Glutamine Analogs With Reduced Gastrointestinal Toxicity
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Solution Overview
Problem
Glutamine antagonists like 6-diazo-5-oxo-L-norleucine (DON) exhibit severe toxicity, such as dose-limiting gastrointestinal issues, hampering their clinical development for cancer treatment.
Innovation Solution
Development of novel glutamine analogs with specific structural modifications, including various substituents and functional groups, to reduce toxicity while maintaining anti-cancer activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glutamine antagonists such as DON are administered at therapeutic dose levels, then anti-cancer activity is achieved, but severe gastrointestinal toxicity occurs
Solution Approach 1:
The patent modifies the chemical structure of glutamine antagonists by changing parameters such as the side chain at position 6 (introducing various R1 groups including alkyl, alkoxy, halogen, and heterocyclic substituents) and modifications at positions 3 and 4 (X and Y groups). These parameter changes in the molecular structure aim to reduce gastrointestinal toxicity while preserving anti-cancer activity against glutamine-dependent cancer cells.
Solution Approach 2:
The patent applies local quality modifications by specifically altering certain regions of the glutamine analog molecule while maintaining others. For example, the carboxylic acid group at position 1 and amino group at position 2 are preserved to maintain glutamine recognition, while positions 3-6 are modified with various substituents to reduce toxicity. This selective modification approach allows the molecule to maintain its anti-cancer mechanism while reducing harmful effects on gastrointestinal tissue.
2Object-affected harmful factors
If prior attempts to mitigate toxicity of glutamine antagonists are made, then some toxicity reduction may be achieved, but anti-cancer activity is compromised
Solution Approach 1:
The patent systematically explores multiple parameter changes in the glutamine analog structure, including various combinations of R1 groups (methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, etc.), X groups (hydrogen, deuterium, various functional groups), and Y groups. This comprehensive parameter optimization allows the identification of compounds that achieve both toxicity reduction and maintained anti-cancer activity, overcoming the trade-off faced in prior attempts.
Solution Approach 2:
The patent creates composite molecular structures by combining different functional groups and substituents in specific configurations. The glutamine analogs incorporate multiple structural elements (amino group, carboxylic acid, various side chains at positions 3-6) that work together synergistically to provide both reduced toxicity and preserved anti-cancer activity, representing a composite approach to drug design.
Data Source
AI summary
The invention relates to novel glutamine analogs, a composition containing the glutamine analogs and the use thereof.