3-Hydroxyflavone Derivatives for Apoptosis Detection
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Solution Overview
Problem
Current methods for detecting cell apoptosis, such as those using annexin V, face challenges including low specificity, dependence on calcium ions, and interference from cell environment components, leading to false positives and kinetic measurement limitations.
Innovation Solution
Development of 3-hydroxyflavone derivatives with a zwitterionic group and long hydrocarbon chain, which selectively bind to the outer leaflet of the plasma membrane, providing a two-color ratiometric response independent of calcium ions and cell environment, allowing for precise apoptosis detection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If annexin V is used for apoptosis detection, then specific binding to phosphatidylserine is achieved, but dependence on calcium ions and cell environment leads to false positives and measurement limitations
Solution Approach 1:
The patent modifies the chemical structure of the probe by changing parameters such as adding a long hydrocarbon chain (1-20 carbon atoms) and a zwitterionic group to the 3-hydroxyflavone core. These structural parameter changes enable the probe to selectively bind to the outer leaflet of the plasma membrane through hydrophobic interactions and electrostatic forces, eliminating dependence on calcium ions and reducing interference from cell environment components.
Solution Approach 2:
The patent introduces a zwitterionic group as an intermediary functional moiety between the fluorophore and the cell membrane. This zwitterionic group acts as a mediator that provides selective interaction with phosphatidylserine and phosphatidylethanolamine in the outer leaflet, enabling specific apoptosis detection without requiring calcium ions or being affected by cell environment variations.
2Ease of operation
If chemical reagents specific for amino groups are used, then detection of cell surface exposure is achieved, but low specificity and strong environment dependence limit application
Solution Approach 1:
The patent applies local quality by creating a probe with a specific spatial arrangement where the fluorophore is positioned to detect local changes in the outer leaflet of the plasma membrane. The long hydrocarbon chain anchors the probe in the membrane while the zwitterionic group specifically interacts with phosphatidylserine and phosphatidylethanolamine, providing localized detection of apoptosis markers without being affected by global environmental factors.
3Reliability
If annexin V is used for apoptosis detection, then binding to membrane surfaces is achieved, but pre-incubation times of up to 1 hour are needed, making kinetic measurements problematic
Solution Approach 1:
The patent changes the binding parameters of the probe by incorporating a long hydrocarbon chain and zwitterionic group that enable rapid binding to the outer leaflet of the plasma membrane. This structural modification allows the probe to achieve specific binding within minutes rather than requiring prolonged pre-incubation times of up to one hour, thus enabling kinetic measurements while maintaining binding specificity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The 3-hydroxyflavone derivatives offer improved selectivity, ease of handling, and quantitative measurements, enabling accurate detection of apoptotic cells with reduced penetration into the cell interior, independent of local probe concentration and incubation time.
Implementation Method 1
The probe is characterized by a long hydrocarbon chain (1-20 carbon atoms) and a zwitterionic group, which confer selective binding properties to the outer leaflet of the plasma membrane
Implementation Method 2
The zwitterionic group in the probe structure enables selective interaction with phosphatidylserine and phosphatidylethanolamine in the outer leaflet through electrostatic forces
Implementation Method 3
The 3-hydroxyflavone derivatives offer improved selectivity, ease of handling, and quantitative measurements, enabling accurate detection of apoptotic cells
Implementation Method 4
providing a two-color ratiometric response independent of calcium ions and cell environment
Data Source
Figure 1a~2
Figure 3~4
Figure 5a~5c
AI summary
The present invention relates a compound of formula (I) wherein: - R1 represents a linear alkyl group of 4 to 20 carbon atoms; - Y represents a linear alkyl group of 1 to 5 carbon atoms or a group of formula -R-O-R'-, -R-CO-R'- or -R-CO-NH-R'-, in which R represents a linear alkyl group of 1 to 3 carbon atoms, R' represents a linear alkylene group of 0-3 carbon atoms, Y being linked to the bicycle in position 6 or 7; - Z represents a linear alkyl chain of 3 or 4 carbon atoms; - A represents an oxygen atom, a sulphur atom, or a -NH group, or an amminoalkyl group -NR'' in which R" represents an alkyl group of 1 to 20 carbon atoms; - Ar represents an aromatic cycle or polycycle consisting of 6 to 14 carbon atoms, or an aromatic heterocycle, said heterocycle containing 4, 5 or 6 carbon atoms and at least one heteroatom selected in the group consisting of N, S, and O, or a condensed aromatic heterobicycle, said heterobicycle consisting of 6 to 9 carbon atoms and at least one heteroatom selected in the group consisting of N, S, and O ; - R2 and R3, which are identical or different, each representing a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R2 and R3 optionally forming a 5- to 7-membered ring with the nitrogen atom; - R4, R5 and R6, identical or different, represent an hydrogen, a linear alkyl group or a linear oxyalkyl group of 1 to 4 carbon atoms.