of the condensing agent to be added is usually 1.2 to 2 times, preferably 1.5 to 2 times the molar amount of the compound represented by the formula (L). The condensing agent is preferably dissolved in an organic solvent and then added to the reaction system.
In the preparation method of the complex, the reaction can be carried out under the condition of heating or not, and relatively, the reaction can be carried out under the condition of heating to obtain higher yield. Since the compound represented by the formula (1) is easily decomposed by light, the reaction is preferably carried out under a dark condition. It is further preferable that the reaction is carried out under an inert atmosphere (such as nitrogen, argon or helium atmosphere, etc.) and protected from light, so that by-products can be further reduced. In the present application, the reaction is usually carried out under nitrogen protection and light shielding conditions at 20 to 35 ℃. TLC was used to follow the reaction to monitor completion. According to the experience of the applicant, when the reaction is carried out at 20-35 ℃, the reaction time is preferably controlled to be 24-48 hours. After the reaction is completed, the solvent is removed from the material obtained by the reaction, and the crude product of the target complex is obtained. In order to obtain a target complex with higher purity, methylene dichloride or ethyl acetate can be directly added into a material obtained by the reaction, water is added into the material for extraction after the material is stirred uniformly, an organic phase is collected, the mixture is stood for precipitation, the precipitate is collected, and the precipitate is dried, so that the pure product of the target complex is obtained.
In the preparation method of the complex, the organic solvent is one or more than two selected from N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane (DCM) and chloroform. The amount of the organic solvent to be used is preferably such that the starting materials to be reacted can be dissolved, and usually, all the starting materials to be reacted are usually dissolved in 5 to 10mL of the organic solvent based on 1mmol of the ligand represented by the formula (L).
In the preparation method of the complex, the compound represented by the formula (1) is an oxaliplatin intermediate, and the preparation can be performed by referring to the prior document (Huang X,Huang R,Gou S,Wang Z,Liao Z,Wang H.Combretastatin A-4Analogue:A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV)Moiety with a Unique Mode of Action.Bioconjug Chem.2016Sep 21;27(9):2132-48.). The ligand shown in the formula (L) is prepared by reacting 3, 5-bis (benzylidene) -4-piperidone derivative with glutaric anhydride, and can be specifically prepared by the following method: putting glutaric anhydride and a compound shown in the following formula (MT) into solvents such as methanol, ethanol, tetrahydrofuran, dioxane, methylene dichloride, chloroform or cyclohexane, and carrying out aminolysis reaction under alkaline conditions to obtain the compound;
Wherein R is F, NO 2、CH3 or OCH 3.
The compound represented by the formula (MT) is 3, 5-bis (4-substituted benzylidene) piperidin-4-one, which can be prepared by referring to the prior document (Almansour AI,Kumar R S,Beevi F,et al.Facile,regio-and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities[J].Molecules(Basel,Switzerland),2014,19(7):10033-10055.). When R in the structure shown in the formula (MT) represents F, the corresponding compound is called a compound F-MT, and the compound F-MT reacts with glutaric anhydride to obtain a ligand L1; when R in the structure shown in the formula (MT) represents NO 2, the corresponding compound is called compound NO 2 -MT, and the compound reacts with glutaric anhydride to obtain ligand L2; when R in the structure shown in the formula (MT) represents CH 3, the corresponding compound is called a compound CH 3 -MT, and the compound reacts with glutaric anhydride to obtain a ligand L3; when R in the structure of formula (MT) represents OCH 3, the corresponding compound is referred to as compound CH 3 O-MT, which is reacted with glutaric anhydride to give ligand L4.
The applicant finds that the target complex has good anti-tumor activity through experiments, so the invention also comprises the application of the 3, 5-bis (4-substituent benzylidene) piperidine-4-ketone-platinum complex or pharmaceutically acceptable salt thereof in preparing anti-tumor drugs.
