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Integrated prodrug based on bioorthogonal chemistry as well as preparation method and medical application of integrated prodrug

A pharmacy and methyl technology, applied in the field of pharmacy, can solve the problems of unclear direct action mechanism and affecting DNA replication of tumor cells, so as to improve druggability, avoid toxic and side effects, and avoid separate drug administration

Active Publication Date: 2021-01-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The direct action mechanism of NO on tumor cells is still unclear, and there are mainly three aspects reported so far: (1) NO reacts with intracellular superoxide anion to form peroxynitrite, which is protonated and decomposed into NO 2 And hydroxyl free radicals, hydroxyl free radicals can combine with various molecules of tumor cells, thereby causing tumor cell damage, such as lipid peroxidation, protein, amino acid cross-linking reaction; (2) NO is very easy to combine with Fe-S center-containing Protein Fe forms Fe-NO, which causes the degradation of Fe-S prosthetic group and aconitase on the mitochondrial respiratory chain, thus preventing the synthesis of intracellular energy and inducing apoptosis; (3) NO can directly act on the reduction of ribonucleic acid Enzymes that affect the replication of tumor cell DNA, and can also nitrate DNA to inhibit tumor cell proliferation

Method used

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  • Integrated prodrug based on bioorthogonal chemistry as well as preparation method and medical application of integrated prodrug
  • Integrated prodrug based on bioorthogonal chemistry as well as preparation method and medical application of integrated prodrug
  • Integrated prodrug based on bioorthogonal chemistry as well as preparation method and medical application of integrated prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Compound I 5a , I 5b preparation of

[0054]

[0055] synthetic route:

[0056]

[0057]

[0058] CH 3 ONa: sodium methoxide; CH 3 OH: methanol; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; CHP: cis-diamine trichloroplatinum; FHP: trans-diamine trichlorohydrin; Et 3 N: triethylamine; TBTU: 2-(1H-benzotrisazoL-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate.

[0059] Take 217mg of Compound I 4 Add 86.6 mg of triethylamine, 265 mg of TBTU, and 5 mL of DMF into a single-necked reaction flask, and stir the reaction solution at room temperature for 30 mins. Then, 200 mg of CHP or FHP was added to the reaction bottle, and the reaction solution was kept in the dark for overnight. Post-processing, concentrate first to go out DMF, make sand from the residue, and obtain the target product I by column chromatography 5a and I 5b .

[0060] Compound I 5a : Pale yellow solid, 97 mg, yield 28%. 1 H NMR (ppm, 300MHz, DMSO-d 6 )δ6.28-6.03(m, 6H),...

Embodiment 2

[0062] Embodiment 2: Compound I 5c preparation of

[0063]

[0064] synthetic route:

[0065]

[0066]

[0067] CH 3 ONa: sodium methoxide; CH 3 OH: Methanol; CH 3 I: methyl iodide; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; CHP: cis-diamine trichlorohydrin; Et 3 N: triethylamine; TBTU: 2-(1H-benzotrisazoL-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate.

[0068] Take 200mg of Compound I 4 In a single-necked reaction flask, add 86.6 mg of triethylamine, 265 mg of TBTU, and add 5 mL of DMF to dissolve, and the reaction solution is stirred at room temperature for 30 min. Then, 200 mg CHP was added into the reaction bottle, and the reaction solution was continued to react overnight under dark conditions. Post-processing, first concentrated to go out DMF, residue sand making, column chromatography obtains the target product 134mg of I 5c , yield 37%. 1 H NMR (ppm, 500MHz, DMSO-d 6)δ6.28-6.03(m,6H),4.15(t,J=5.0Hz,2H),3.90(s,3H),3.52(t,J=5.0Hz,2H),2.95(s...

Embodiment 3

[0082] Embodiment 3: research compound I 5a Anti-tumor proliferation inhibitory activity in zebrafish.

[0083] First, a certain amount of CellTracker was transplanted into the yolk of juvenile zebrafish TM CM-Dil fluorescent dye-labeled A2780 cells, and then let the zebrafish grow for 24 hours. Under the confocal microscope, it can be seen that the yolk part of the zebrafish has strong yellow fluorescence, so as to construct a zebrafish experimental model of successful tumor cells. Next, the zebrafish that had been implanted with tumor cells were mixed with I 5a (1 μM), cisplatin (1 μM) and zebrafish culture medium without adding other compounds, after 72 hours, observe the yellow fluorescence distribution in the zebrafish body under a confocal microscope, and count the corresponding fluorescence intensity values ​​to evaluate compound I 5a Anti-tumor proliferation inhibitory effect. Figure 10 for further study of compound I 5a Anti-tumor proliferation inhibitory activi...

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Abstract

The invention discloses an integrated prodrug based on bioorthogonal chemistry, a preparation method of the integrated prodrug, and application of the integrated prodrug as a novel integral bioorthogonal prodrug in antitumor drugs. A compound disclosed in the invention can be selectively activated in tumor cells, tetravalent platinum in the structure of the compound is reduced into cis-platinum, cis-platinum serves as a novel biological orthogonal catalyst to catalyze NO donor fragments to partially release NO, and the NO cooperates with cis-platinum to play an anti-tumor activity role; and however, the compound in normal cells does not have the process, so the safety of the compound is relatively good.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and relates to a preparation method and application of a nitric oxide (NO) donor containing a tetravalent platinum complex, in particular to a new tetravalent platinum complex with tumor selectivity It is a small molecule with NO donor azonium dialkoxide segment, and the two are linked by succinyl. Background technique [0002] At present, the morbidity and mortality of malignant tumors have been showing a significant upward trend, and chemotherapy was once the standard therapy for cancer treatment. However, due to the lack of targeting, traditional small molecule drugs will accidentally kill normal cells while killing tumor cells, causing serious toxic and side effects, so their wide application in clinical practice is limited. As an emerging discipline, bioorthogonal chemistry is widely used in labeling, tracking, manipulating and activating target molecules through bond formation and bond br...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61K31/282A61P35/00
CPCA61P35/00C07F15/0093
Inventor 黄张建张奕华孙涛吴建兵朱杰朱明超
Owner CHINA PHARM UNIV
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