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Clofarabine modified oligonucleotide

An oligonucleotide, clofarabine technology, applied in the field of medicinal chemistry, can solve the problems of programmed cell death, damage to mitochondrial membrane integrity, etc.

Pending Publication Date: 2022-05-13
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membranes, leading to the release of pro-apoptotic mitochondrial proteins, cytochrome c and apoptosis-inducing factors, leading to programmed cell death

Method used

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  • Clofarabine modified oligonucleotide
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  • Clofarabine modified oligonucleotide

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Experimental program
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preparation example Construction

[0069] The second aspect of the present invention provides the preparation method of the clofarabine modified oligonucleotide provided by the first aspect of the present invention, comprising: passing the clofarabine phosphoramidite monomer and / or the gemcitabine phosphoramidite monomer through solid The phase synthesis method is connected with the nucleic acid aptamer fragment.

[0070] In the preparation method of the clofarabine-modified oligonucleotide provided by the present invention, the conditions of suitable solid-phase synthesis method should be known to those skilled in the art, for example, the reaction conditions of solid-phase synthesis can be It is the coupling reaction condition of natural bases such as A, T, C, and G. For another example, the reaction temperature of the solid phase synthesis method can be 15~35°C, 15~20°C, 20~25°C, 25~30°C, or 30~35°C; the reaction time can be 1~20 minutes, 1~2 minutes, 2-4 minutes, 4-6 minutes, 6-8 minutes, 8-10 minutes, 10-...

Embodiment 1

[0138] Preparation of clofarabine phosphoramidite monomer:

[0139] 1) Add clofarabine (1 equivalent) to a one-mouth bottle, add 20 mL of N,N-dimethylformamide, imidazole (15 equivalents), and add tert-butyldimethylsilyl chloride (3.2 equivalents) to the solution at room temperature ). The mixture was stirred for 12h. The solvent was removed in vacuo using a rotary evaporator, and separation and purification were carried out by silica gel column chromatography to obtain TBDMS-clofarabine (99%) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ8.05 (d, J = 2.6Hz, 1H), 6.51 (s, 2H), 6.43 (dd, J = 17.5, 3.9Hz, 1H), 4.99 (dt, J = 52.1,2.9Hz,1H),4.61(dt,J=18.0,2.9Hz,1H),3.94(q,J=4.5Hz,1H),3.84(d,J=4.6Hz,2H),0.92(d, J=3.8Hz,18H),0.14(d,J=1.9Hz,6H),0.10(s,6H)ppm.

[0140] The reaction formula of clofarabine reacting with tert-butyldimethylsilyl chloride (TBDMSCl) in N,N-dimethylformamide (DMF) under the effect of imidazole (imidazole) is as follows:

[0141]

[0142] 2) Add T...

Embodiment 2

[0155] Preparation of gemcitabine phosphoramidite monomer:

[0156] 1) Add gemcitabine (710 mg, 2.7 mmol) and 20 mL DMF to a 100 mL single-necked round bottom flask, and add acetic anhydride (280 μL, 2.96 mmol) to the solution at room temperature. N 2 The mixture was stirred overnight under protection. The solvent DMF was removed in vacuo using a rotary evaporator, the residue was mixed with silica gel, and separated and purified by silica gel column chromatography to obtain Ac-gemcitabine (616 mg, 75%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ11.02(s,1H),8.24(d,J=7.6Hz,1H),7.25(d,J=7.6Hz,1H),6.33(d,J=6.6Hz,1H),6.17(t, J=7.4Hz, 1H), 5.31(t, J=5.4Hz, 1H), 4.24-4.14(m, 1H), 4.11(q, J=5.3Hz, 1H), 3.89(dt, J=8.5, 3.0 Hz,1H),3.80(ddd,J=12.7,5.2,2.4Hz,1H),3.65(ddd,J=12.7,5.9,3.6Hz,1H),3.16(d,J=5.3Hz,2H),2.11 (s,3H)ppm.

[0157] Gemcitabine and acetic anhydride (Ac 2 O) in N, the reaction formula of N-dimethylformamide (DMF) reaction is as follows:

[0158]

[0159] 2...

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Abstract

The invention relates to the field of medicinal chemistry, in particular to oligonucleotide modified by clofarabine. The invention provides oligonucleotide modified by clofarabine, which comprises a nucleic acid aptamer fragment, and the nucleic acid aptamer fragment is modified by a clofarabine phosphoramidite monomer group. According to the invention, nucleoside drugs clofarabine and / or gemcitabine are designed and synthesized into a phosphoramidite monomer which can be used for solid-phase synthesis, and fixed-point precise functionalization of clofarabine and / or gemcitabine on oligonucleotide is realized by using a solid-phase synthesis technology; the prepared clofarabine and / or gemcitabine modified oligonucleotide can release clofarabine under the action of nuclease, still has high cytotoxicity to tumor cells, retains the drug activity of clofarabine and / or gemcitabine, and has a good industrialization prospect.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a clofarabine-modified oligonucleotide. Background technique [0002] Clofarabine is a purine nucleoside antimetabolite that differs from other purine nucleoside analogs in the presence of chlorine in the purine ring and fluorine in the ribose moiety of clofarabine. Clofarabine stops the growth of cancer cells by interfering with the synthesis of nucleic acids to stop cells from making DNA and RNA. Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and to the 5'-triphosphate metabolite by mono- and diphosphate kinases. In order to achieve the inhibitory effect on ribonucleotide reductase, terminate the extension of DNA chain and inhibit the repair by competitively inhibiting DNA polymerase, thereby inhibiting the synthesis of DNA. In preclinical models, clofarabine has shown the ability to inhibit DNA repair by incorpo...

Claims

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Application Information

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IPC IPC(8): C12N15/115A61K47/54A61K31/7076A61P35/00A61P35/02
CPCC12N15/115A61K47/549A61K31/7076A61P35/00A61P35/02C12N2310/16
Inventor 谭蔚泓王雪强何嘉轩彭天欢司马颖钰符婷
Owner HUNAN UNIV
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