The invention further includes a pharmaceutical composition comprising a therapeutically effective amount of the above 3, 5-bis (4-substituted benzylidene) piperidin-4-one-platinum complex or a pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention provides four cases of 3, 5-bis (4-substituent benzylidene) piperidine-4-ketone-platinum complexes with novel structures and a preparation method thereof. Tests of the applicant show that the complexes have more remarkable inhibition activity relative to ligands or oxaliplatin when aiming at certain tumor cell strains, and simultaneously have lower toxic and side effects relative to the oxaliplatin, so that the complexes are expected to be used for preparing antitumor drugs.
Drawings
FIG. 1 shows the antitumor activity of a high concentration group (4 mg/kg) of complex I1 (shown as 10 a), a low concentration group (2 mg/kg) of complex I1, a blank group (10% DMSO+60% PEG300+30% physiological saline) and an oxaliplatin (2 mg/kg) positive control group in experimental example 2 against SW480 xenograft tumor models of nude mice; wherein, (a) relative increment rate T/C (%) of each group, (B) tumor size photograph of nude mice dissected 21 days after administration, (C) body weight change curve of nude mice 21 days after administration, (D) tumor inhibition rate of each group to experimental mice, <0.05, <0.01, < 0.001.
FIG. 2 shows the antitumor activity of the complex I2 (shown as 10 b) in the high concentration group (4 mg/kg), the complex I2 low concentration group (2 mg/kg), the blank control group (10% DMSO+60% PEG300+30% physiological saline) and the oxaliplatin (2 mg/kg) positive control group in experimental example 2 against SW480 xenograft tumor model of nude mice; wherein, (A) relative increment rate T/C (%) value of each group, (B) tumor size photograph of nude mice sectioned after 21 days of administration, (C) body weight change curve of nude mice after 21 days of administration, (D) tumor inhibition rate of each group to experimental mice, ns p > 0.05, p <0.01.
FIG. 3 shows the antitumor activity of the complex I3 (shown as 10 c) in the high concentration group (4 mg/kg), the complex I3 low concentration group (2 mg/kg), the blank control group (10% DMSO+60% PEG300+30% physiological saline) and the oxaliplatin (2 mg/kg) positive control group in experimental example 2 against SW480 xenograft tumor models of nude mice; wherein, (A) the relative increment rate T/C (%) of each group and (B) the tumor size photograph of the nude mice dissected 21 days after administration. (C) A weight change profile of nude mice administered for 21 days, (D) tumor inhibition rate of each group on experimental mice, P <0.05, P <0.01, P < 0.001, P < 0.0001.
FIG. 4 shows the antitumor activity of the high concentration group (4 mg/kg) of complex I4 (shown as 10d in the figure), the low concentration group (2 mg/kg) of complex I4, the blank control group (10% DMSO+60% PEG300+30% physiological saline) and the positive control group of oxaliplatin (2 mg/kg) on SW480 xenograft tumor model of nude mice in experimental example 2; wherein, (a) relative increment rate T/C (%) of each group, (B) tumor size photograph of nude mice sectioned 21 days after administration, (C) body weight change curve of nude mice 21 days after administration, (D) tumor inhibition rate of each group to experimental mice, <0.05, <0.01, < 0.001, < 0.0001.
FIG. 5 shows the antitumor activity of the complex I1 (shown as 10 a) in the high concentration group (10 mg/kg), the complex I1 low concentration group (5 mg/kg), the complex I2 (shown as 10 b) in the high concentration group (10 mg/kg), the complex I2 low concentration group (5 mg/kg), the blank control group (10% DMSO+60% PEG300+30% physiological saline) and the oxaliplatin (5 mg/kg) positive control group on the CT26 cell transplantation tumor model of BALB/C mice in experimental example 3; wherein, (A) relative increment rate T/C (%) of each group, (B) tumor size photograph of nude mice dissected 13 days after administration. (C) Weight change profile of nude mice administered 13 days, (D) tumor inhibition rate of each group on experimental mice, < P <0.05, < P <0.01, < P < 0.001, < P < 0.0001.
