阅读说明：本技术 一种基于喜树碱对gsh响应的荧光标记前药的设计与合成 (Design and synthesis of fluorescence labeled prodrug based on response of camptothecin to GSH ) 是由 叶亚熙 张卿 陈新月 俞雅文 于 2019-10-25 设计创作，主要内容包括：本发明公开了一种基于喜树碱对GSH响应的荧光标记前药的设计与合成,其结构如式所示,(The invention discloses a design and synthesis of a fluorescence labeling prodrug based on response of camptothecin to GSH, the structure of which is shown as the formula,)

1. Structure of fluorescence labeling prodrug based on response of camptothecin to GSH

2. A synthetic method of fluorescence labeling prodrug based on response of camptothecin to GSH is shown in formula,

the preparation method comprises the following steps of,

compound A (90.1mg, 0.35mmol), B (83.41mg, 0.35mmol), EDCCl (143mg, 0.75mmol), DMAP (5.5mg, 0.045mmol) were dissolved in this order in dry dichloromethane (10mL) with stirring, the reaction was stirred at room temperature for 4h, then Compound C (134mg, 0.35mmol), EDCCl (76.5mg, 0.4mmol), DMAP (5.5mg, 0.045mmol) were added and stirred overnight. The reaction was stopped and the filtrate was collected by filtration. The organic layers were dried over anhydrous sodium sulfate overnight and chromatographed on silica gel (eluent V dichloromethane: V methanol-50: 1) to give the final compound of formula D.

Technical Field

The invention belongs to the field of diagnosis and treatment

Background

Chemotherapeutic drugs remain the first line of cancer treatment, but treatment regimens cannot exclude individual differences; the side effect of the chemotherapy drugs is obvious; the efficacy assessment is delayed.

The microenvironment of a tumor is a component of its physiology, structure and function. The relationship between tumor and interstitial cell is essentially the growth and development of tumor or cell, and the non-malignant cells and secreted proteins of tumor and interstitial cell are involved in the generation and development of tumor. Research shows that the tumor microenvironment has low pH, hypoxia and metabolic disorder of various enzymes. The clinical relevance of the tumor microenvironment to tumor treatment should therefore be emphasized. Increased awareness of this interaction may provide valuable references for cancer management, risk assessment, and diagnostic treatment.

The small molecular fluorescent probe has the advantages of high sensitivity, good selectivity and the like, and can be used for detecting related substances. If the small molecular fluorescent probe is used for marking the antitumor drugs, the adverse reaction of the related drugs can be reduced, and the in-vivo positioning condition and the treatment effect of the drugs can be traced and reported.

Disclosure of Invention

The invention provides a synthetic method of a fluorescence labeling prodrug based on response of camptothecin to GSH, which aims to solve the existing problems and provides application of the compound in antitumor drugs.

A synthetic process of a fluorescence labeled prodrug based on response of camptothecin to GSH comprises the following steps:

Reagents and conditions：2-(benzo[d]thiazol-2-yl)-6-methoxyphenol，4，4′-disulfanediyldibutyric acid，DMAP/EDC，DCM，r.t.，4h；camptothecin，DMAP/EDC

the preparation method comprises the following steps:

the preparation method comprises the following steps of,

compound A (90.1mg, 0.35mmol), B (83.41mg, 0.35mmol), EDCCl (143mg, 0.75mmol), DMAP (5.5mg, 0.045mmol) were dissolved in this order in dry dichloromethane (10mL) with stirring, the reaction was stirred at room temperature for 4h, then Compound C (134mg, 0.35mmol), EDCCl (76.5mg, 0.4mmol), DMAP (5.5mg, 0.045mmol) were added and stirred overnight. The reaction was stopped and the filtrate was collected by filtration. The organic layers were dried over anhydrous sodium sulfate overnight and chromatographed on silica gel (eluent V dichloromethane: V methanol-50: 1) to give the final compound of formula D.

Detailed Description

The preparation method comprises the following steps of,

compound A (90.1mg, 0.35mmol), B (83.41mg, 0.35mmol), EDCCl (143mg, 0.75mmol), DMAP (5.5mg, 0.045mmol) were dissolved in this order in dry dichloromethane (10mL) with stirring, the reaction was stirred at room temperature for 4h, then Compound C (134mg, 0.35mmol), EDCCl (76.5mg, 0.4mmol), DMAP (5.5mg, 0.045mmol) were added and stirred overnight. The reaction was stopped and the filtrate was collected by filtration. After washing three times with dichloromethane and saturated brine in this order, the organic phases were combined and the organic layer was dried over anhydrous sodium sulfate overnight and subjected to silica gel column chromatography (eluent V dichloromethane: V methanol-50: 1) to give compound D as a gray solid in 10% yield. m.p.205.0-206.5 ℃.¹H NMR(400MHz，Chloroform-d)δ8.25(s，1H)，8.14(d，J＝8.4Hz，1H)，7.99(d，J＝8.1Hz，1H)，7.85-7.78(m，3H)，7.72(ddd，J＝8.5，6.8，1.5Hz，1H)，7.54(ddd，J＝8.1，6.8，1.2Hz，1H)，7.41(ddd，J＝8.3，7.2，1.3Hz，1H)，7.31(ddd，J＝8.2，7.2，1.2Hz，1H)，7.25(t，J＝8.1Hz，1H)，7.15(s，1H)，6.99(dd，J＝8.3，1.4Hz，1H)，5.59(d，J＝17.2Hz，1H)，5.32(d，J＝17.2Hz，1H)，5.22-5.12(m，2H)，3.78(s，3H)，2.79-2.66(m，6H)，2.58(q，J＝7.3Hz，2H)，2.13-1.98(m，6H)，0.90(t，J＝7.5Hz，3H).MS EI⁺：807.95(C₄₂H₃₇N₃O₈S₃，[M]⁺).

Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.