All-trans retinoic acid-camptothecin anticancer drug conjugate as well as preparation method and application thereof

A technology of all-trans retinoic acid and anti-cancer drugs, which is applied in drug combinations, anti-tumor drugs, and pharmaceutical formulations. effect of nature

Active Publication Date: 2015-04-01
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • All-trans retinoic acid-camptothecin anticancer drug conjugate as well as preparation method and application thereof
  • All-trans retinoic acid-camptothecin anticancer drug conjugate as well as preparation method and application thereof
  • All-trans retinoic acid-camptothecin anticancer drug conjugate as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Example 1 Preparation of ATRA-SN38 conjugate (C10 hydroxyl)

[0055] The preparation method of a kind of ATRA-SN-38 conjugate (C-10 hydroxyl) of this embodiment (synthetic route sees figure 1 ),include:

[0056] SN-38 (500mg, 1.27mmol), DMAP (171.4mg, 1.40mmol), ATRA (383.2mg, 1.27mmol), EDC·HCl (268mg, 1.40mmol) were dissolved in 15mL DMF, and DIEA (180.9mg, 1.40mmol) was added ), reacted overnight, after removing the reaction solvent, the solid was dissolved in dichloromethane, washed 7 times with water, washed 1 time with saturated aqueous sodium bicarbonate solution, 5% citric acid and saturated saline successively, dried over anhydrous sodium sulfate, filtered, After collecting the filtrate, the solvent was removed under reduced pressure; the solid was separated and purified by column chromatography (ethyl acetate: n-hexane = 1:1) to obtain the product ATRA-SN38 conjugate 1 (hereinafter referred to as conjugate 1).

[0057] NMR data of conjugate 1:

[0058] 1 H...

Embodiment 2

[0059] Example 2 The first preparation method of the conjugate 1 nanoparticle

[0060] The conjugate 1 (20 mg) of Example 1 was dissolved in 1 mL of Tween 80 solution, and then slowly injected into water (final concentration 2 mg / mL), and gently shaken and vibrated to form nanoparticles, which were designated as RSN38. The nanoparticle solution can be directly used for clinical oral administration or injection.

Embodiment 3

[0061] Example 3 The second preparation method of conjugate 1 nanoparticles

[0062] The conjugate 1 (20 mg) obtained in Example 1 was dissolved in 1 mL of dimethyl sulfoxide (DMSO), and then rapidly injected into water (final concentration 2 mg / mL). The solution was dialyzed to remove DMSO and form nanoparticles. The nanoparticle solution can be directly used for clinical oral administration or injection.

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Abstract

The invention discloses an all-trans retinoic acid-camptothecin anticancer drug conjugate as well as a preparation method and application thereof. The structural formula of the all-trans retinoic acid-camptothecin anticancer drug conjugate is shown in a formula (I), (II), (III), (IV), (V) or (VI). The all-trans retinoic acid-camptothecin anticancer drug conjugate has good solubility in Tween, polyoxyethylene castor oil, a Poly(ethylene adipate)-polylactic acid copolymer and a Poly(ethylene adipate)-poly (lactic acid-glycollic acid) copolymer, can be self assembled into nanometer grains in water, can be directly injected or taken orally or processed into other dosage forms. According to the all-trans retinoic acid-camptothecin anticancer drug conjugate disclosed by the invention, as all-trans retinoic acid and SN-38 or camptothecin take synergistic effect, compared with a conjugate only containing one of irinotecan, SN-38 and all-trans retinoic acid, the all-trans retinoic acid-camptothecin anticancer drug conjugate has good tumor suppression effect.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to an all-trans retinoic acid-camptothecin anticancer drug conjugate and a preparation method and application thereof. Background technique [0002] All-trans retinoic acid (ATRA), also known as tretinoin, retinoic acid, etc., is a natural derivative of vitamin A, an intermediate metabolite of vitamin A in the body, and is indispensable for maintaining growth and development substance. ATRA can inhibit cell proliferation and has a strong induction [0003] The role of tumor cell differentiation (Tang, X.H.Gudas, L.J.Retinoids, retinoic acid receptors, and cancer.Annu.Rev.Pathol., 2011,6:345), is the current domestic clinical treatment of acute promyelocytic leukemia, myeloid hyperplasia, etc. It is the drug of choice for malignant blood diseases, and it has also attracted much attention in other clinical fields such as skin diseases and some solid tumors. The structural formul...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCY02P20/55C07D491/22
Inventor 王杭祥
Owner ZHEJIANG UNIV
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