Synergistic Anti-Ferroptosis with a Minimalistic, Peroxide-Triggered Carbon Monoxide Donor for Parkinson’s Disease

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Parkinson's disease (PD) is a debilitating neurodegenerative disease, with current treatments primarily focusing on improving dopaminergic activity, providing symptomatic relief but failing to halt progression. Ferroptosis drives PD pathogenesis and potential therapeutic target. Herein, we introduce novel peroxide-activated carbon monoxide (CO) donor, PCOD, featuring streamlined structure designed potentially enhance blood-brain barrier (BBB) penetration optimize outcomes. PCOD releases CO upon activation by nucleophilic peroxides, e.g., ONOO- H2O2. This mechanism provides potent strategy against ferroptosis: first, scavenging peroxides that generate oxidative radicals involved in ferroptosis, second, proposed inhibit Fenton chemistry through coordination Fe2+. In MPTP-treated mice, prevents neuron loss the substantia nigra alleviates symptoms. peroxide-triggered release offers promising innovative combat ferroptosis neurodegeneration PD.

Language: Английский

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Structure Modification and Metabolic Pathway Optimizations of Anticancer Drugs

Highlights in Science Engineering and Technology, Journal Year: 2025, Volume and Issue: 129, P. 186 - 193

Published: March 3, 2025

Anti-cancer drugs have a critical position in modern medicine, and their structural modification metabolic pathway optimization are key strategies to enhance efficacy safety. Through the introduction of functional groups, changes molecular ring structure, covalent non-covalent modifications, pharmacokinetic properties anticancer can be optimized, which significantly improve stability, bioavailability, targeting, as well reduce toxic side effects. This paper reviews main for drugs, including group addition, modification, analyses case classical such paclitaxel Adriamycin. These optimizations resulted significant improvements stability therapeutic drug. In generation reduction metabolites, metabolites through combination liposome encapsulation, nanoparticle inhibitors, discussed this paper. Despite advances structure metabolism drug development, prediction individual variability still challenges that need addressed. future, combining precision genomics, big data artificial intelligence technologies, personalized design anti-cancer pathways expected achieve more efficient safer cancer treatment options.

Language: Английский

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A novel pyrimidine-based hydrophilic fluorescent probe for detection and imaging of endogenous carbon monoxide in living organisms

Journal of Molecular Structure, Journal Year: 2025, Volume and Issue: unknown, P. 142342 - 142342

Published: April 1, 2025

Language: Английский

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Compelling Evidence: A Critical Update on the Therapeutic Potential of Carbon Monoxide

Medicinal Research Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

ABSTRACT Carbon monoxide (CO) is an endogenous signaling molecule. It produced via heme degradation by oxygenase (HMOX), releasing stoichiometric amounts of CO, iron, and biliverdin (then bilirubin). The HMOX‐CO axis has long been shown to offer beneficial effects modulating inflammation, proliferation cell death as they relate tissue organ protection. Recent years have seen a large number studies examining CO pharmacology, its molecular targets, cellular mechanisms action, pharmacokinetics, detection methods using various delivery modalities including inhaled gas, solutions, types donors. Unfortunately, one widely used donor type includes four commercially available carbonyl complexes with metal or borane, CORM‐2 (Ru 2+ ), CORM‐3 CORM‐A1 (BH 3 CORM‐401 (Mn + which minimal and/or unpredictable production extensive CO‐independent chemical reactivity biological activity. As result, not all “CO activities” in the literature can be attributed CO. In this review, we summarize key findings based on gas solution for certainty active principal avoid data contamination resulting from confirmed potential reactivities activities “carrier” portion CORMs. Along similar line, discuss interesting research areas brain newly proposed CO/HMOX/dopamine role cognitive stimulation circadian rhythm. This review critical future development field steering clear complications caused chemically reactive molecules.

Language: Английский

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Nitrosoamine–3-Hydroxyflavothione Hybrids Enable Oxygen-Tolerant Photoredox Catalysis for Red-Light-Stimulated CO/NO Release for Combating Bacteria

ACS Macro Letters, Journal Year: 2025, Volume and Issue: unknown, P. 757 - 764

Published: May 20, 2025

Single gas donors have proved to vast therapeutic potential; however, the investigation of multigas releasing molecules is limited. Besides, porphyrins and their derivatives are essential energy electron transfer agents for activating gaseous signaling molecule (GSM) donors, despite, catalysis latter greatly limited in oxygen-rich environments. We, therefore, report photosensitive small-molecule hybrids composed oxo-/thio-flavonols as singlet oxygen (1O2) scavengers catalytic stability N-nitrosoamine moieties competent co-release carbon monoxide (CO) nitric oxide (NO) amounts that depend on structural designs. The self-assembled micellar co-encapsulation CO/NO PdTPTBP afforded intracellular GSMs delivery during red-light irradiation. bactericidal effect irradiated micelles against planktonic Gram-positive Gram-negative bacteria displayed a significant killing rate S. aureus via membrane hyperpolarization rupture achieved an excellent combination index 0.44. This represents high potential biomedical applications.

Language: Английский

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