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Transferrin receptor targeting polypeptide analogue-adriamycin conjugate and a preparing method and application thereof

A technology targeting polypeptides and transferrin, applied in the field of medicinal chemistry, can solve problems such as patient pain, toxic side effects, and clinical application limitations of doxorubicin, and achieve the goal of improving selectivity, reducing toxic side effects, and good tumor cell selectivity Effect

Pending Publication Date: 2019-11-22
CHENGDE MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Doxorubicin is one of the tumor chemotherapy drugs widely used clinically, but due to the lack of selectivity, it will kill normal tissue cells while killing tumor cells, causing serious side effects and causing great pain to patients. The clinical application of doxorubicin is greatly limited due to the disadvantages of causing drug resistance

Method used

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  • Transferrin receptor targeting polypeptide analogue-adriamycin conjugate and a preparing method and application thereof
  • Transferrin receptor targeting polypeptide analogue-adriamycin conjugate and a preparing method and application thereof
  • Transferrin receptor targeting polypeptide analogue-adriamycin conjugate and a preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Synthesis of TfR targeting peptide BP9a

[0058] Reference literature Li Songtao, Zhao Hongling, Yin Zhifeng, et al. Synthesis of transferrin receptor targeting peptide analog BP9a in liver cancer cells [J]. Chemical and Bioengineering. 2018, 35:27-29, 2-CTC resin ( 1.3mmol / g, 5mmol) reacted with Fmoc-Ser(tBu)-OH(15mmol) under the action of DIPEA(15mmol) to obtain Fmoc-Ser(tBu)-2-CTC resin, wherein 2-CTC resin and DIPEA and Fmoc- The molar ratio of Ser(tBu)-OH is 1:3:3; the resulting Fmoc-Pro-CTC resin is removed from the Fmoc protecting group with a volume concentration of 20% piperidine / DMF solution, and the ninhydrin test is positive, indicating that The Fmoc protecting group was successfully removed; using the Fmoc / tBu cross-protection strategy, using DIC(22.5mmol) / HOBt(22.5mmol) as the condensation reagent, according to the standard Merrifield polypeptide solid-phase synthesis method, sequentially condense the remaining Fmoc-amino acid (22.5mmol), wherei...

Embodiment 2

[0059] The reaction of embodiment 2 doxorubicin and SPDP

[0060] Referring to the records of Yoon S, Kim WJ, Yoo HS. Dual-responsive breakdown of nanostructures with high doxorubicin payload for apoptotic cancer therapy. Small. 2013, 9 (2): 284-293, weigh DOX·HCl (17.4mg, 30μmol) and SPDP (11.2mg, 36μmol) was dissolved in DMSO (5mL), then TEA (6.25μL, 45μmol) was added, the reaction was stirred at 50°C, and monitored by thin-layer chromatography (developing solvent: DCM:methanol, 13:1, v:v) Reaction process, after 6 hours of reaction, the target product DOX-S-S-Pyr was separated and purified by silica gel column chromatography (mobile phase: DCM:methanol, 20:1, v:v), and characterized by RP-HPLC and ESI-MS. RP-HPLC analysis purity is 95.7%; ESI-MS: m / z, [M+H] + : 741.5 (theoretical value), 741.3 (experimental value).

Embodiment 3

[0061] Example 3 Synthesis of BP9a-SS-DOX conjugates

[0062] BP9a (14.1 mg, 15 μmol) obtained in Example 1 and DOX-SS-Pyr (13.3 mg, 18 μmol) obtained in Example 2 were dissolved in anhydrous DMF (5 mL), wherein the molar ratio of BP9a to DOX-SS-Pyr 1:1.2;N 2 The reaction was stirred at room temperature under protection, and the reaction process was monitored by RP-HPLC. After the reaction was completed, the reaction solution was settled with glacial ether (50mL), and after centrifugation, the precipitate was washed with glacial ether (20mL×3), and finally the semi-preparative reversed-phase high-performance liquid chromatography was carried out. After purification and lyophilization, the target conjugate BP9a-SS-DOX was obtained. RP-HPLC analysis purity is 97.6%; ESI-MS: m / z, [M+H] + : 1566.7 (theoretical value), 1566.8 (experimental value); [M+2H] 2+ : 783.8 (theoretical value), 784.1 (experimental value).

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Abstract

The invention provides a transferrin receptor targeting polypeptide analogue-adriamycin conjugate BP9a-SS-DOX, wherein BP9a is a transferrin receptor targeting polypeptide analogue, the peptide sequence is NH2- Cys1-Ala2-His3-Leu4-His5-Asn6-Arg7-Ser8-OH, and -SS- represents for a disulfide-containing connecting arm. The invention further provides a preparing method of the transferrin receptor targeting polypeptide analogue-antitumor medicine conjugate and application thereof to preparing medicines for preventing or treating tumors. It is verified that the conjugate has good tumor cell selectivity, can target and kill tumor cells with overexpression of transferrin receptors, and is beneficial for reducing the toxic and side effects of adriamycin on normal cells with low expression of transferrin receptors. The scientific basis is provided for the research and development of novel antitumor medicines targeting the transferrin receptors, and the conjugate has broad development prospects and high application value.

Description

【Technical field】 [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a transferrin receptor targeting polypeptide analog-doxorubicin conjugate, and also relates to its preparation method and application. 【Background technique】 [0002] Doxorubicin is one of the tumor chemotherapy drugs widely used clinically, but due to the lack of selectivity, it will kill normal tissue cells while killing tumor cells, causing serious side effects and causing great pain to patients. The clinical application of doxorubicin is greatly limited due to the disadvantages of causing drug resistance. Therefore, improving the selectivity of doxorubicin to tumor tissue cells, reducing its toxic and side effects on normal tissue cells, and realizing its targeted therapy for tumors have important social significance for the benefit of cancer patients. [0003] Transferrin receptor (TfR) is a type II transmembrane glycoprotein that can mediate the endocytosis ...

Claims

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Application Information

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IPC IPC(8): A61K47/62A61K47/54A61K31/704A61P35/00A61P35/02
CPCA61K47/62A61K47/54A61K31/704A61P35/00A61P35/02Y02P20/55
Inventor 李松涛赵红玲赵桂琴范彦芳
Owner CHENGDE MEDICAL UNIV
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