Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7360 - 7376

Published: Feb. 15, 2025

Hypoxia, a hallmark of many solid tumors, is linked to increased cancer aggressiveness, metastasis, and resistance conventional therapies, leading poor patient outcomes. This challenges the efficiency photodynamic therapy (PDT), which relies on generation cytotoxic reactive oxygen species (ROS) through irradiation photosensitizer (PS), process partially dependent levels. In this work, we introduce novel family potent PSs based ruthenium(II) polypyridyl complexes with 2,2′-bipyridyl ligands derived from COUPY coumarins, termed COUBPYs. Ru-COUBPY exhibit outstanding in vitro cytotoxicity against CT-26 cells when irradiated light within phototherapeutic window, achieving nanomolar potency both normoxic hypoxic conditions while remaining nontoxic dark, impressive phototoxic indices (>30,000). Their ability generate Type I II ROS underpins their exceptional PDT efficiency. The lead compound study, SCV49, shows favorable vivo pharmacokinetic profile, excellent toxicological tolerability, tumor growth inhibition mice bearing subcutaneous tumors at doses as low 3 mg/kg upon deep-red (660 nm). These results allow us propose SCV49 strong candidate for further preclinical development, particularly treating large tumors.

Language: Английский

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A Nanoencapsulated Ir(III)-Phthalocyanine Conjugate as a Promising Photodynamic Therapy Anticancer Agent

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(30), P. 38916 - 38930

Published: July 23, 2024

Despite the potential of photodynamic therapy (PDT) in cancer treatment, development efficient and photostable photosensitizing molecules that operate at long wavelengths light has become a major hurdle. Here, we report for first time an Ir(III)-phthalocyanine conjugate (

Language: Английский

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Dinuclear Tridentate Ru(II) Complex with Strong Near-Infrared Light-Triggered Anticancer Activity

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(13), P. 11125 - 11137

Published: June 21, 2024

The design of the dinuclear Ru(II) complex (Ru2) with strong near-infrared (NIR) absorption properties has been reported for efficient anticancer phototherapy. Under 700 nm LED light excitation, Ru2 exhibited remarkable synergistic type I/II photosensitization ability and photocatalytic activity toward intracellular biomolecules. showed impressive light-triggered under normoxia hypoxia compared clinically used photosensitizer Chlorin e6. mechanistic studies that induced redox imbalance perturbed energy metabolism biosynthesis in A549 cancer cells. Overall, this work provides a new strategy developing metal-based complexes phototherapy NIR light.

Language: Английский

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Red and NIR light-triggered enhancement of anticancer and antibacterial activities of dinuclear Co(ii)-catecholate complexes

Dalton Transactions, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Photoactive complexes of bioessential 3d metals, activable within the phototherapeutic window (650-900 nm), have gained widespread interest due to their therapeutic potential. Herein, we report synthesis, characterization, and light-enhanced anticancer antibacterial properties four new dinuclear Co(II) complexes: [Co(phen)(cat)]2 (Co-1), [Co(dppz)(cat)]2 (Co-2), [Co(phen)(esc)]2 (Co-3), [Co(dppz)(esc)]2 (Co-4). In these complexes, phen (1,10-phenanthroline) dppz (dipyrido[3,2-a:2',3'-c]phenazine) act as neutral N,N-donor ligands, while cat2- esc2- serve O,O-donor catecholate ligands derived from catechol (1,2-dihydroxybenzene) esculetin (6,7-dihydroxy coumarin). Their high-spin paramagnetic nature dimeric identity in solution were confirmed by magnetic susceptibility, UV-visible, emission, mass spectral data. Co-1-Co-4 exhibited an absorption band 600-850 nm range, originating a charge transfer transition. The electrically demonstrated sufficient stability both dark under irradiated conditions. Co-2 Co-4 notable toxicity towards A549 lung carcinoma cells, with potency increasing significantly brief (5 min) exposure 660 (red) 808 (NIR) laser light (IC50 ∼ 8.9 14.9 μM). Notably, normal NIH-3T3 fibroblast cells was minimal. Cellular assays highlighted that induced cell death followed apoptotic pathway, primarily mitochondrial damage. also significant against Gram-(+) S. aureus Gram-(-) P. aeruginosa, effectiveness enhanced upon irradiation (MIC 15-142 increase efficacies attributed generation cytotoxic singlet oxygen (1O2) species red/NIR exposure. NIR produced more pronounced effects compared nm. This study is first on cobalt exhibiting red light-triggered enhancement activities, illuminating path for development long-wavelength absorbing efficacy.

Language: Английский

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In Vitro and In Vivo Anticancer Activities of Water-Soluble Ru(II)(η6-p-cymene) Complexes via Activating Apoptosis Central Regulators and Possibilities of New Antitumor Strategies in Triple Negative Breast Cancers

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

Published: Jan. 29, 2025

In this study, we synthesized 12 monofunctional tridentate ONS-donor salicylaldimine ligand (L)-based Ru(II) complexes with general formula [(Ru(L)(p-cymene)]+·Cl– (C1-C12), characterized by 1H NMR, 13C UV, FT-IR spectroscopy, HR-ESI mass spectrometry, and single-crystal X-ray analysis showing ligand's orientation around the center. All of these were tested for their anticancer activities in multiple cancer cells. The superior antitumor efficacy C2, C8, C11 was demonstrated reduced mitochondrial membrane potential, impaired proliferative capacity, disrupted redox homeostasis, along enhanced apoptosis through caspase-3 activation downregulation Bcl-2 expression. 4T1 breast orthotopic mouse model, assessment bioluminescence metastatic spread, tumor burden, histopathological evaluation, immunohistochemistry (IHC), hematological profiling tissue Protein expression caspase-3, cleaved TNF-α, bcl-2 that C8 treatment led to prolonged survival suppressed progression triple negative cancer.