FIG. 6 shows the antitumor activity of the complex I3 (shown as 10C) in the high concentration group (10 mg/kg), the complex I3 low concentration group (5 mg/kg), the complex I4 (shown as 10 d) in the high concentration group (10 mg/kg), the complex I4 low concentration group (5 mg/kg), the blank control group (10% DMSO+60% PEG300+30% physiological saline) and the oxaliplatin (5 mg/kg) positive control group on the CT26 cell transplantation tumor model of BALB/C mice in experimental example 3; wherein, (A) relative increment rate T/C (%) of each group, (B) tumor size photograph of nude mice dissected 13 days after administration. (C) Weight change profile of nude mice administered 13 days, (D) tumor inhibition rate of each group on experimental mice, < P <0.05, < P <0.01, < P < 0.001, < P < 0.0001.
Detailed Description
In order to better explain the technical scheme of the present invention, the present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
In the following examples, the structures of compound F-MT, compound NO 2 -MT, compound CH 3 -MT, and compound CH 3 O-MT are as follows:
example 1: preparation of ligand L1
Compound F-MT (1 g,3.21mmol,1.0 equiv) was taken and placed in 100ml of methylene chloride, triethylamine (0.54 ml,3.86mmol,1.2 equiv) was added under ice bath, then glutaric anhydride dissolved with methylene chloride (the amount of glutaric anhydride was 0.44g,3.86mmol,1.2equiv, at this time pH=9) was slowly added dropwise thereto, the reaction was stirred under ice bath for 2 hours, slowly warmed to room temperature, further reacted at room temperature for 2 hours, the reaction was stopped, the solvent was distilled off from the obtained material, and the residue was recrystallized with a small amount of EA to give a pale yellow powdery solid in 83.4% yield.
Characterization data for the product obtained in this example are as follows:
HRMS(m/z)(ESI):C24H21F2NO4[M-H]-calcd for:424.1360,found:424.1358.
1H NMR(400MHz,DMSO)δ11.97(s,1H),7.67(s,2H),7.63(dd,J＝8.5,5.7Hz,4H),7.34(t,J＝8.7Hz,4H),4.79(d,J＝4.7Hz,4H),2.15(dt,J＝54.1,7.3Hz,4H),1.63–1.49(m,2H).
13C NMR(101MHz,DMSO)δ186.10(s),174.01(s),170.68(s),163.80(s),161.33(s),135.06(s),132.92(d,J＝7.7Hz),132.39(d,J＝4.8Hz),130.93(d,J＝1.9Hz),130.72(s),116.00(s),115.78(s),45.98(s),42.32(s),32.70(s),30.97(s),19.85(s).
Thus, the pale yellow powdery solid obtained in this example was confirmed to be ligand L1 (3, 5-bis (4-fluorobenzylidene) piperidin-4-one-pentanoic acid) having the following structural formula:
example 2: preparation of ligand L2
Example 1 was repeated except that compound NO 2 -MT was used instead of compound F-MT.
Finally, a pale yellow powdery solid was obtained in 86.1% yield.
Characterization data for the product obtained in this example are as follows:
HRMS m/z Calc for C24H20N3O8Na[M+Na]+：502.1226；found：502.1224.
1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.31(d,J＝8.6Hz,4H),7.82(d,J＝8.7Hz,4H),7.75(s,2H),4.84(s,4H),2.13(dt,J＝14.4,6.8Hz,4H),1.60–1.48(m,2H).
13C NMR(101MHz,DMSO-d6)δ186.07(s),174.06(s),170.95(s),147.42(s),140.81(s),140.60(s),135.41(d,J＝10.7Hz),134.16(s),131.57(d,J＝4.3Hz),123.81(s),46.09(s),42.39(s),32.76(s),31.01(s),19.87(s).
