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Small-molecule prodrug based on pH sensitivity and composed of conjugate of orthoester and dasatinib, and preparation method thereof

A technology of dasatinib and ortho ester, which is applied in the field of small molecule prodrugs and preparations, can solve the problems of adverse biodistribution systemic toxicity, etc., and achieve the effects of avoiding induced toxicity, good tumor treatment, and high drug loading

Active Publication Date: 2020-07-28
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Dasatinib has been used in the treatment of various cancers, but systemic administration may lead to poor biodistribution and severe systemic toxicity

Method used

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  • Small-molecule prodrug based on pH sensitivity and composed of conjugate of orthoester and dasatinib, and preparation method thereof
  • Small-molecule prodrug based on pH sensitivity and composed of conjugate of orthoester and dasatinib, and preparation method thereof
  • Small-molecule prodrug based on pH sensitivity and composed of conjugate of orthoester and dasatinib, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] This embodiment discloses a method for preparing a small molecule prodrug composed of a pH-sensitive orthoester and dasatinib conjugate:

[0066] Dasatinib has a general structural formula as shown in compound I-1, and dasatinib is used as a starting material to prepare DAS-OE as shown in formula I through a multi-step reaction.

[0067] The synthesis process of DAS-OE is as follows:

[0068]

[0069] The preparation method of S1, DAS-COOH includes the following steps:

[0070] Dasatinib DAS (compound shown in formula I-1) (337×10 -3 g, 0.69×10 -3 mol) dissolved in DMF (5×10 -3 L), add TEA (2×10 -5 L), then add the corresponding succinic anhydride (69.10×10 -3 g, 0.69×10 -3 mol); The reaction mixture was stirred for 72h under nitrogen at room temperature, and the solvent was removed by vacuum distillation after the reaction. Use dichloromethane (5×10 -3 L) Wash 3 times with methanol (3×10 -3 L) Wash twice and vacuum dry to obtain a white powder (the compound represented by form...

Embodiment 2

[0076] Such as figure 1 Shown, use 1 The structure of DAS-OE in Example 1 was characterized by H-NMR.

[0077] Such as figure 2 As shown, FT-IR characterizes the infrared structure of DAS-OE, DAS, DAS-COOH, OE and other substances in Example 1.

[0078] 1 The H-NMR detection method is as follows:

[0079] Weigh 7 mg of small molecule prodrugs and add them to the EP tube, dissolve them with deuterated reagents, and add them to the standby NMR, and detect the characteristic peaks of protons under the NMR spectrometer.

[0080] The FT-IR detection method is as follows:

[0081] Grind 1~2mg sample and 200mg pure KBr evenly, place them in a grinding tool, press them into thin slices under the action of a hydraulic machine, and then place them in a Fourier infrared spectrometer for detection.

[0082] use 1 H-NMR characterizes the DAS-OE structure shown in formula I, such as figure 1 Shown. It can be seen that the characteristic peak a is the characteristic peak of orthoester, and the charac...

Embodiment 3

[0085] Determination and Characterization of the Molecular Weight of Dasatinib Small Molecule Prodrug

[0086] The molecular weight of DAS-OE shown in formula I is characterized by liquid chromatography mass spectrometry, such as image 3 Shown. MS analysis showed that the m / z ratio of DAS-OE was 1448.51, which was close to the m / z ratio of theoretical molecular weight (1448.45). It shows that the synthesis of our small molecule prodrug of dasatinib is successful.

[0087] The detection method is as follows:

[0088] Liquid chromatography mass spectrometry (LC-MS, LTQ Orbitrap XL / LTQ Orbitrap XL) is used to detect the molecular weight of the synthesized small molecule prodrugs. The sample can be dissolved in a mixture of dichloromethane and methanol (volume ratio 4:1). The instrument can first ionize small molecule prodrug samples into ions, and then separate ions of different mass-to-charge ratios to detect the molecular weight of the sample to be tested.

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Abstract

The invention discloses a small-molecule prodrug based on based on pH sensitivity and composed of a conjugate of orthoester and dasatinib. The molecular structural formula of the small-molecule prodrug is as shown in the specification. In the formula, R is an alkyl group. The invention also discloses a method for preparing the small-molecule prodrug based on pH sensitivity and composed of the conjugate of orthoester and dasatinib. The small-molecule prodrug provided by the invention has the advantages of accurate chemical structure, high drug loading capacity and controllable drug release.

Description

Technical field [0001] The present invention relates to the technical field of small molecule prodrugs and drug controlled release, in particular to a small molecule prodrug composed of a pH-sensitive orthoester and dasatinib conjugate and a preparation method. Background technique [0002] Cancer is one of the deadliest killers of human beings, and chemotherapy is still the main clinical treatment method. Unfortunately, traditional small molecule chemotherapy drugs have a series of shortcomings, such as poor bioavailability, non-specific biodistribution, insufficient accumulation in tumor cells, serious side effects, and low efficiency. Based on the rapid development of biomaterials and nanotechnology, various nanoscale drug delivery systems (NDDS), including nanoparticles, micelles, and liposomes, have been established for tumor-specific drug delivery. These adjuvant carriers (NDDS) are indeed effective and have shown many benefits in enhancing permeability and blocking effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/506A61K31/704A61K9/51A61K47/54A61P35/00
CPCC07D417/14A61K31/506A61K31/704A61K9/5123A61K47/545A61P35/00A61K2300/00Y02P20/55
Inventor 唐汝培高加路王鑫
Owner ANHUI UNIVERSITY
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