Language: Английский

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Novel 2-(5-Arylthiophen-2-yl)-benzoazole Cyclometalated Iridium(III) dppz Complexes Exhibit Selective Phototoxicity in Cancer Cells by Lysosomal Damage and Oncosis

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 67(1), P. 691 - 708

Published: Dec. 23, 2023

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1–Ir4, were rationally designed synthesized, where the aryl group attached to thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new assessed as photosensitizers explore structure–activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, exhibited high selective potency across several cancer cell lines predisposed therapy; benzothiazole derivatives (Ir1 Ir2) best performers, Ir2 being also activatable green red light. Notably, when irradiated, induced leakage lysosomal content into cytoplasm HeLa cells oncosis-like death. The capability Ir photoinduce death 3D spheroids has been demonstrated. investigated can catalytically photo-oxidate NADH photogenerate 1O2 and/or •OH cell-free media.

Language: Английский

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Novel Re(I) Complexes as Potential Selective Theranostic Agents in Cancer Cells and In Vivo in Caenorhabditis elegans Tumoral Strains

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7891 - 7910

Published: March 7, 2024

A series of rhenium(I) complexes the type fac-[Re(CO)3(N^N)L]0/+, Re1–Re9, was synthesized, where N^N = benzimidazole-derived bidentate ligand with an ester functionality and L chloride or pyridine-type ligand. The new compounds demonstrated potent activity toward ovarian A2780 cancer cells. most active complexes, Re7–Re9, incorporating 4-NMe2py, exhibited remarkable in 3D HeLa spheroids. emission red region Re9, which contains electron-deficient benzothiazole moiety, allowed its operability as a bioimaging tool for vitro vivo visualization. Re9 effectivity tested two different C. elegans tumoral strains, JK1466 MT2124, to broaden oncogenic pathways studied. results showed that able reduce tumor growth both strains by increasing ROS production inside Moreover, selectivity compound cancerous cells it did not affect neither development nor progeny nematodes.

Language: Английский

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A hetero-bimetallic Ru(ii)–Ir(iii) photosensitizer for effective cancer photodynamic therapy under hypoxia

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(20), P. 2776 - 2779

Published: Jan. 1, 2024

A hetero-bimetallic Ru( ii )–Ir( iii ) complex Ru-Ir was developed to act as a type-I and type-II dual photosensitizer for effective cancer photodynamic therapy under hypoxia.

Language: Английский

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Leveraging the Photofunctions of Transition Metal Complexes for the Design of Innovative Phototherapeutics

Small Methods, Journal Year: 2024, Volume and Issue: 8(11)

Published: Sept. 25, 2024

Abstract Despite the advent of various medical interventions for cancer treatment, disease continues to pose a formidable global health challenge, necessitating development new therapeutic approaches more effective treatment outcomes. Photodynamic therapy (PDT), which utilizes light activate photosensitizer produce cytotoxic reactive oxygen species (ROS) eradicating cells, has emerged as promising approach due its high spatiotemporal precision and minimal invasiveness. However, widespread clinical use PDT faces several challenges, including inefficient production ROS in hypoxic tumor microenvironment, limited penetration depth biological tissues, inadequate accumulation photosensitizers at site. Over past decade, there been increasing interest utilization photofunctional transition metal complexes applications their intriguing photophysical photochemical properties. This review provides an overview current design strategies used innovative phototherapeutics, aiming address limitations associated with achieve The challenges future perspectives on translation are also discussed.

Language: Английский

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Ru(II)‐Cyanine Complexes as Promising Photodynamic Photosensitizers for the Treatment of Hypoxic Tumours with Highly Penetrating 770 nm Near‐Infrared Light

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(61)

Published: Aug. 7, 2023

Light-activated treatments, such as photodynamic therapy (PDT), provide temporal and spatial control over a specific cytotoxic response by exploiting toxicity differences between irradiated dark conditions. In this work, novel strategy for developing near infrared (NIR)-activatable Ru(II) polypyridyl-based photosensitizers (PSs) was successfully developed through the incorporation of symmetric heptamethine cyanine dyes in metal complex via phenanthrimidazole ligand. Owing to their strong absorption NIR region, PSs could be efficiently photoactivated with highly penetrating light (770 nm), leading high photocytotoxicities towards several cancer cell lines under both normoxic hypoxic Notably, our lead PS (Ru-Cyn-1), which accumulated mitochondria, exhibited good photocytotoxic activity challenging low-oxygen concentration (2 % O2 ) upon irradiation conditions owing combination type I II PDT mechanisms. The fact that Protoporphyrin IX (PpIX), metabolite clinically approved 5-ALA PS, found inactive same positions Ru-Cyn-1 promising agent treatment deep-seated tumours.

Language: Английский

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