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Acid-sensitive camptothecin-20-position ester derivatives and their anti-tumor applications

A technology of ester derivatives and camptothecin, which is applied in the field of camptothecin-20 ester derivatives and their anti-tumor applications, can solve the problems of large toxic and side effects, cannot be used for a long time, etc., and achieves easy hydrolysis, easy availability of raw materials, high yield effect

Active Publication Date: 2018-03-02
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But cantharidin in clinical application, its toxic and side effects are bigger, can not use for a long time

Method used

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  • Acid-sensitive camptothecin-20-position ester derivatives and their anti-tumor applications
  • Acid-sensitive camptothecin-20-position ester derivatives and their anti-tumor applications
  • Acid-sensitive camptothecin-20-position ester derivatives and their anti-tumor applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 , Preparation of 5-ene-norcantharidin 2:

[0033] Take out a certain amount of maleic anhydride 1 from the reagent bottle, place it in a dry grinder and grind it finely, then weigh 12.021g of the finely grinded maleic anhydride with an electronic balance, put it in a dry three-necked flask, stopper Put on the stopper, add diethyl ether and stir, and when the amount of diethyl ether is 90mL, the maleic anhydride is completely dissolved. After the maleic anhydride was completely dissolved, 13 mL of furan was slowly added through the dropping funnel for 13 minutes. The temperature was controlled to start the reaction at 38°C. After reacting for 1 hour, white solids appeared in the solution, and the longer the time, the more white solids there were. After reacting for 24 hours, it was suction-filtered to obtain Compound 2 as a white solid, namely 5,6-didehydronorcantharidin. The dry weight is 17.459g, and the yield is 85.75%. Melting point: 122~123℃, ratio sh...

Embodiment 2

[0035] Example 2 , the preparation of 5-ene-norcantharidin monoacid benzyl ester 3:

[0036] Weigh 5 g of raw material 2 and dissolve it in 40 ml of dichloromethane to form a suspension. Then, 4.7ml of benzyl alcohol and 366mg of DMAP were added dropwise to the suspension. Stirred at room temperature for 3 days, the solvent was removed by rotary evaporation to obtain the crude product of 5,6-didehydronorcantharidin monomethyl ester 2. Dissolve the obtained crude product in 25ml of dichloromethane, wash once with 7ml of 1N hydrochloric acid, leave the organic phase, then wash once with 10ml saturated brine, leave the organic phase, add an appropriate amount of anhydrous MgSO 4 Dry for 15-30 minutes, filter with suction, rinse the filter cake 2-3 times with dichloromethane, leave the filtrate, and the filtrate is rotary evaporated to obtain a white solid of 5-ene-norcantharidin monoacid benzyl ester 3 (4.08g ), the yield is 50%. 1 HNMR (DMSO-d 6 ): δ12.43(s,1H),7.30-7.35(m,...

Embodiment 3

[0037] Example 3. Preparation of camptothecin (2-benzyloxycarbonyl-5-ene) norcantharidinate 4

[0038]

[0039] Add camptothecin (60mg, 0.17mmol) and 10ml methylene chloride in the reaction flask, then add 5-ene-norcantharidin monoacid benzyl ester (3,93.2mg, 0.34mmol, 2equ.), EDCI ( 161.3 mg, 0.84 mmol) and DMAP (13.4 mg, 0.11 mmol). The reaction solution was heated to reflux for 24 hours. Add dichloromethane (30ml) to dilute the reaction solution, and wash with water, saturated sodium carbonate solution and saturated brine successively. Anhydrous MgSO for organic phase 4 dry. After the solvent was spin-dried, the residue was purified by column chromatography to obtain a coupling product (compound 4, 73.5 mg) as a yellow solid, with a yield of 71.6%. R f =0.44 (DCM / MeOH=95 / 5). 1 HNMR (CDCl 3 ): δ8.39(s,1H),8.20(d,J=8Hz,1H),7.94(d,J=8Hz,1H),7.84(d,J=8Hz,1H),7.81(s,1H) ,7.67(t,J=8Hz,1H),7.38(m,5H),7.18(s,1H),6.99(d,J=4Hz,1H),5.71(d,J=8Hz,1H),5.42( d,J=8Hz,1H),5.27(d...

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Abstract

The invention provides a camptothecin-20-position ester derivative having a structural formula shown as the figure 4, a preparation method of the derivative, and an antineoplastic application of the derivative. It is proved through an activity test that the camptothecin-20-position ester derivative designed and synthesized in the invention and shown as the figure 4 is a suitable antineoplastic medical candidate, especially an anti-liver-cancer, anti-stomach-cancer, and anti-colorectal-cancer medical candidate. Compared with camptothecin and cantharidin which are taken as positive-control medicines, the derivative has improved water solubility and stability, is relatively sensitive to acid, and is easy to hydrolyze. Besides, according to a synthetic method of the camptothecin norcantharidin ester derivative, raw materials are easy to get; the synthetic route is high in yield; and the method is very 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 novel acid-sensitive camptothecin-20-position ester derivative and its antitumor application. Background technique [0002] Campylodendron is endemic to my country and is mainly distributed in the Yangtze River Basin and several southwestern provinces such as Guizhou, Sichuan, and Guangxi. Guizhou is one of the main producing areas of camptophylla, which grows in almost all counties of the province, and many counties have successfully carried out artificial cultivation. Camptothecin (CPT for short) was first extracted from camptothecin by American chemist Wall et al. Camptothecin contains a five-membered ring parallel structure, wherein 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00A61K31/4745A61P35/00
CPCC07D519/00
Inventor 赵长阔王先恒杨福红
Owner ZUNYI MEDICAL UNIVERSITY
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