Photoredox-Mediated Immunotherapy Utilizing Rhenium(I) Photocatalysts with Electron Donor–Acceptor–Donor Configuration

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

Published: Jan. 24, 2025

The hypoxic environment of solid tumors significantly diminishes the therapeutic efficacy oxygen-dependent photodynamic therapy. Developing efficient photosensitizers that operate via photoredox catalysis presents a promising strategy to overcome this challenge. Herein, we report rational design two rhenium(I) tricarbonyl complexes (Re-TPO and Re-TP) with electron donor–acceptor–donor configuration. Notably, Re-TP exhibits aggregation-induced emission properties enhanced spin–orbit coupling compared Re-TPO, thus exhibiting promoted photosensitizing capability. In addition generating type I II reactive oxygen species, excited facilitates photocatalytic oxidation NADH NAD+ photoreduction pyruvic acid lactic acid. This metabolic intervention triggers PD-L1-linked immune responses disrupts tumor redox balance, leading ferroptosis immunogenic cell death. combined immunotherapy effects suppress both primary distant B16 tumors. investigation provides compelling model for designing metal-based PSs photoredox-mediated photoimmunotherapy against

Language: Английский

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Intracellular Photocatalytic NADH/NAD(P)H Oxidation for Cancer Drug Development

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7161 - 7181

Published: Feb. 20, 2025

Photocatalytic cancer therapy (PCT) has emerged as a cutting-edge anticancer mechanism of action, harnessing light energy to mediate the catalytic oxidation intracellular substrates. PCT is significant current importance due its potential address limitations conventional chemotherapy, particularly drug resistance and side effects. This approach offers noninvasive, targeted treatment option by utilizing metal-based photocatalysts induce redox metabolic disorders within cells. The disrupt cell metabolism converting NADH/NAD(P)H NAD+/NAD(P)+ via photoredox processes, altering NAD+/NADH or NAD(P)+/NAD(P)H ratios, which are crucial for cellular metabolism. Ir(III), Ru(II), Re(I), Os(II) demonstrated promising efficacy. Despite these developments, gaps remain in literature translating this new into clinical trials. Perspective critically examines developments research area provides future directions designing efficient PCT.

Language: Английский

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Piperazine-Based Co(III), Ni(II), Cu(II), and Zn(II) Carbodithioate Complexes as Potential Anticancer Agent

ACS Omega, Journal Year: 2025, Volume and Issue: 10(14), P. 13829 - 13838

Published: April 1, 2025

The development of facile and cost-effective anticancer metallodrugs possessing minimal side effects is urgently needed. Piperazine-containing drugs are already available on the market. A piperazine-based potassium 4-(ethoxycarbonyl)piperazine-1-carbodithioate [pecpcdt] (L) ligand its metal complexes [Co(ecpcdt)3] (1), [Ni(ecpcdt)2] (2), [Cu(ecpcdt)2] (3), [Zn(ecpcdt)2] (4) were synthesized. These compounds characterized by different spectroscopic methods single-crystal X-ray crystallography data. Ni(II) Cu(II) have distorted square planar geometry, whereas Co(III) complex has octahedral geometry around ions. Complexes weakly fluorescent in solution compared to free ligand. further examined for their vitro activities against primary Dalton's lymphoma (DL) cells along with standard drug cisplatin. studies been performed through various biochemical assays, findings thus obtained suggest that they demonstrate an effective activity. (1) shows superior cytotoxicity DL than (4), superiority preferences these follows > (3) (2) (4). Further assays a cobalt(III) having highest efficacy gain insights into mechanism cell death showed reduced mitochondrial membrane potential increased ROS production, highlighting mitochondrial-dependent apoptosis as major tumor death. On other hand, viability normal splenocytes was minimally affected treatment.

Language: Английский

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Porphyrin-Derived Carbon Dots for Red-Light Activated Photodynamic Therapy of Breast Cancer

ACS Applied Bio Materials, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

In recent years, cancer has emerged as a major global health threat, ranking among the top causes of mortality. While treatments such surgery, immunotherapy, radiation therapy, and chemotherapy remain widely used, photodynamic therapy been gaining significant interest. Most photosensitizing agents employed in clinical settings are derived from tetrapyrrolic frameworks, including porphyrins, chlorins, phthalocyanines. Although these compounds have demonstrated therapeutic effectiveness, they suffer critical drawbacks, limited solubility water inadequate (photo)stability. To address issues, herein, formulation previously reported promising photosensitizer tetrakis(4-carboxyphenyl) porphyrin into carbon dots is reported. The were found with enhanced aqueous solubility, high (photo)stability, greater singlet oxygen quantum yield overcoming limitations molecular photosensitizer. being nontoxic dark, induced phototherapeutic effect breast cells multicellular tumor spheroids.