Thus, the pale yellow powdered product obtained in this example was identified as ligand L2 (3, 5-bis (4-nitrobenzylidene) piperidin-4-one-pentanoic acid) having the following structural formula:
Example 3: preparation of ligand L3
Example 1 was repeated except that compound CH 3 -MT was used instead of compound F-MT.
Finally, a pale yellow powdery solid was obtained in 82.1% yield.
Characterization data for the product obtained in this example are as follows:
HRMS m/z Calc for C26H27NO4Na[M+Na]+：440.1838；found：440.1841.
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),7.65(s,2H),7.45(d,J＝8.0Hz,4H),7.31(d,J＝7.9Hz,4H),4.80(d,J＝11.1Hz,4H),2.36(s,6H),2.13(dt,J＝52.8,7.3Hz,4H),1.61–1.49(m,2H).
13C NMR(101MHz,DMSO-d6)δ186.07(s),174.06(s),170.61(s),139.63(d,J＝2.5Hz),136.17(d,J＝7.8Hz),131.70(dd,J＝33.0,19.2Hz),131.32–131.13(m),130.63(s),129.52(d,J＝6.5Hz),51.26(s),46.14(s),42.54(s),32.73(s),30.96(s),21.04(s),19.87(s).
thus, the pale yellow powdered product obtained in this example was identified as ligand L3 (3, 5-bis (4-methylbenzylidene) piperidin-4-one-pentanoic acid) having the following structural formula:
Example 4: preparation of ligand L4
Example 1 was repeated except that compound CH 3 O-MT was used instead of compound F-MT.
Finally, a pale yellow powdery solid was obtained in a yield of 84.3%.
Characterization data for the product obtained in this example are as follows:
HRMS m/z Calc for C26H27NO6Na[M+Na]+：472.1732；found：472.1736.
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),7.64(s,2H),7.53(d,J＝8.0Hz,4H),7.06(d,J＝8.7Hz,4H),4.80(d,J＝10.1Hz,4H),3.83(s,6H),2.16(dt,J＝58.6,7.3Hz,4H),1.61–1.53(m,2H).
13C NMR(101MHz,DMSO-d6)δ186.28(s),174.54(s),171.03(s),167.43(s),160.83(s),136.30(d,J＝2.6Hz),133.04(d,J＝3.7Hz),132.18(s),131.98(s),131.00(d,J＝18.6Hz),129.13(s),127.89–127.63(m),127.35(d,J＝23.5Hz),114.89(s),55.82(s),46.63(s),42.96(s),33.21(s),20.37(s),14.01(s).
Thus, the pale yellow powdered product obtained in this example was identified as ligand L4 (3, 5-bis (4-methoxybenzylidene) piperidin-4-one-pentanoic acid) having the following structural formula:
example 5: preparation of Complex I1
Ligand L1 (0.21 g,0.5mmol,1.0 equiv), TBTU (0.24 g,0.75mmol,1.5 equiv) and Et 3 N (0.104 ml,0.75mmol,1.5 equiv) were taken at room temperature and placed in 5ml of N, N-dimethylformamide, then the compound of formula (1) (0.202 g,0.45mmol,0.9 equiv) was added after stirring for 15min under nitrogen protection and light-shielding, and reacted for 24h under nitrogen protection and light-shielding, after completion of the reaction, 150ml of methylene chloride and 50ml of water were added to the resultant material of the reaction to extract multiple times, the organic phase was collected, left standing overnight with precipitation, the precipitate was collected, and dried to give a pale yellow powdery solid with a yield of 46.8%.
Characterization data for the product obtained in this example are as follows:
HRMS(m/z)(ESI):C32H34ClF2N3O8Pt[M-H]-:calcd for:855.1572,found:855.1564.
