Hybrid Nrf2 Activator and CORM Molecules for Rapid CO Release
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Solution Overview
Problem
Current Nrf2/HO-1 activators require time to mount a cellular stress response, leading to delayed beneficial effects, and many CO-releasing molecules fail to release carbon monoxide, thereby lacking therapeutic efficacy in inflammatory and cardiovascular diseases.
Innovation Solution
Development of hybrid molecules combining a Nrf2 activator moiety with a CO-releasing molecule (CORM) that rapidly liberate CO, activating the Nrf2/HO-1 pathway, providing enhanced therapeutic efficacy with faster CO release, improved anti-inflammatory action, and low cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Nrf2/HO-1 activators are used to activate the cytoprotective pathway, then beneficial therapeutic effects are achieved, but the response is delayed due to the time required to mount the cellular stress response
Solution Approach 1:
The patent combines the Nrf2 activator and CO-releasing molecule into a single hybrid compound that performs both functions simultaneously. The CO is released immediately upon cellular uptake, providing immediate cytoprotective effects while also activating Nrf2 to upregulate HO-1 and other protective genes, thereby eliminating the delay associated with waiting for gene transcription and protein synthesis alone
Solution Approach 2:
The invention merges two separate therapeutic mechanisms (Nrf2 activation and CO release) into a single molecular entity. The hybrid compound contains both the Nrf2 activator moiety and the CORM moiety connected by a linker, allowing simultaneous delivery of both functions to the target cell, thus resolving the time delay contradiction
2Reliability
If CO-releasing molecules are used to deliver carbon monoxide, then therapeutic effects are achieved, but many compounds fail to release CO effectively, lacking therapeutic efficacy
Solution Approach 1:
The patent optimizes the CORM moiety structure and its connection to the Nrf2 activator through systematic variation of parameters such as the metal center, ligand environment, and linker properties. This ensures the hybrid compound maintains reliable CO release capability while simultaneously providing Nrf2 activation, thereby achieving both therapeutic efficacy and manufacturability
3Reliability
If Nrf2 activators are used to induce HO-1 expression, then cytoprotective effects are achieved, but glutathione depletion occurs leading to cytotoxicity
Solution Approach 1:
The patent utilizes the CO-releasing capability to convert a potentially harmful effect (glutathione depletion from Nrf2 activation) into a beneficial outcome. The CO released by the hybrid compound directly activates cytoprotective pathways and reduces oxidative stress independently of glutathione, thereby compensating for the glutathione depletion and preventing cytotoxicity while maintaining the cytoprotective benefits of Nrf2 activation
Data Source
AI summary
The present invention relates to highly efficient Nrf2 activators-CO-releasing molecules of formula (I) and (II) capable of increasing HO-1 protein expression and simultaneously releasing CO, their synthesis and their use in therapeutic applications, in particular their use in the treatment of inflammatory or cardiovascular diseases, wherein CORM represents a carbonyl metal complex chosen from among: Mn(CO)5, formula (III), (IV), (V), (VI), (VII), (VIII) and (IX).