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US-20260125411-A1 - COMPOUND EMITTING LIGHT UNDER SPECIFIC CONDITIONS, AND METHOD FOR DETECTING CANCER STEM CELLS USING SAME

US20260125411A1US 20260125411 A1US20260125411 A1US 20260125411A1US-20260125411-A1

Abstract

The present invention provides a compound with which a molecular probe capable of distinguishing NSCs from CSCs can be produced, and a method for detecting cancer stem cells using the compound. The present invention relates to a compound having a formyl group, a substrate moiety, a quenching moiety, and a luminescent moiety that is non-luminous due to the quenching moiety, wherein the luminescent moiety may be rendered luminous by detaching the substrate moiety by a substrate-degrading enzyme and also converting the formyl group to a carboxy group by an aldehyde dehydrogenase to allow the quenching moiety to dissociate.

Inventors

  • Koji Miki
  • Yoshinobu Baba
  • Masahiro Oe
  • Kanae Suzuki
  • Huiying Mu
  • Yoshifumi Ueda
  • Yasuo Mori
  • Hiroshi Yukawa
  • Kouichi Ohe
  • Koki Miki

Assignees

  • KYOTO UNIVERSITY
  • NATIONAL UNIVERSITY CORPORATION TOKAI NATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM

Dates

Publication Date
20260507
Application Date
20231227
Priority Date
20221228

Claims (12)

  1. 1 . A compound, comprising: a formyl group; a substrate moiety; a quenching moiety; and a luminescent moiety that is non-luminous due to the quenching moiety, wherein the luminescent moiety may be rendered luminous by detaching the substrate moiety by a substrate-degrading enzyme and also converting the formyl group to a carboxy group by an aldehyde dehydrogenase to allow the quenching moiety to dissociate.
  2. 2 . The compound according to claim 1 , wherein the substrate moiety is a sugar chain, an amino acid, a peptide chain, a boryl group, a phosphoryl group, an aryl methyl group, or an acyl group.
  3. 3 . The compound according to claim 2 , wherein the sugar chain is D-galactose, and the sugar chain-degrading enzyme is β-galactosidase.
  4. 4 . The compound according to claim 1 , wherein the luminescent moiety is able to emit near-infrared light.
  5. 5 . A compound, represented by the following formula: wherein Ar is an aromatic ring, X is an oxygen atom, a nitrogen atom, a sulfur atom, or a selenium atom, L is a linker, Su is a substrate moiety, and the π-system is a π-conjugated system.
  6. 6 . The compound according to claim 5 , wherein the aromatic ring is represented by the following formula: wherein Y is a halogen group, SO 3 Na, SO 3 H, or COOR.
  7. 7 . The compound according to claim 5 , wherein the substrate moiety is a sugar chain, an amino acid, a peptide chain, a boryl group, a phosphoryl group, an aryl methyl group, or an acyl group.
  8. 8 . The compound according to claim 5 , wherein the π-conjugated system is represented by the following formula: wherein the aromatic ring optionally has an electron-withdrawing group.
  9. 9 . The compound according to claim 5 , wherein the compound is represented by the following formula: wherein Z is an electron-withdrawing group.
  10. 10 . A cancer stem cell detection reagent, comprising the compound according to claim 1 .
  11. 11 . A method for detecting cancer stem cells, the method comprising: administering the cancer stem cell detection reagent according to claim 10 to cells; and irradiating the cells with near-infrared light to detect cancer stem cells by emission from the compound.
  12. 12 . The method for detecting cancer stem cells according to claim 11 , wherein the cells are contained in biological tissue and are detected in vivo or in vitro.

