NO-Releasing Isoxazoline Compound for Targeted Cancer Cell Death
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer treatments face challenges in finding substances with improved efficacy and reduced side effects, and existing antitumor agents may not effectively target cancer cells without causing significant toxicity.
Innovation Solution
The development of an isoxazoline compound, GIT27-NO, which releases nitric oxide (NO) and exhibits strong antitumor and antiviral properties, capable of inducing different types of cell death in cancer cells, including apoptosis and autophagy, while minimizing toxicity through specific cellular targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antitumor agents are used, then tumor growth inhibition is achieved, but toxicity to normal cells increases
Solution Approach 1:
The patent applies local quality by designing compound (I) to selectively release nitric oxide only within tumor cells through specific cellular uptake mechanisms and intracellular enzymatic activation. The compound accumulates preferentially in cancer cells due to their altered metabolic characteristics, ensuring that the cytotoxic effect is localized to the target cells while sparing normal tissue.
Solution Approach 2:
The patent uses nitric oxide as an intermediary substance that mediates the antitumor effect. Compound (I) serves as a prodrug that is converted intracellularly to release NO, which then exerts its cytotoxic effect through multiple mechanisms including activation of guanylate cyclase, inhibition of mitochondrial respiration, and induction of apoptosis. This intermediary approach allows for more selective and controllable tumor cell killing.
2Reliability
If nitric oxide is released to induce cell death, then tumoricidal activity is enhanced, but non-specific cytotoxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the physical and chemical properties of nitric oxide through its incorporation into compound (I). The compound changes the delivery parameters of NO, controlling its release kinetics, concentration, and spatial distribution. This allows the tumor cell to be exposed to lethal concentrations of NO while normal cells remain protected due to differences in compound uptake and activation parameters.
Solution Approach 2:
The patent segments the cytotoxic effect by designing compound (I) to be selectively taken up by tumor cells through specific transport mechanisms. The compound is segmented from systemic circulation and targeted specifically to cancer cells, where it is then converted to release NO locally. This segmentation ensures that the cytotoxic action is confined to the tumor cell population.
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
GIT27-NO demonstrates significant tumoricidal activity by inducing cell death in various cancer cell lines and inhibiting tumor growth in vivo, with its NO-releasing mechanism crucial for cytotoxicity, offering a promising approach for cancer treatment with reduced side effects.
Implementation Method 1
GIT27-NO, which releases nitric oxide (NO) and exhibits strong antitumor and antiviral properties, capable of inducing different types of cell death in cancer cells
Data Source
AI summary
The present invention relates to an isoxazole derivative, the compound of formula (I)herein after referred to as GIT27-NO, which is the NO-donating structurally modified form of (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid, herein after referred to as VGX-1027. Treatment of three tumor cell lines, rat astrocytoma C6, mouse fibrosarcoma L929, and mouse melanoma B16 cells with GIT27-NO resulted in a significant reduction of cell respiration and of number of viable cells, while VGX-1027 was completely ineffective. Hemoglobin, which act as NO-scavenger, restored cell viability, thus indicating the NO-mediated tumoricidal effect of compound (I). GIT27-NO triggered apoptotic cell death in L929 cell cultures, while autophagic cell death is mainly responsible for the diminished viability of C6 and B16 cells. Moreover, GIT27-NO induced the production of reactive oxygen species which can be neutralized by antioxidant N-acetyl cysteine (NAC), indicating that reactive oxygen species (ROS) are at least partly involved in the reduction of cell viability. The anti-tumor activity of GIT27-NO is mediated through activation of MAP kinases (ERK1/2, p38 and JNK) in cell-specific manner. The role of MAP kinases was further confirmed by specific inhibitors of these molecules, PD98059, SB202190, and SP600125. Finally, in vivo treatment with GIT27-NO significantly reduced tumor growth in syngeneic C57BL/6 mice implanted with B16 melanoma.