Oleanane Cinnamamide Derivative Reduces Cardiotoxicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
CDDO-Me, a semi-synthetic oleanolic acid derivative, exhibits strong anti-tumor activity but is associated with myocardial toxicity, necessitating the development of modified compounds with enhanced anti-tumor efficacy and reduced toxicity.
Innovation Solution
A 2-cyano-3,12-dioxoolean-1,9(11)-dien-17-phenylacrylamide compound is synthesized through a method involving Curtius rearrangement and condensation reactions, using environmentally friendly reagents and mild conditions, resulting in compounds with improved anti-tumor activity and reduced myocardial toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CDDO-Me is used as an anti-tumor medicament, then anti-tumor activity is improved, but myocardial toxicity increases
Solution Approach 1:
The patent introduces different substituents (R1, R2, R3) at specific positions of the oleanolic acid derivative structure to create compounds with locally modified properties. This allows enhancement of anti-tumor activity at the target site while reducing myocardial toxicity through careful selection of substituent groups such as fluorine, chlorine, methyl, and methoxy groups at different positions.
Solution Approach 2:
The patent systematically varies chemical parameters including substituent types (halogens, alkyl groups, alkoxy groups), substituent positions (R1 at C6, R2 at C11, R3 at C17), and molecular structure modifications to optimize the balance between anti-tumor efficacy and myocardial toxicity. This includes changing from CDDO-Me to phenylacrylamide derivatives with different R group configurations.
2Object-affected harmful factors
If structural modification is performed to reduce toxicity, then myocardial toxicity is reduced, but anti-tumor activity may be compromised
Solution Approach 1:
The patent designs compounds that can simultaneously achieve multiple functions: maintaining anti-tumor activity against various cancer cell lines (A549, MCF-7, HepG2, S180) while reducing myocardial toxicity. The phenylacrylamide core structure with variable substituents provides a universal platform for achieving both anti-tumor efficacy and reduced cardiotoxicity across different tumor types.
Solution Approach 2:
The patent employs Curtius rearrangement as a key reaction step to efficiently transform the carboxylic acid group to an amine, which is then condensed with phenylacrylic acid to form the phenylacrylamide structure. This streamlined approach allows rapid generation of multiple derivatives with optimized toxicity profiles without compromising anti-tumor activity.
3Reliability
If multiple substituents are introduced to enhance activity, then anti-tumor activity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent divides the molecular structure into distinct segments: the core oleanolic acid framework, the phenylacrylamide group, and variable substituent groups (R1, R2, R3). This segmentation allows independent optimization of each segment and simplifies the synthesis process by enabling modular assembly through the Curtius rearrangement and condensation reactions.
Solution Approach 2:
The patent performs preliminary structural optimization by introducing the phenylacrylamide core structure with defined substituent patterns before final biological testing. The Curtius rearrangement step prepares the amino intermediate in advance, which then undergoes condensation with phenylacrylic acid to form the final active compound, streamlining the overall manufacturing process.
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 synthesized compounds demonstrate excellent anti-tumor activity, with IC50 values comparable to or higher than CDDO-Me, and significantly reduced toxicity to cardiomyocytes and renal tubular epithelial cells, making them potential candidates for anticancer medications.
Implementation Method 1
A 2-cyano-3,12-dioxoolean-1,9(11)-dien-17-phenylacrylamide compound is synthesized through a method involving Curtius rearrangement and condensation reactions
Implementation Method 2
A 2-cyano-3,12-dioxoolean-1,9(11)-dien-17-phenylacrylamide compound is synthesized through a method involving Curtius rearrangement and condensation reactions
Data Source
AI summary
The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and in particular to a 2-cyano-3,12-dioxoolean-1,9(11)-dien-17-phenylacrylamide derivative and a preparation method thereof; and the present invention further relates to use of the novel compound in the preparation of an anticancer medicament.