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Anti-pancreatic cancer application of polycyclic fused macrocyclic lactam compounds

A macrocyclic lactam and compound technology, applied in the field of natural medicinal chemistry, can solve the problems of restricting drug efficacy and non-negligible toxicity, and achieve the effects of high lethality, good market application and promotion prospects, and clear activity

Active Publication Date: 2019-01-11
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At this stage, the standard first-line drug for the treatment of pancreatic cancer is gemcitabine (gemcitabine), which is a difluoronucleoside metabolic antagonist drug that destroys cell replication, but drug resistance in the later stage severely restricts the efficacy of the drug
In addition, the combined drug regimen FOLFIRINOX, including irinotecan, oxaliplatin, 5-fluorouracil and leucovorin, has also been clinically proven to prolong the survival of patients with pancreatic cancer. However, as a camptothecin compound, irinotecan’s toxic effects cannot be ignored [X.Liu, et al., "Irinotecan Delivery by Lipid-Coated Mesoporous Silica Nanoparticles Shows Improved Efficacy and Safety over Liposomes for Pancreatic Cancer," ACS Nano, p .Ahead of Print,2016.]

Method used

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  • Anti-pancreatic cancer application of polycyclic fused macrocyclic lactam compounds
  • Anti-pancreatic cancer application of polycyclic fused macrocyclic lactam compounds
  • Anti-pancreatic cancer application of polycyclic fused macrocyclic lactam compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1, Structural Identification of Polycyclic Fused Macrocyclic Lactam Compounds

[0027] Get S.xiamenensis M6 bacterial strain (being Streptomyces xiamenensis (Streptomyces xiamenensis) CGMCCNo.4.3534 and carry out liquid fermentation culture (30 liters), 7 days, supernatant after centrifugation is extracted 3 times with ethyl acetate. The extracts are combined, concentrated, Get 3 grams of total extract. Get total extract and add 9 grams of reverse phase mixing samples after dissolving with appropriate amount of chloroform-methanol mixed solvent, go up to the normal phase silica gel glass decompression column that is packed with 50 grams, elute with methanol-water gradient Specifically: 50%, 80%, 100% methanol-water gradient elution, each gradient elution volume is 200mL, 150-100ml / bottle reception, the polarity of the elution solvent is adjusted by increasing the amount of methanol in chloroform Incremental, each eluting fraction receives 200 milliliters respe...

Embodiment 2

[0035] Example 2. Polycyclic fused macrocyclic lactam compounds inhibit the proliferation and viability of human pancreatic cancer cells

[0036] The materials are as follows:

[0037] Cells: human pancreatic cancer cells PANC-1, BxCP1; drug: compound 1 obtained from the above examples. Among them, compound 1 was used as the drug-treated experimental group, and compound 2 was used as the drug-treated comparison group.

[0038] Method: PANC-1, BxCP1 cells were seeded in 96-well plate, 0.5×10 per well 3 cells. After 24 hours, the liquid was changed and drugs were added, the control group was DMSO, and the final concentration was 1 / 1000. Cell viability was measured 0, 1, 2, 3, 4, 5, and 6 days after adding the drug. The measurement method is aspirating out the medium, adding 100 μl of complete medium and 10 μl of CCK-8 reagent to each well, and incubating in the incubator for 60 minutes to measure the light absorption value with a microplate reader at a wavelength of 450 nm...

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Abstract

The invention discloses a pancreas cancer prevention use of polycyclic fused macrocyclic lactam compounds. The structural formula of the polycyclic fused macrocyclic lactam compounds is shown in the description; and in the formula, R1 is OCH3 or H, R2 is Cl or OH, and R3 is OCH3 or H. The polycyclic fused macrocyclic lactam compounds are separated through separating and purifying a fermentation liquid of Streptomyces xiamenensis CGMCC No.4.3534 from mangrove soil. Prepared ikarugamycin and derivatives thereof can inhibit proliferation and vitality of human pancreas cancer cells, and can be used to prepare pancreas cancer prevention drugs.

Description

technical field [0001] The invention belongs to the field of natural medicinal chemistry, and in particular relates to the anti-pancreatic cancer application of a class of polycyclic tetramate macrolactam (polycyclic tetramate macrolactam, hereinafter referred to as PTM). Background technique [0002] Pancreatic ductal adenocarcinoma (Pancreatic ductal adenocarcinoma, PDAC, hereinafter referred to as pancreatic cancer) is one of the common malignant tumors of the digestive system, the mortality rate is close to the incidence rate, and the 5-year overall survival rate is less than 6% [T.Seufferleinand J.Mayerle, " Pancreatic cancer in 2015 Precision medicine in pancreatic cancer-fact or fiction?," Nat. Rev. Gastroenterol. Hepatol., vol. 13, pp. 74-75, 2016.]. In recent years, its morbidity and mortality have shown an increasing trend worldwide, becoming one of the malignant tumors with the worst prognosis [J.D.Byrne, et al., "Iontophoretic device delivery for the localized tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/08C07D491/18C12P17/18A61K31/407A61P35/00
CPCC07D487/08C07D491/18C12P17/18C12P17/182
Inventor 徐岷涓张志刚徐俊杨小妹何昆燕余河霖蒋书恒
Owner SHANGHAI JIAO TONG UNIV
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