Thionucleoside Derivative Overcoming Gemcitabine Resistance
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Solution Overview
Problem
Current cancer treatments using nucleoside analogs like gemcitabine face challenges due to congenital or acquired resistance, leading to decreased patient survival rates, necessitating the development of new compounds effective against resistant tumors.
Innovation Solution
A thionucleoside derivative, represented by a specific general formula, is developed, which includes various protective groups and substituents, forming nitrogen, oxygen, or phosphorus-containing heterocyclic rings, offering enhanced efficacy against tumors resistant to gemcitabine.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gemcitabine is used as a standard chemotherapy, then it is effective against many cancerous tumors, but congenital or acquired resistance develops leading to decreased patient survival rate
Solution Approach 1:
The patent modifies the chemical structure of gemcitabine by replacing the oxygen atom in the sugar ring with sulfur to create thionucleoside derivatives. This fundamental parameter change in the molecular structure allows the compound to overcome resistance mechanisms that render gemcitabine ineffective, while retaining the core antitumor activity. The sulfur substitution alters the compound's properties enough to bypass resistance pathways.
Solution Approach 2:
The invention creates composite chemical structures by combining the gemcitabine base with modified sugar moieties containing sulfur atoms at specific positions (2-thio or 4-thio). These composite thionucleoside structures integrate the antitumor pharmacophore of gemcitabine with modified sugar rings that confer resistance-overcoming properties, resulting in a new class of compounds effective against resistant tumors.
2Reliability
If new drugs are developed to overcome resistance, then drug efficacy against resistant tumors improves, but the complexity of drug development and structural modification increases
Solution Approach 1:
Instead of completely redesigning the gemcitabine molecule, the patent applies localized modifications by introducing sulfur atoms at specific positions (2-position or 4-position) of the sugar ring only. This local quality change maintains the overall structure and pharmacological activity while conferring new properties to overcome resistance, thereby managing complexity through targeted rather than comprehensive modification.
Data Source
AI summary
Disclosed are a compound and a pharmaceutical composition that exhibit an excellent drug efficacy against a tumor, in particular a tumor which has acquired resistance to gemcitabine. Specifically, provided is a thionucleoside derivative represented by General Formula [1] (in the formula, R1 represents a hydroxyl group which may be protected, a C1-20 alkoxy group which may be substituted, or the like; R2 represents a C1-20 alkoxy group which may be substituted, a C3-8 cycloalkoxy group which may be substituted, or the like; and R3 represents a hydrogen atom or the like); or a salt thereof. Further, provided is a pharmaceutical composition containing such a thionucleoside derivative or a salt thereof.