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GLUTs-targeted glycosylated tetravalent platinum compound, synthesis method and application thereof

A technology of compound and glycosylation, which is applied in the direction of sugar derivatives, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve problems affecting drug research and development, improve bioavailability, increase target tropism, improve the effect of partition coefficient

Active Publication Date: 2021-10-26
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the same mechanism of action, most cisplatin analogs with this structure will have different degrees of cross-resistance with cisplatin, which greatly affects the research and development of this type of drug

Method used

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  • GLUTs-targeted glycosylated tetravalent platinum compound, synthesis method and application thereof
  • GLUTs-targeted glycosylated tetravalent platinum compound, synthesis method and application thereof
  • GLUTs-targeted glycosylated tetravalent platinum compound, synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the synthesis of compound shown in general formula B

[0052] Synthesis of Compound B1

[0053]

[0054] Add 500 mg of cisplatin to 50 mL of acetic acid and stir at room temperature. Then, 5 mL of hydrogen peroxide was added dropwise to the reaction solution, and stirring was continued at room temperature for about 2 hours until the reaction solution became clear. The acetic acid was spin-dried with an oil pump, and diethyl ether was added to the concentrate to precipitate a yellow precipitate. After centrifugation and drying, yellow solid B1 (601.8 mg, 96%) was obtained.

[0055] Synthesis of Compounds B2, B3 and B4

[0056]

[0057] Compounds B2, B3 and B4 were synthesized with reference to compound B1.

Embodiment 2

[0058] Embodiment 2: the synthesis of compound shown in general formula C

[0059] 3-((2R, 3R, 4S, 5R, 6R)-3,4,5-tris((tert-butoxycarbonyl)oxy)-6-((tert-butoxycarbonyl)oxy)methyl)tetrahydro Synthesis of -2H-pyran-2-yl)oxy)propionic acid (compound 6)

[0060]

[0061] Dissolve 10 g of D-glucose in 50 mL of acetic anhydride, add 1 mL of perchloric acid dropwise under ice bath, and continue stirring after removing the ice bath. When the reaction solution turns into a clear state, it is deemed that the reaction is complete, and the acetic anhydride is spin-dried, and the acetic acid is fully extracted with a saturated NaHCO3 solution, and the organic phase is dried with anhydrous MgSO4, and the organic solvent is spin-dried with a rotary evaporator, The concentrate was further concentrated with an oil pump for about 30 minutes to obtain compound 1, which can be directly used in the next reaction.

[0062] Dissolve peracetylglucose 1 (10 g, 25.6 mmol) in 100 mL of dichlorometh...

Embodiment 3

[0075] Embodiment 3: general formula is the synthesis of the compound of A

[0076] Synthesis of Compound A1

[0077]

[0078] Under nitrogen protection, compound 6 (200 mg, 0.31 mmol) was dissolved in 5 mL of anhydrous DMF, and TBTU (147.6 mg, 0.46 mmol), Et3N (46.5 mg, 0.46 mmol) were added. After stirring at room temperature for 30 minutes, compound B1 (174.9 mg, 0.47 mmol) was added in portions. After reacting at room temperature in the dark for 24 hours, it was concentrated to remove DMF, and the concentrate was purified by column chromatography to obtain compound D1 (213.1 mg, 68%) as a pale yellow solid. 1 H NMR (400MHz, CDCl 3 )δ6.00–5.94(m,6H),5.04(t,J=9.2Hz,1H),4.92–4.74(m,2H),4.65(t,J=8.3Hz,1H),4.32(d,J =11.1Hz,1H),4.15(d,J=11.7Hz,1H),4.04(s,1H),3.87(s,1H),3.76(d,J=9.0Hz,1H),2.57(s,2H ),2.11(s,3H),1.42(d,J=10.3Hz,36H). 13 C NMR (101MHz, CDCl 3 )δ 181.40, 180.70, 152.74, 152.56, 152.02, 100.90, 84.26, 83.40, 83.17, 82.99, 75.29, 74.81, 71.65, 70.64, 67.34, 6...

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Abstract

The invention provides a GLUTs-targeted glycosylated tetravalent platinum compound, a synthesis method and application thereof; the structural general formula of the GLUTs-targeted glycosylated tetravalent platinum compound is shown in the specification, wherein R1 is one of glucose, galactose, mannose and rhamnose; and R2 and R3 are independently C1-C4 lower alkanes. According to the invention, a glycosyl group is introduced into a tetravalent platinum parent nucleus; a series of novel glycosylation modified tetravalent platinum compounds are designed and synthesized; the targeting property of a medicine to tumour cells is improved by utilizing sugar transporter GLUTs highly expressed on the surfaces of the tumour cells; the anti-cancer and anti-tumour capacities are further improved; the in-vivo anti-tumour activity result shows that the series of compounds can inhibit tumour growth to a certain extent, and have relatively high safety is shown; and the potential of further research and development is achieved.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a glycosylated tetravalent platinum compound, a synthesis method and an application thereof. Background technique [0002] Chemotherapy can effectively control or eliminate metastases. Therefore, chemotherapy plays an important role in the treatment of advanced malignancies and refractory cancers. Since 1978, platinum-based antineoplastic drugs represented by cisplatin, carboplatin, and oxaliplatin have become the mainstay of treatment for testicular cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, head and neck cancer, and nasopharyngeal cancer. Chemotherapy drug of choice for malignant tumors. [0003] The divalent platinum complex has the general formula of cis-[PtL2X2], where L is a carrier group, such as ammonia or nitrogen, and X is a leaving group, such as halide ion, sulfate and carboxylate. Due to the same mechanism of act...

Claims

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Application Information

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IPC IPC(8): C07H23/00A61K31/7135A61K33/243A61K47/54A61P35/00
CPCC07H23/00A61K33/243A61K47/549A61P35/00Y02P20/55
Inventor 王欣常芸
Owner NANKAI UNIV