Description

TECHNICAL FIELD The present invention relates to a compound that is rendered luminous under specific conditions and a method for detecting cancer stem cells using the compound. BACKGROUND ART Cancer cells are known to contain approximately a few percent of cancer stem cells (CSCs) which exhibit resistance to anticancer drugs and contribute to cancer metastasis. Visualizing CSCs may be useful in developing truly effective anticancer drugs and diagnosing highly malignant cancer tissue. Aldehyde dehydrogenase 1A1 (ALDH1A1) is known as a biomarker that is highly expressed in cells with stemness properties. Molecular probes capable of detecting ALDH1A1 activity may be useful for identifying CSCs, but few examples have been reported. In 1999, the ALDH1A1-responsive molecular probe ALDEFLUOR™, which was later made commercially available, was announced (Non-Patent Literature 1), making it possible to identify CSCs. Very recently, a wavelength-shifting probe (Non-Patent Literature 2) and turn-on probes (Non-Patent Literatures 3 to 5) have been reported, each of which compensates for the shortcomings of ALDEFLUOR™, which is an always-on probe. Thus, several molecular probes capable of detecting ALDH1A1 (or ALDH1) activity have been developed to date. However, ALDH1A1, which is a biomarker for stem cells, is also expressed in normal stem cells (NSCs) contained in normal tissue. In other words, the molecular probes developed so far cannot distinguish NSCs from CSCs as illustrated in FIG. 10. Therefore, in clinical settings, the molecular probes developed so far have the disadvantage of not being able to eliminate false positives caused by NSCs when staining tissue sections containing normal tissue and/or blood cells to determine whether they contain highly malignant tumors containing a large number of CSCs. CITATION LIST Non-Patent Literature Non-Patent Literature 1: R. W. Storms, et al. Proc. Natl. Acad. Sci. USA 1999, 96, 9118Non-Patent Literature 2: S. Maity, et al. Chem. Sci. 2017, 8, 7143. DOI: 10.1039/c7sc03017gNon-Patent Literature 3: C. Anorma, et al. ACS Cent. Sci. 2018, 4, 1045. DOI: 10.1021/acscentsci.8b00313; T. E. Bearrood, et al. Bioconjugate Chem. 2020, 31, 224. DOI: 10.1021/acs.bioconjchem.9b00723Non-Patent Literature 4: M. Oe, et al. ACS Sens. 2021, 6, 3320. DOI: 10.1021/acssensors.1c01136Non-Patent Literature 5: Q. W. Wang, et al. Anal. Chem. 2022, 94, 49, 17328-17333 SUMMARY OF INVENTION Technical Problem The present invention aims to provide a compound with which a molecular probe capable of distinguishing NSCs from CSCs can be produced, and a method for detecting cancer stem cells using the compound. Solution to Problem The present inventors conducted research into compounds capable of detecting ALDH1A1 (or ALDH1) activity, and focused on β-galactosidase (β-gal), which is known to be expressed in cancer cells but not in normal cells. The inventors then found that such a sugar chain may be introduced into a compound containing a formyl group and a quenching moiety in order to distinguish NSCs from CSCs, thus completing the present invention, as illustrated in FIG. 11. Specifically, Embodiment 1 of the present invention relates to a compound, having a formyl group, a substrate moiety, a quenching moiety, and a luminescent moiety that is non-luminous due to the quenching moiety, wherein the luminescent moiety may be rendered luminous by detaching the substrate moiety by a substrate-degrading enzyme and also converting the formyl group to a carboxy group by an aldehyde dehydrogenase to allow the quenching moiety to dissociate. Embodiment 2 of the present invention (2) relates to the compound according to Embodiment 1 of the present invention, wherein the substrate moiety is a sugar chain, an amino acid, a peptide chain, a boryl group, a phosphoryl group, an aryl methyl group, or an acyl group. Embodiment 3 of the present invention relates to the compound according to Embodiment 2 of the present invention, wherein the sugar chain is D-galactose, and the sugar chain-degrading enzyme is β-galactosidase. Embodiment 4 of the present invention relates to the compound according to any one of Embodiments 1 to 3 of the present invention, wherein the luminescent moiety is able to emit near-infrared light. Embodiment 5 of the present invention relates to a compound represented by the following formula: wherein Ar is an aromatic ring, X is an oxygen atom, a nitrogen atom, a sulfur atom, or a selenium atom, L is a linker, Su is a substrate moiety, and the π-system is a π-conjugated system. Embodiment 6 of the present invention relates to the compound according to Embodiment 5 of the present invention, wherein the aromatic ring is represented by the following formula: wherein Y is a halogen group, SO3Na, SO3H, or COOR. Embodiment 7 of the present invention relates to the compound according to Embodiment 5 or 6 of the present invention, wherein the substrate moiety is a sugar chain, an amino acid, a peptide chain, a