Micheliolide Derivatives C2 C14 Hydroxylation Solubility

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Solution Overview

Problem

Current Micheliolide derivatives lack improved pharmacological properties for use as anticancer and anti-inflammatory agents due to limitations such as scarce water-solubility and chemical instability, which complicates their development and application.

Innovation Solution

The development of novel Micheliolide derivatives functionalized at carbon atoms C2 and C14 using engineered cytochrome P450 enzymes for hydroxylation, allowing for the installation of a broad range of functionalities and the production of bifunctionalized derivatives, including modifications at the C13 position, via a chemoenzymatic strategy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional Micheliolide derivatives are used, then anticancer and anti-inflammatory activity is achieved, but water solubility remains scarce and chemical stability is poor

Engineering Contradiction:

Improveanticancer and anti-inflammatory activityVSAvoidwater solubility and chemical stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of Micheliolide derivatives through functionalization at C2 and C14 positions with various groups (halogens, hydroxyl, amino, carboxyl, etc.). These structural parameter changes improve water solubility and chemical stability while preserving or enhancing the pharmacological activity against cancer and inflammation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures by combining the Micheliolide core scaffold with additional functional groups and moieties at specific positions. This composite approach allows the molecule to simultaneously maintain its biological activity while acquiring improved solubility and stability properties from the added functional groups

Inventive Principle:

Principle #40Composite materials

2Stability of the object's composition

If functional groups are added to improve solubility and stability, then pharmacological properties are enhanced, but manufacturing complexity increases

Engineering Contradiction:

Improvewater solubility and chemical stabilityVSAvoidmanufacturing complexity

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent employs preliminary action by using engineered cytochrome P450 enzymes to pre-install hydroxyl groups at specific C2 and C14 positions during the biocatalytic step. This preliminary functionalization simplifies subsequent chemical manufacturing steps, as the critical hydroxylation reactions are already performed by the enzyme before the compound enters traditional chemical synthesis pathways

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent replaces traditional chemical synthesis mechanisms with biocatalytic mechanisms by using engineered cytochrome P450 enzymes to perform the hydroxylation reactions. This substitution of chemical synthesis with enzymatic catalysis improves manufacturing efficiency, selectivity, and environmental compatibility while reducing the need for complex protecting group strategies and harsh reaction conditions

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 resulting Micheliolide derivatives exhibit enhanced pharmacological properties, including improved anticancer activity and increased water solubility, addressing the limitations of existing derivatives.

Implementation Method 1

engineered cytochrome P450 enzymes for hydroxylation

Methodology Applied

Scientific EffectHydroxylation: Oxidation

Implementation Method 2

engineered cytochrome P450 enzymes for hydroxylation

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Data Source

PatentUS11634400B2Micheliolide derivatives, methods for their preparation and their use as anticancer and antiinflammatory agents

Publication Date: 2023.04.25 UNIVERSITY OF ROCHESTER

AI summary

The present invention relates to derivatives of the sesquiterpene lactone micheliolide, methods and compositions for their preparation, and methods for using the micheliolide derivatives in pharmaceutical compositions as anticancer and anti-inflammatory agents. The invention also relates to methods for producing micheliolide derivatives modified at positions C2 and C14. The invention also relates to methods for producing parthenolide derivatives modified at positions C2 and C14 in conjunction with modifications at position C13, via chemoenzymatic methods. The invention further relates to methods for using parthenolide derivatives for treating cancer and inflammatory diseases.