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Glycosylated quadrivalent platinum compounds with anticancer activity, and preparation method and application thereof

A technology for anticancer activity, compounds

Inactive Publication Date: 2016-06-01
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there have been a lot of work on the modification of tetravalent platinum, so far there are few reports on the glycosylation of tetravalent platinum compounds

Method used

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  • Glycosylated quadrivalent platinum compounds with anticancer activity, and preparation method and application thereof
  • Glycosylated quadrivalent platinum compounds with anticancer activity, and preparation method and application thereof
  • Glycosylated quadrivalent platinum compounds with anticancer activity, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Example 1: Preparation of glycosyl-modified tetravalent platinum compound represented by general formula 1

[0096] 1. Synthesis of Hydroxycisplatin (IV) 10-1

[0097]

[0098] Add 1.0 g of cisplatin and 30 mL of distilled water into a 250 mL round bottom flask, stir to disperse them, slowly add 50 mL of 30% hydrogen peroxide dropwise into the reaction system, raise the temperature to 60°C and stir for 4 hours. Stop the reaction, place it at -4°C for crystallization for 12 hours, separate by filtration to obtain a yellow solid, add appropriate amount of distilled water, heat to 80°C to dissolve it, place it at 4°C for crystallization for 12 hours, and filter to obtain yellow crystals of compound 10-1 (0.82g ,74%).

[0099] 2. Synthesis of hydroxyoxaliplatin (IV) 10-2

[0100]

[0101] Add 1.0 g of oxaliplatin and 30 mL of distilled water to a 250 mL round bottom flask, stir to disperse them, slowly add 50 mL of 30% hydrogen peroxide dropwise to the reaction system...

Embodiment 2

[0112] Example 2: Preparation of asymmetric naked sugar modified tetravalent platinum represented by general formula 4

[0113] 1. Synthesis of tetravalent platinum compound 12-1

[0114]

[0115] Add compound 10-1 (0.6g, 1.8mmol) and palmitic anhydride (0.94g, 1.9mmol) into a 250mL round bottom flask, add 30mL of anhydrous DMSO under nitrogen protection, stir and react at 30°C for 7 days, reduce DMSO was removed by pressure evaporation, acetone was added, and a large amount of white solid powder was precipitated, which was filtered by suction and washed 3 times with acetone to obtain compound 12-1 (0.99 g, 96%).

[0116] 2. Synthesis of tetravalent platinum compound 12-2

[0117]

[0118] Add compound 10-2 (0.8g, 1.8mmol) and palmitic anhydride (0.94g, 1.9mmol) to a 100mL round bottom flask, add 40mL of anhydrous DMSO under nitrogen protection, stir and react at 30°C for 7 days, reduce DMSO was removed by pressure evaporation, and acetone was added to precipitate a wh...

Embodiment 3

[0129] Example 3: Preparation of bridged peracetylglycosylated tetravalent platinum compounds with general formula 5

[0130]

[0131] Add tetravalent platinum 10 and 1-glycosidic bond-modified acid chloride compound 16 into a 50 mL round bottom flask, replace the air in the system with nitrogen, add anhydrous acetone, stir at room temperature for 12-36 hours, and stop the reaction. Acetone was removed by concentration, and the target product 5 was obtained by column chromatography.

[0132]

[0133] 5-1: yellow solid; 1 HNMR (400MHz, CDCl 3 )δ6.05(br,6H),5.21(s,2H),5.05(d,J=11.9Hz,4H),4.63(s,2H),4.28(d,J=49.9Hz,8H),3.76( s,2H),2.35–1.74(m,24H). 13 CNMR (101MHz, CDCl 3 )δ178.22, 171.32, 170.83, 170.10, 169.51, 100.21, 72.36, 72.15, 71.07, 68.20, 65.84, 61.63, 21.12, 21.02, 20.61. HRMS: Calcd.forC 32 h 48 Cl 2 N 2 o 24 Pt(M+NH 4 ) + :1128.1952,found:1128.1893.

[0134] 5-2: yellow solid; 1 HNMR (400MHz, CDCl 3 )δ6.33–5.83(br,6H),5.41(s,2H),5.32–5.12(m,2H),5....

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Abstract

The invention relates to glycosylated quadrivalent platinum compounds with anticancer activity, and a preparation method and application thereof. The glycosyl group is introduced into the quadrivalent platinum parent nucleus for the first time to design and synthesize a series of novel glycosylation-modified quadrivalent platinum compounds of which the anticancer and antitumor capacities are inspected. A series of original creative researches are hopeful to obtain multiple precursor molecules which are effective for tumors, thereby providing new candidate drug molecules for the existence of the traditional bivalent platinum drugs, and also providing a new pathway for modification of the quadrivalent platinum compounds. The basically creative drug researches have important theoretical value and practical meanings for national economical and social development, health of people and the like.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a novel glycosylation-modified tetravalent platinum compound, a preparation method thereof, and an application thereof in anticancer and antitumor drugs. Background technique [0002] Since cisplatin was found to have anticancer activity in 1967, the application and research of platinum metal anticancer drugs have developed rapidly, and now it has formed the first generation cisplatin, the second generation carboplatin and the third generation oxali Platinum-dominated bivalent platinum-based cancer clinical drugs. At present, divalent platinum-based anticancer drugs have become an indispensable chemotherapeutic drug for clinical cancer treatment. However, divalent platinum compounds have common characteristics such as poor stability, low bioavailability, inability to take orally, strong toxic and side effects (such as nephrotoxicity, ototoxicity, neuroto...

Claims

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Application Information

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IPC IPC(8): C07F15/00C07H13/06C07H15/04C07H7/033C07H1/00A61K31/555A61K31/7042A61P35/00
CPCC07F15/0006C07H1/00C07H7/033C07H13/06C07H15/04
Inventor 王欣王鹏王庆鹏
Owner NANKAI UNIV
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