1H NMR(400MHz,DMSO)δ8.45–8.18(m,3H),7.65(t,J＝8.0Hz,7H),7.35(t,J＝8.6Hz,4H),4.79(s,4H),2.61–2.53(m,1H),2.43(dd,J＝17.8,8.0Hz,1H),2.18(dt,J＝14.8,7.1Hz,4H),2.06(d,J＝10.2Hz,1H),1.99–1.92(m,1H),1.56(dd,J＝14.3,7.1Hz,2H),1.43(d,J＝10.2Hz,2H),1.36–1.14(m,2H),1.06(dd,J＝27.3,14.1Hz,2H).
13C NMR(101MHz,DMSO)δ186.20(s),180.26(s),170.71(s),163.21(s),161.34(s),135.01(d,J＝13.7Hz),133.11(s),133.10–131.86(m),130.82(d,J＝20.0Hz),115.92(dd,J＝21.4,8.9Hz),61.39(d,J＝14.9Hz),35.62(s),30.88(d,J＝7.1Hz),30.54(s),23.49(s),20.65(s).
195Pt NMR(107MHz,DMSO-d6)δ-1090.60(s).
Thus, the pale yellow powdery solid obtained in this example was confirmed to be the target complex I1, which has the following structural formula:
example 6: preparation of Complex I1
Example 5 was repeated, except that: the TBTU is replaced with HOBT.
Finally, a pale yellow powdery solid was obtained in a yield of 42.1%.
The product obtained in this example was characterized by high resolution mass spectrometry, nmr hydrogen spectrometry, nmr carbon spectrometry, etc., and was identified as the target complex I1.
Example 7: preparation of Complex I2
Example 5 was repeated, except that ligand L1 was replaced with ligand L2.
Finally, a pale yellow powdery solid was obtained in 39.2% yield.
Characterization data for the product obtained in this example are as follows:
HRMS(m/z)(ESI):C32H34ClN5O12Pt[M-H]-calcd for:909.1462,found:855.1564.
1H NMR(400MHz,DMSO)δ8.31(d,J＝8.4Hz,7H),7.82(d,J＝6.4Hz,4H),7.74(d,J＝11.9Hz,2H),7.62(t,J＝9.9Hz,1H),4.82(s,4H),2.55(dd,J＝9.6,4.6Hz,1H),2.44(dd,J＝14.8,7.1Hz,1H),2.24–2.09(m,4H),2.05(d,J＝10.4Hz,1H),1.96(d,J＝11.1Hz,1H),1.56–1.51(m,2H),1.43(d,J＝11.3Hz,2H),1.36–1.17(m,2H),1.15–0.95(m,2H).
13C NMR(101MHz,DMSO)δ186.22(s),180.44(s),170.97(s),163.34(s),147.45(s),140.86(s),140.58(s),135.45(s),134.26(s),134.02(s),131.75(s),131.54(s),123.87(s),61.50(d,J＝10.6Hz),35.67(s),30.80(t,J＝15.0Hz),30.31–30.05(m),23.57(s),20.67(s).
195Pt NMR(107MHz,DMSO-d6)δ-1090.51(s).
thus, the pale yellow powdery solid obtained in this example was confirmed to be the target complex I2, which has the following structural formula:
Example 8: preparation of Complex I2
Example 7 was repeated, except that no nitrogen protection was effected during the reaction only in the absence of light.
Finally, a pale yellow powdery solid was obtained in 37.2% yield.
The product obtained in this example was characterized by high resolution mass spectrometry, nmr hydrogen spectrometry, nmr carbon spectrometry, etc., and was identified as target complex I2.
Example 9: preparation of Complex I3
Example 5 was repeated, except that ligand L3 was used instead of ligand L1.
Finally, a pale yellow powdery solid was obtained in 44.1% yield.
Characterization data for the product obtained in this example are as follows:
HRMS(m/z)(ESI):C34H40ClN3O8Pt[M-H]-calcd for:847.2073,found:847.2078.