Language: Английский

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Gold(I) N-Heterocyclic Carbene Complexes as Ferroptosis Inducing Anticancer Agents

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(5), P. 856 - 864

Published: April 24, 2025

This study presents the chemical synthesis and biological evaluation of a series gold(I)-N-heterocyclic carbene complexes as potential anticancer agents. The compounds demonstrated broad activity against various cancer cell lines, exhibiting cytotoxicity in low micromolar range. Mechanistic investigations revealed that these preferentially accumulate mitochondria cells, where they induce generation reactive oxygen species lipid peroxides, ultimately triggering ferroptosis. Further studies multicellular tumor spheroids confirmed compounds' ability to penetrate three-dimensional cellular structures effectively eradicate them at concentrations. work represents first known example complex inducing ferroptosis, expanding therapeutic gold(I)-based metallodrugs.

Language: Английский

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Induction of Cuproptosis with a Highly Cytotoxic Tripodal Cu(II) Complex for Anticancer Therapy

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

Published: June 3, 2025

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies primarily focused incorporation Cu into nanostructures, this work presents first example a molecular tripodal Cu(II) complex potent inducer. Herein, series complexes were chemically synthesized biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in low micromolar nanomolar range. Mechanistic revealed that catalytically produced hydroxyl radicals mitochondria cancerous cells, causing protein oligomerization disruption iron-sulfur cluster proteins, ultimately triggering by cuproptosis. Contrary traditional agents cause reduction tumor size, induced fragmentation three-dimensional spheroids.

Language: Английский

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Shift of cell-death mechanisms in primary human neutrophils with a ruthenium photosensitizer

JBIC Journal of Biological Inorganic Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 14, 2024

Abstract Primary human neutrophils are the most abundant white blood cells and central for innate immunity. They act as early responders at inflammation sites, guided by chemotactic gradients to find infection or sites. Neutrophils can undergo both apoptosis well NETosis. NETosis is a form of neutrophil cell death that releases chromatin-based extracellular traps (NETs) capture neutralize pathogens. Understanding controlling balance between these cell-death mechanisms crucial. In this study, chemical synthesis biologic assessment ruthenium complex light-activated photosensitizer creates reactive oxygen species (ROS) in primary reported. The remains non-toxic dark. However, upon exposure blue light 450 nm, it exhibits potent cytotoxic effects cancerous non-cancerous lines. Interestingly, metal shifts mechanism from apoptosis. Cells irradiated directly source immediately apoptosis, whereas those further away perform slower rate. This indicates high ROS levels trigger lower ability control type undergone could have implications managing acute chronic infectious diseases. Graphical abstract

Language: Английский

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Combinatorial Synthesis toward the Discovery of Highly Cytotoxic Fe(III) Complexes

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Cancer remains one of the deadliest diseases worldwide, with some tumors proving difficult to treat and increasingly resistant current therapies. Capitalizing on this, there is a need for new therapeutic agents novel mechanisms action. Among promising candidates, Fe(III) complexes have gained significant attention as potential chemotherapeutic agents. However, research these compounds has been limited small number, leading inefficiencies in drug discovery. This study addresses limitations by developing combinatorial library 495 synthesized from aminophenol, hydroxybenzaldehyde, pyridine derivatives. The were screened cytotoxicity against human breast adenocarcinoma noncancerous fibroblasts, identifying class modest cancer cell selectivity. lead compound effectively eradicated tumor spheroids at low micromolar concentrations, highlighting this approach rapid

Language: Английский

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Necrosis Inducing Tetranuclear Ru(II) - Re(I) Metal Complex for Anticancer Therapy

Dalton Transactions, Journal Year: 2024, Volume and Issue: 54(3), P. 942 - 950

Published: Dec. 18, 2024

This study reports on the chemical synthesis and biological evaluation of a tetranuclear Ru( ii )–Re( i ) complex as chemotherapeutic agent.

Language: Английский

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