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Camptothecin derivatives and their antitumor applications

A kind of derivative, the technology of camptothecin, which is applied to the new camptothecin derivative and its anti-tumor application field, can solve the problems such as toxic reaction and decreased drug activity, and achieve the effects of low cost, easy availability of raw materials and high yield

Active Publication Date: 2016-12-14
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it was later found that the activity of the drug decreased significantly after the ring-opening by alkali treatment, and it was accompanied by severe toxic reactions, especially hemorrhagic cystitis.

Method used

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  • Camptothecin derivatives and their antitumor applications
  • Camptothecin derivatives and their antitumor applications
  • Camptothecin derivatives and their antitumor applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1. Preparation of side chain 5,6-dihydronorcantharidin monomethyl ester 2

[0031] 1) Preparation of 5,6-didehydronorcantharidin 1:

[0032] Take out a certain amount of maleic anhydride from the reagent bottle, place it in a dry grinding body and grind it finely, then weigh 12.021g of the finely ground maleic anhydride with an electronic balance, put it in a dry three-necked flask, and plug it Stopper, add diethyl ether and stir, when the volume of diethyl ether is 90 mL, the maleic anhydride is completely dissolved. After the maleic anhydride was completely dissolved, 13 mL of furan was slowly added with a dropping funnel for 13 minutes (minutes, also abbreviated as min). The temperature was controlled to start the reaction at 38°C. After reacting for 1 hour (hour, also abbreviated as h), white solids appeared in the solution, and the longer the time, the more white solids there were. After reacting for 24 hours, suction filtration was performed to obta...

Embodiment 2

[0036] Embodiment 2. Preparation of camptothecin derivative 3

[0037] .

[0038]1.2 g (3.48 mmol) camptothecin was dissolved in 20 ml chloroform, and 5,6-dihydronorcantharidin monomethyl ester 2 (1.38 g, 7 mmol), 1-(3-dimethylaminopropyl base)-3-ethylcarbodiimide hydrochloride (abbreviated as EDCI; 3.2 g, 16.8 mmol) and 4-dimethylaminopyridine (abbreviated as DMAP; 240 mg, 2.44 mmol). React at room temperature for 10 hours. Add 30 ml of chloroform, extract and wash with water, saturated sodium carbonate solution, and saturated saline, respectively, and dry the organic layer with anhydrous magnesium sulfate. The solvent is spin-dried and separated by column chromatography to obtain a yellow solid (1.62 g, 89%). 1 HNMR (CDCl 3 ) : δ 8.40(s, 1H), 8.20(d, 1H), 7.94(d, 1H), 7.83(t, 1H), 7.67(t, 1H), 7.19(s, 1H), 6.95(q, 2H ),5.72(d, 1H), 5.42(d, 1H), 5.29(s, 2H), 3.83(s, 3H), 2.95(s, 2H), 2.88(s, 2H),2.17-2.38(m, 2H), 1.01 (t, 3H). 13 CNMR (CDCl 3 ) :δ 167.13, 164.98, 1...

Embodiment 3

[0039] Embodiment 3, activity test of novel camptothecin derivative

[0040] Using sulforhodamine (sulforhodamine B, SRB) staining.

[0041] When inoculating cells, each cell was inoculated in two 96-well plates in parallel, one was the control plate (T0) and the other was the experimental plate. After culturing in a CO2 incubator for 20 h, the control plate (T0) was taken out, fixed with 50% trichloroacetic acid (TCA), and tested. The test compound was added to the test plate (final concentrations were 5, 2.5, 1.25, 0.625, 0.313 μg·mL-1), and a negative control group (C), an experimental group (T), and a solvent control group were set up. Set 5 duplicate wells in each group, take out the culture plate after continuing to culture for 48 h, fix with pre-cooled 50% TCA (final concentration: 10%), place in 4 °C refrigerator for 1 h, rinse with deionized water, and dry naturally. Stain with 100 μL of 0.4% SRB, rinse with 0.1% acetic acid after 10 min, dry in the air, and final...

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Abstract

The invention provides a novel camptothecin derivative expressed by a structural formula 3 as shown in the specification, and a preparation method and the antitumor application of the novel camptothecin derivative. Activity tests prove that the designed and synthesized camptothecin derivative 3 has an excellent anti-hepatoma effect and is expected to be applied clinically as a cantharidin anti-tumor medicine. Besides, the synthesis method of the camptothecin derivative 3 is easily available in raw materials, low in cost, simple in synthesis routine, high in yield and easy to operate and implement.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to a class of novel camptothecin derivatives and their antitumor application. Background technique [0002] Campylodendron is a unique species in my country, mainly distributed in the Yangtze River Basin and various provinces in Southwest China. Guizhou is one of the main producing areas of camptophyllum, which is distributed in almost all counties of the province, including wild and artificial cultivation. [0003] Camptothecin (CPT for short) was first extracted by American chemist Wall et al. from the endemic Chinese Davidiaceae plant Camptothecin. Camptothecin contains a five-membered ring parallel structure, in which the AB ring is a quinoline ring, the C ring is a pyrrole ring, the D ring is a conjugated pyridine ring, and the E ring is a chiral center with an S configuration (C20 ) of α-hydroxyl six-membered lactone. The ABCD ring is a huge conjugate...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00A61P35/00
CPCC07D519/00
Inventor 王先恒高磊赵长阔贾佳李晓飞
Owner ZUNYI MEDICAL UNIVERSITY
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