1H NMR(400MHz,DMSO)δ8.49–8.17(m,3H),7.64(d,J＝9.3Hz,3H),7.45(t,J＝6.3Hz,4H),7.32(d,J＝5.9Hz,4H),4.79(s,4H),2.55(d,J＝8.5Hz,1H),2.45(d,J＝9.1Hz,1H),2.37(s,6H),2.17(dt,J＝14.9,7.1Hz,4H),2.05(d,J＝9.1Hz,1H),1.96(d,J＝11.5Hz,1H),1.58–1.51(m,2H),1.43(d,J＝10.3Hz,2H),1.36–1.16(m,2H),1.06(dd,J＝26.3,14.3Hz,2H).
13C NMR(101MHz,DMSO)δ186.14(s),180.24(s),170.63(s),163.19(s),139.59(d,J＝9.2Hz),136.07(s),132.70–131.53(m),131.50–130.41(m),130.41–130.21(m),129.51(d,J＝13.1Hz),61.46(s),46.17(d,J＝2.4Hz),42.38(s),35.61(s),31.97–31.42(m),31.97–28.93(m),23.50(s),21.21–21.15(m),20.83(d,J＝38.2Hz).
195Pt NMR(107MHz,DMSO-d6)δ-1090.49(s).
Thus, the pale yellow powdery solid obtained in this example was confirmed to be the target complex I3, and its structural formula is shown below:
Example 10: preparation of Complex I3
Example 9 was repeated, except that: HOBT was used instead of TBTU and dimethyl sulfoxide was used instead of N, N-dimethylformamide, and the reaction was carried out at 35 ℃.
Finally, a pale yellow powdery solid was obtained in 43.6% yield.
The product obtained in this example was characterized by high resolution mass spectrometry, nmr hydrogen spectrometry, nmr carbon spectrometry, etc., and was identified as the target complex I3.
Example 11: preparation of Complex I4
Example 5 was repeated, except that ligand L1 was replaced with ligand L4.
Finally, a pale yellow powdery solid was obtained in 42.3% yield.
Characterization data for the product obtained in this example are as follows:
HRMS(m/z)(ESI):C34H40ClN3O10Pt[M-H]-calcd for:879.1972,found:879.1981.
1H NMR(400MHz,DMSO)δ8.49–8.13(m,3H),7.69–7.46(m,7H),7.07(d,J＝7.5Hz,4H),4.79(d,J＝3.5Hz,4H),3.83(s,6H),2.55(d,J＝10.7Hz,1H),2.43(d,J＝11.1Hz,1H),2.20(dt,J＝14.7,7.1Hz,4H),2.06(d,J＝10.5Hz,1H),1.97(d,J＝11.8Hz,1H),1.62–1.54(m,2H),1.43(d,J＝9.4Hz,2H),1.37–1.17(m,2H),1.06(dd,J＝25.3,13.9Hz,2H).
13C NMR(101MHz,DMSO)δ185.89(s),180.26(s),170.60(s),163.19(s),160.35(s),135.76(s),132.58(d,J＝15.9Hz),130.62(s),130.41(s),126.99(s),126.87(d,J＝22.4Hz),114.44(d,J＝9.9Hz),61.39(d,J＝15.1Hz),55.36(s),35.63(s),30.91(d,J＝12.5Hz),30.54(s),23.49(s),20.68(s).
195Pt NMR(107MHz,DMSO-d6)δ-1090.44(s).
thus, the pale yellow powdery solid obtained in this example was confirmed to be the target complex I4, which has the following structural formula:
example 12: preparation of Complex I4
Example 11 was repeated, except that: HATU was used instead of TBTU and tetrahydrofuran was used instead of N, N-dimethylformamide.
Finally, a pale yellow powdery solid was obtained in 40.9% yield.
The product obtained in this example was characterized by high resolution mass spectrometry, nmr hydrogen spectrometry, nmr carbon spectrometry, etc., and was identified as target complex I4.
