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GnRH analogs-antineoplastic drug conjugate and preparation method and application thereof

A technology for anti-tumor drugs and conjugates, applied in the field of medicinal chemistry, can solve the problems of low stability of conjugates, toxic and side effects, and achieve good application prospects, reduce toxic and side effects, and enhance the effects of stability.

Active Publication Date: 2019-01-22
CHENGDE MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problem that the existing GnRH analogue-antineoplastic drug conjugates are not stable enough to release cytotoxic molecules prematurely and cause toxic and side effects, the present invention proposes a strategy for structural modification of GnRH, that is, in the GnRH Gly 6 use D -Cys substitution, while C-terminal Pro 9 Ethylamine was amidated to obtain a new GnRH analog, expressed as [ D -Cys 6 -des Gly 10 -Pro 9 -NHEt]-GnRH

Method used

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  • GnRH analogs-antineoplastic drug conjugate and preparation method and application thereof
  • GnRH analogs-antineoplastic drug conjugate and preparation method and application thereof
  • GnRH analogs-antineoplastic drug conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 [ D -Cys 6 -des Gly 10 -Pro 9 -NH 2 Synthesis of ]-GnRH:

[0066] 2-CTC resin (degree of substitution 1.3mmol / g, 5mmol) reacts with Fmoc-Pro-OH (15mmol) under the action of DIPEA to obtain Fmoc-Pro-2-CTC resin, wherein 2-CTC resin and DIPEA and Fmoc-Pro- The molar ratio of OH was 1:3:3; the obtained Fmo c-Pro-2-CTC resin was removed by piperidine / DMF solution with a volume concentration of 20%, and the ninhydrin test was positive, indicating that Fmoc protected The group was successfully removed; using the F moc / tBu cross-protection strategy, using DIC (22.5mmol) / HOBt (22.5mmol) as the condensation reagent, the remaining Fmoc was sequentially condensed from the C-terminal to the N-terminal according to the standard Merrifield peptide solid-phase synthesis method -amino acid (22.5mmol), wherein the molar ratio of Fmoc-Pro-CTC resin, condensation reagent DIC / HOBt and Fmoc-amino acid is 1:4.5 / 4.5:4.5; reaction time 2h, obtain [ D -Cys 6 -des Gly 10 -Pro ...

Embodiment 2

[0068] Reaction of doxorubicin with 3-maleimidopropionate hydroxysuccinimidyl ester (SMP)

[0069] With reference to the records of Shi NQ, Gao W, Xiang B, et al. Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage [J]. Int J Nanomedicine.2012,7:1613–1621, weigh Dox·HCl (227mg, 0.39mmol) and SMP (114.5mg, 0.43mmol) were dissolved in anhydrous DMF (40mL), then TEA (125μL, 0.90mmol) was added, stirred at room temperature for 2h, and the reaction solution was settled with glacial ether (100mL) , after centrifugation, the precipitate was washed with glacial ether (50mL×3), and dried under vacuum at constant temperature to obtain 174.5mg of doxorubicin derivatives (Dox-SMP, yield 64%), which were analyzed by HPLC, ESI-MS and 1 H-N MR( figure 2 ) to be characterized.

[0070] HPLC analysis purity is 96%; ESI-MS: m / z, [M+Na] + : 717.6 (theoretical value), 717.2 (experimental value); 1 H-NMR (300Hz, DMSO-D6): The single peak...

Embodiment 3

[0071] Example 3 Synthesis of GnRHa-Linker-Dox conjugates:

[0072] GnRHa (33.6mg, 28μmol) obtained in Example 1 and Dox-SMP (20mg, 28μmol) obtained in Example 2 were dissolved in anhydrous DMF (10mL), and TEA (80μL, 577μmol) was added, wherein GnRHa and Dox-SMP The molar ratio with TEA is 1:1:21; N 2The reaction was stirred at room temperature under protection, and the reaction progress was monitored by 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 purified by semi-preparative high performance liquid chromatography and freeze-dried. Finally, the target conjugate GnRHa-Linker-Dox was obtained. ESI-MS: m / z, [M+H] + : 1895.0 (theoretical value), 1894.9 (experimental value); [M+2H] 2+ : 948.0 (theoretical value), 947.8 (experimental value).

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Abstract

The invention provides a GnRH analogs-antineoplastic drug conjugate. The structure of the conjugate is GnRHa-Linker-Dox. The GnRHa is a GnRH analogue. The Linker is a connecting arm and is used for coupling the GnRHa with an antineoplastic drug. The Dox is an antineoplastic drug doxorubicin. The invention further provides a preparation method of the GnRH analogs-antineoplastic drug conjugate and application to drugs for the prevention or treatment of tumors of the GnRH analogs-antineoplastic drug conjugate. The conjugate has good tumor cell selectivity, can target tumor cells which over-express GnRH receptors, and the toxic side effects of the doxorubicin are reduced. The The conjugate lays a foundation for research and development of a new type of anti-tumor drug targeting GnRH receptors,and good application prospects are achieved.

Description

【Technical field】 [0001] The invention belongs to the field of medicinal chemistry, in particular to a GnRH analogue-antitumor drug conjugate, and also relates to its preparation method and application. 【Background technique】 [0002] Due to the lack of selectivity, the chemical drugs clinically used to treat tumors will kill normal tissue cells as well as tumor cells, causing serious side effects and causing great pain to patients. In addition, it is easy to cause drug resistance and other shortcomings. The clinical application of drugs is greatly limited. Therefore, finding new anticancer drugs with high efficiency and low toxicity has become one of the most challenging problems in the research of innovative drug therapy for tumors. [0003] Human gonadotropin-releasing hormone (GnRH) is a polypeptide hormone secreted by the hypothalamus, and its amino acid sequence is Pyr 1 -His 2 -Trp 3 -Ser 4 -Tyr 5 -Gly 6 -Leu 7 -Arg 8 -Pro 9 -Gly 10 -NH 2 (pEHWSYGLRPG-NH ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/704A61P35/00
CPCA61K31/704A61K47/64A61P35/00
Inventor 李松涛赵红玲赵桂琴毛晓霞王建平郝婷邓淑华
Owner CHENGDE MEDICAL UNIV
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