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JP-7857022-B2 - The complex and its use

JP7857022B2JP 7857022 B2JP7857022 B2JP 7857022B2JP-7857022-B2

Inventors

  • 田中 克典
  • アンバラ ラクマット プラディプタ

Assignees

  • 国立研究開発法人理化学研究所

Dates

Publication Date
20260512
Application Date
20211013
Priority Date
20201023

Claims (7)

  1. It includes an acrolein reaction site having the chemical structure represented by formula (1), and a release site having other chemical structures, The detachment site is bonded to the acrolein reaction site via a linker that can be cleaved by the reaction between the acrolein reaction site and acrolein. (In equation (1), R1 and R2 independently refer to a C1-C5 alkyl group which may be substituted with a hydrogen atom, a halogen atom, or at least one halogen atom, provided that at least one of R1 and R2 is a C1-C5 alkyl group; R3 and R4 independently refer to a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an optionally substituted amino group, a C1-C5 alkoxy group, a C1-C5 alkylthio group, or a C1-C5 alkyl group (wherein the hydrogen atoms constituting the alkyl group may be substituted by substituents selected from halogen atoms, hydroxyl groups, unsubstituted amino groups, alkylamino groups, and (hetero)arylamino groups); * indicates the linkage site with the linker. The linker is a linker having a chemical structure represented by formula (2) , (In equation (2), R independently refers to a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an optionally substituted amino group, a C1-C5 alkoxy group, a C1-C5 alkylthio group, or a C1-C5 alkyl group (wherein the hydrogen atoms constituting the alkyl group may be substituted by substituents selected from halogen atoms, hydroxyl groups, unsubstituted amino groups, alkylamino groups, and (hetero)arylamino groups); * indicates the binding site with the acrolein reaction site. ※※ indicates the connection site with the detachment site. The aforementioned detachment site is a compound having a nitrogen atom, In formula (2), the aforementioned ** is a composite, which is a bonding site with the nitrogen atom contained in the detachment site.
  2. The composite according to claim 1, wherein R in formula (2) independently refers to a hydrogen atom, a halogen atom, or a C1-C5 alkyl group (wherein the hydrogen atom constituting the alkyl group may have substituents selected from a halogen atom, a hydroxyl group, an unsubstituted amino group, an alkylamino group, and a (hetero)arylamino group).
  3. The composite according to claim 1 or 2 , wherein R1 and R2 in formula (1) independently refer to a C1-C5 alkyl group which may be substituted with at least one halogen atom.
  4. The complex according to any one of claims 1 to 3 , wherein the release site is an antitumor compound.
  5. The complex according to any one of claims 1 to 4 , wherein the detachment site detaches upon reaction with acrolein present around tumor cells.
  6. A tumor treatment agent comprising the complex described in claim 4 or 5 .
  7. The complex according to any one of claims 1 to 5 , or the therapeutic agent according to claim 6 , is delivered to the target tissue requiring treatment. A drug delivery system that reacts acrolein with the complex or the therapeutic agent to detach the detachment site.

Description

This invention relates to a composite material and its use. In cancer targeting therapy, development is underway on drug delivery systems that aim to optimize treatment by enhancing drug efficacy while suppressing side effects. These systems selectively deliver drugs to specific tissues (target tissues) that require treatment, while also reducing side effects by minimizing impact on normal tissues. For example, research is being conducted on prodrugs that exhibit antitumor activity under conditions characteristic of tumor cells, such as a hypoxic environment, in order to deliver drugs to target tumor cells (Non-Patent Literature 1-2). Furthermore, research is being conducted on prodrugs that release drugs upon reaction with specific trigger compounds (Non-Patent Literature 3-4). However, the compounds described in Non-Patent Documents 1-4 are still in the test tube stage, and furthermore, the compounds described in Non-Patent Documents 3-4 require additional compounds as triggers for drug release. Acrolein ( CH₂ =CHCHO) is the smallest unsaturated aldehyde molecule and is highly reactive. Acrolein is known to be produced during the combustion of organic matter, and it is also thought to be produced in the body as a metabolite of lipids or polyamines in diseases associated with oxidative stress, such as cancer, Alzheimer's disease, and cerebral infarction. Furthermore, recent studies have revealed that acrolein exhibits higher toxicity than hydroxyl radicals, which were previously considered the main cause of oxidative stress. Therefore, it has recently attracted attention, particularly for detecting acrolein generated in cells and for elucidating the relationship between acrolein and diseases related to oxidative stress. For example, Non-Patent Document 5 describes a novel compound that selectively reacts with acrolein among molecules present in living organisms. Calder et.al., Tetrahedron, 2020, Volume 78, Issue 21, Article 131170Herrlinger et.al., ChemBioChem, 2020, 21(16), p2329-2347Brakel et.al., Bioconjugate Chem., 2008, 19, 714-718Matikonda et al., Chem. Sci., 2015, 6, 1212-1218ACS Sens. 2016, 1, 623-632. This figure shows the fluorescence spectra obtained by fluorescence measurement of a complex (coumarin-ABC) and a control (coumarin) according to one embodiment of the present invention.This figure shows the real-time measurement results for the fluorescence intensity of coumarin-ABC in and without acrolein.This figure shows the results of measuring the fluorescence intensity of coumarin-ABC and coumarin in MCF10A (normal human mammary gland cells).This figure shows the results of measuring the fluorescence intensity of coumarin-ABC and coumarin in A549 (human lung adenocarcinoma cells).This figure shows the measurement results (concentration-dependent) of the fluorescence intensity of coumarin-ABC and coumarin in HeLa S3 (human cervical cancer cells).This figure shows the real-time measurement results for the fluorescence intensity of coumarin-ABC (2 μM) in normal cells and cancer cells.This figure shows the real-time measurement results for the fluorescence intensity of coumarin-ABC (20 μM) in normal cells and cancer cells.This figure shows the HPLC analysis results of a mixture of coumarin-ABC and glutathione (GSH).This figure shows the HPLC analysis results of a mixture of coumarin-ABC and acrolein.This figure shows the cell viability of MCF10A (normal human mammary cells) in the presence of a complex (MMC-ABC) according to one aspect of the present invention or a control.This figure shows the cell viability of A549 (human lung adenocarcinoma cells) and HeLa S3 (human cervical cancer cells) in the presence of MMC-ABC or a control.This graph shows the change in tumor volume in A549 tumor-carrying mice after intratumoral administration of MMC-ABC or a control.This graph shows the change in body weight in A549 tumor-carrying mice after intratumoral administration of MMC-ABC or a control.This graph shows the survival rates in A549 tumor-carrying mice after intratumoral administration of MMC-ABC or a control.These are photographs of mice taken on day 2 after intratumoral administration of MMC-ABC or a control, and on day 4 after the end of administration.This figure shows the cell viability of MCF10A, A549, or HeLa S3 in the presence of DOX-ABC and DOX.These are photographs of mice after intratumoral administration of control (compound 9), DOX, or DOX-ABC.This graph shows the change in tumor volume in A549 tumor-carrying mice after intratumoral administration of control (compound 9), DOX, or DOX-ABC.This graph shows the survival rates in A549 tumor-bearing mice after intratumoral administration of control (compound 9), DOX, or DOX-ABC.This graph shows the change in tumor volume in A549 tumor-carrying mice after intratumoral administration of either the control (compound 9) or PUR-ABC. [1. Complex] A complex according to one embodiment of the present invention (hereinafter also simply referred to as "t