Experimental example 1: in vitro anti-tumor activity experiment of the target complex of the invention on various human tumor cell strains:
In order to illustrate the antitumor effect of the 3, 5-bis (4-substituent benzylidene) piperidin-4-one-platinum complex, the applicant carried out antitumor activity experiments on all four complexes and took oxaliplatin as a positive control drug.
The compounds were tested for in vitro antitumor activity using the MTT method. Taking cells in logarithmic growth phase, inoculating 180 mu L (about 4500-5000 cells) of cell-containing culture medium in each well into a 96-well culture plate, and culturing for 24h under the condition of fully humidifying 5% CO 2 at 37 ℃. After the cells had adhered, samples were added in an amount of 20. Mu.L per well, 6 duplicate wells were set per sample, and corresponding blank controls were set. After the culture is continued for 48 hours, 10 mu L of MTT reagent (with the concentration of 5 mg/mL) is added into each hole, after the incubation is continued for 4 hours, the supernatant is sucked and removed, 150 mu L of DMSO is added into each hole, and the reaction is carried out for 5-8 minutes by slight shaking, so that the crystal particles are fully dissolved. Zeroing the blank control group, and measuring the absorbance value after removing the background light absorption value by using an enzyme-labeled instrument at 490nm wavelengthValue), calculating the cell proliferation inhibition rate, continuously using 5 concentration gradients to continuously make IC 50 values of corresponding cell strains for the tested compound with good anti-tumor effect, repeating all experiments for 3 times, and taking an average value. The experimental results are detailed in table 1 below.
Table 1: results of in vitro anti-tumor Activity of complexes I1-I4
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As can be seen from the data in Table 1, ligands L1-L4 have a moderate or higher inhibitory effect on T-24, MDA-231, MGC-803, hePG-2, SW-480 tumor cell lines. The complex I1-I4 has moderate or better inhibition effect on T-24, MDA-231, MGC-803, hePG-2 and SW-480 cell lines. The inhibition activity of the positive control oxaliplatin on T-24, MDA-231 and SW-480 cell lines is more than 50 mu M. Overall, the inhibition activity of both ligand L1-L4 and complex I1-I4 on these cells was significantly better than that of the positive control oxaliplatin.
The above results demonstrate that it is feasible to prepare novel 3, 5-bis (4-substituted benzylidene) piperidin-4-one-platinum complexes by introducing 3, 5-bis (4-substituted benzylidene) piperidin-4-one-pentanoic acid ligands onto platinum structures, and that efficient novel antitumor complexes can be screened by the synergistic effect of metals and ligands.
Experimental example 2: in vivo antitumor Activity test of the target Complex of the invention on SW480 (human colon cancer cell)
The applicant planted SW480 cells (2×10 6～4×106) each under the armpit of nude mice by subcutaneous injection, and then grouped them into blank control group, oxaliplatin (2 mg/kg) positive control group, and high concentration group (4 mg/kg) and low concentration group (2 mg/kg) of complexes I1 (10 a), I2 (10 b), I3 (10 c), I4 (10 d) when the tumor size was as long as 80-120 mm 3, respectively, five nude mice per group. The administration mode of intraperitoneal injection is adopted, the administration is carried out every other day, the administration is carried out for 21 days, and the weight and the tumor size of the nude mice are recorded every other day in the administration process. The following day after the end of administration, nude mice were sacrificed by spinal dislocation and tumors, heart, liver, spleen, kidney, and lung were scraped. The tumor weight was weighed and the tumor inhibition rate of the target compound was calculated. The tissue was fixed with 4% tissue fixative, and subsequently used for pathological experiments.
