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Rubiaceae-type cyclopeptide taken as Hedgehog signal channel inhibitor as well as preparation method and application of rubiaceae-type cyclopeptide

A signaling pathway, Rubiaceae technology, applied in the field of medicine, can solve the problems of expensive aminopropyl bonded silica materials, poor controllability and reproducibility of methanol recrystallization technology, and not commonly used

Inactive Publication Date: 2014-06-25
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage is that activated carbon has strong adsorption to samples, aminopropyl bonded silica gel material is more expensive, and is not commonly used in laboratories and industries, and the controllability and reproducibility of methanol recrystallization technology are not good.

Method used

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  • Rubiaceae-type cyclopeptide taken as Hedgehog signal channel inhibitor as well as preparation method and application of rubiaceae-type cyclopeptide
  • Rubiaceae-type cyclopeptide taken as Hedgehog signal channel inhibitor as well as preparation method and application of rubiaceae-type cyclopeptide
  • Rubiaceae-type cyclopeptide taken as Hedgehog signal channel inhibitor as well as preparation method and application of rubiaceae-type cyclopeptide

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Experimental program
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Effect test

Embodiment 1

[0031] Rubiaceae type cyclic peptides RA-V(1), RA-VII(2), RA-I(3), RA-XI(4), RA-XII(5), RA-XXII(6), RA-XXIII (7), RY-II (8) and Rubiyunnanin C (9) preparation methods:

[0032] The rhizome (10kg) of Golden Sword Grass was taken, dried and pulverized, and then refluxed with methanol for 3 times (30L×3 times) for 3h, 3h and 2h. The extract was concentrated under reduced pressure to obtain 1.3 kg of total extract. The total extract was subjected to silica gel column chromatography, eluted with chloroform / methanol gradient (100:0, 10:1, 8:2, 7:3, 0:100), combined with cyclic peptide TLC detection method to combine 10: 1 and 8:2 contain the portion of the cyclic peptide. Each of the following steps must be combined with the cyclic peptide TLC detection method for separation and purification. The combined cyclic peptide fractions (527 g) were again subjected to silica gel column chromatography, eluted with a gradient of chloroform / methanol (70:1-8:2), and the combined cyclic pept...

Embodiment 2

[0036]Rubiaceae type cyclic peptides RA-V(1), RA-VII(2), RA-I(3), RA-XI(4), RA-XII(5), RA-XXII(6), RA-XXIII (7), RY-II (8) and Rubiyunnanin C (9) were activated by SAG (Smo agonist) in Shh Light II cells, and the inhibitory activity of all cyclic peptides on the Hedgehog signaling pathway was systematically detected. The experimental principles, methods and results are as follows:

[0037] Experimental principle: Dual-luciferase reporter gene is a commonly used system for detecting the activity of signaling pathways. Luciferin emits fluorescence under the catalysis of luciferase, and the intensity of luminescence is detected by a fluorescent luminescence microplate reader to reflect the activity of the signaling pathway. Shh Light II cells are stably transfected with two luciferase reporter genes in NIH3T3 fibroblasts, one is the Gli-dependent firefly luciferase (8xGliBS-Firefly Luciferase) that specifically reflects the strength of the Hedgehog pathway signal, and the other i...

Embodiment 3

[0044] Rubiaceae type cyclic peptides RA-V(1), RA-VII(2), RA-I(3), RA-XI(4), RA-XII(5), RA-XXII(6), RA-XXIII (7), RY-II (8) and Rubiyunnanin C (9) were activated by SAG in NIH3T3 cells, and the inhibitory activity of all cyclic peptides on the Hedgehog signaling pathway was detected by fluorescent quantitative PCR. The experimental principles, methods and results are as follows:

[0045] Experimental principle: Fluorescent quantitative PCR is one of the most accurate methods for detecting gene mRNA content. The target genes Gli1 and Ptch1 of the Hedgehog signaling pathway are also important components of the pathway, and the detection of the mRNA levels of Gli1 and Ptch1 of the Hedgehog pathway target genes by fluorescent quantitative PCR is one of the important indicators reflecting the activation degree of the pathway.

[0046] Experimental methods: (1) Cell culture: NIH3T3 cells were cultured in DMEM containing 10% newborn bovine serum. NIH3T3 cells should not grow too den...

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Abstract

The invention provides a rubiaceae-type cyclopeptide taken as a novel Hedgehog signal channel inhibitor as well as a preparation method and an application of the rubiaceae-type cyclopeptide in preparation of a medicine for treating and preventing relevant cancers activated by the abnormity of Hedgehog signal channels. The rubiaceae-type cyclopeptide is prepared by the condensation of one D-alpha-alanine, one L-alpha-alanine, three substituted N-methyl-L-alpha-tyrosines and one L-alpha-amino acid of another type via peptide bonds, wherein six amino acids are condensed into an eighteen-membered rings; and benzene rings between two adjacent tyrosines are connected via an oxygen bridge so as to form a fourteen-membered ring.

Description

Technical field: [0001] The invention belongs to the technical field of medicines, and specifically relates to a series of Rubiaceae-type cyclic peptides used as Hedgehog signal pathway inhibitors, a pharmaceutical composition using the same as an active ingredient, its preparation method and its application in cancer treatment and prevention. Background technique: [0002] The Hedgehog signaling pathway is one of the classic and important signal transduction pathways in cells. The activation of this pathway can regulate the transcription and expression of various downstream genes, and thus affect the proliferation, differentiation, apoptosis and migration of cells. Therefore, this signaling pathway plays an important role in the early embryonic development of animals and the homeostasis of adult tissues and organs, and its abnormal function is closely related to many human diseases, such as birth defects and cancer. [0003] The Hedgehog signaling pathway was first found to...

Claims

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Application Information

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IPC IPC(8): A61K38/12A61P35/00C07K7/64C07K1/20C07K1/16
Inventor 谭宁华毛炳宇赵思蒙江世友
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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