The experimental results are shown in fig. 1 to 4. Experimental results show that the weight of the experimental mice of the complexes I1-I4 is reduced less than that of the mice of the positive control group, and meanwhile, the tumors of the experimental mice of the complexes I1-I4 are smaller, which shows that compared with the oxaliplatin of the positive control group, the complexes I1-I4 have lower toxicity and higher tumor inhibition effect, and also indirectly the curcumin analogue (ligand L) plays the anti-tumor and cytoprotective properties of curcumin, and the anti-tumor effect is improved when the complex is combined with the oxaliplatin, so that the toxic and side effects of the oxaliplatin are effectively reduced.
Experimental example 3: in vivo antitumor activity experiment of target complex of the invention on CT26 (mouse colon cancer cell)
The applicant planted CT26 cells (1X 10 6～2×106) under the armpit of BALB/C mice by subcutaneous injection, and when the tumor size was as large as 60-100 mm 3, the mice were grouped into blank control groups, oxaliplatin (5 mg/kg) positive control groups, and high concentration groups (10 mg/kg) and low concentration groups (5 mg/kg) of complexes I1-I4, respectively, with five BALB/C mice in each group. The mice were dosed by intraperitoneal injection for 13 days at intervals, and their weights and tumor sizes were recorded during the dosing course at intervals. The following day after the end of administration, nude mice were sacrificed by spinal dislocation and tumors, heart, liver, spleen, kidney, and lung were scraped. The tumor weight was weighed and the tumor inhibition rate of the target compound was calculated. The tissue was fixed with 4% tissue fixative, and subsequently used for pathological experiments.
The experimental results are shown in fig. 5 and 6. Experimental results show that the tumor inhibition rate on mice with immune function is far greater than that on immunocompromised nude mice, and the combination of curcumin analogues and oxaliplatin further improves the anti-tumor effect through the immune regulation function, wherein the inhibition rate of the complex I2 (10 b) on CT26 tumor models of BALB/C mice reaches 78.02%, and compared with the positive drug oxaliplatin, the anti-tumor effect is safer; the safety and the anti-tumor effect of the complex I4 (10 d) are similar to those of oxaliplatin; the complex I1 (10 a) and the complex I3 (10 c) have moderate tumor inhibiting effect and high safety.

Claims (10)

1. 3, 5-Bis (4-substituted benzylidene) piperidin-4-one-platinum complexes of the structure shown in formula (I) below, or a pharmaceutically acceptable salt thereof:
Wherein R is F, NO 2、CH3 or OCH 3.
2. A process for the preparation of 3, 5-bis (4-substituted benzylidene) piperidin-4-one-platinum complexes according to claim 1, characterized in that it comprises the steps of: the ligand shown in the following formula (L) and the compound shown in the following formula (1) are taken out to carry out coordination reaction in an organic solvent, so that a corresponding crude product of the target complex is prepared;
Wherein R is F, NO 2、CH3 or OCH 3.
3. The process of claim 2, wherein the condensing agent is added prior to the reaction.
4. The process according to claim 3, wherein the condensing agent is one or a combination of two or more selected from HATU, et 3 N, DIPEA, HOBT, EDCI and TBTU.
5. The process according to any one of claims 2 to 4, wherein the reaction is carried out in the absence of light.
6. The process according to any one of claims 2 to 4, wherein the reaction is carried out under inert atmosphere and protected from light.
7. The process according to any one of claims 2 to 4, wherein the organic solvent is one or a combination of two or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane and chloroform.
8. The process according to any one of claims 2 to 4, wherein the reaction temperature is 20 to 35 ℃.
9. Use of the 3, 5-bis (4-substituted benzylidene) piperidin-4-one-platinum complex or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an antitumor drug.
10. A pharmaceutical composition comprising a therapeutically effective amount of the 3, 5-bis (4-substituted benzylidene) piperidin-4-one-platinum complex according to claim 1 or a pharmaceutically acceptable salt thereof.
CN202410148481.4A 2024-02-02 2024-02-02 3, 5-Bis (4-substituent benzylidene) piperidin-4-one-platinum complex and preparation method and application thereof Pending CN118027110A (en)

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